TW202019424A - Methods of treating ocular conditions - Google Patents
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Abstract
Description
本文提供之本發明係關於用菸鹼乙醯膽鹼受體(nAChR)促效劑對個體治療乾眼病、增加淚液產生或減少眼部不適之方法。The present invention provided herein relates to a method for treating dry eye disease, increasing tear production, or reducing eye discomfort in individuals with nicotinic acetylcholine receptor (nAChR) agonists.
估計1600萬美國成年人已診斷患有乾眼病,一種藉由淚膜破壞表徵之多因素、年齡相關之眼表面病況。健康淚膜保護及潤滑眼睛且沖走外來粒子,含有降低感染風險之抗微生物劑,且產生有助於折射力以使視力清晰的光滑表面。An estimated 16 million American adults have been diagnosed with dry eye disease, a multifactorial, age-related ocular surface condition characterized by tear film destruction. Healthy tear film protects and lubricates the eyes and flushes away foreign particles, contains antimicrobial agents that reduce the risk of infection, and produces a smooth surface that helps refraction to make vision clear.
乾眼病可對個體之日常生活品質具有顯著影響,因為其可導致持續性刺痛、刮擦、燒灼感、光敏感、視力模糊及眼疲勞。乾眼病亦可導致嚴重疼痛、視覺障礙、淚膜高滲透壓及不穩定性、發炎及角膜受傷。乾眼病可由淚膜穩態喪失表徵。儘管乾眼流行率由於不同定義及診斷標準而難以報導,但據估計,全球5%至35%超過50歲之群體罹患此病況(2007)。在美國(US),據估計,多達320萬女性及170萬男性(超過50歲)患有乾眼,預計截至2030年受影響患者之數目增加40%。Dry eye disease can have a significant impact on an individual's quality of daily life because it can cause persistent tingling, scratching, burning sensation, light sensitivity, blurred vision, and eye fatigue. Dry eye disease can also cause severe pain, visual impairment, high osmotic pressure and instability of the tear film, inflammation and corneal injury. Dry eye disease can be characterized by a loss of tear film homeostasis. Although the prevalence of dry eye is difficult to report due to different definitions and diagnostic criteria, it is estimated that 5% to 35% of the global population over 50 years of age suffer from this condition (2007). In the United States (US), it is estimated that as many as 3.2 million women and 1.7 million men (over 50 years old) have dry eyes, and the number of affected patients is expected to increase by 40% by 2030.
乾眼病之醫藥治療選擇包括:人工淚液替代物、軟膏、凝膠、熱敷、環境改變、局部環孢靈(Restasis® )、立他司特(lifitegrast) (Xiidra® )及ω-3脂肪酸補充劑。此等選擇中無一者對於大多數群體提供實質性功效且由於副作用,亦即刺痛/燒灼及滴注後味覺不良(味覺障礙)而全部具有不佳患者順應性。Medical treatment options for dry eye include: artificial tear replacements, ointments, gels, hot compresses, environmental changes, topical cyclosporine (Restasis ® ), lifitegrast (Xiidra ® ) and omega-3 fatty acid supplements . None of these options provide substantial efficacy for most groups and all have poor patient compliance due to side effects, i.e. stinging/burning and poor taste after instillation (dysgeusia).
可用於乾眼病治療之多種醫療裝置選擇包括:淚點塞、濕氣室護目鏡及向量熱眼瞼脈動(Lipiflow® )。最近,TrueTearTM (一種鼻內神經刺激器)已批准用於治療乾眼病。該裝置經設計以經由刺激鼻淚反射路徑之受控電流增加淚液產生。A variety of medical device options that can be used for the treatment of dry eye include: punctal plugs, wet air goggles, and vector hot eyelid pulsation (Lipiflow ® ). Recently, TrueTear ™ (an intranasal nerve stimulator) has been approved for the treatment of dry eye disease. The device is designed to increase tear production via a controlled current that stimulates the nasolacrimal reflex path.
不管乾眼流行率及疾病負擔,仍存在顯著未滿足的對有效療法之需求。另外,需要增加淚液產生及減少眼部不適之有效療法。Regardless of the prevalence of dry eye and disease burden, there is still a significant unmet need for effective treatment. In addition, there is a need for effective treatments that increase tear production and reduce eye discomfort.
本發明係關於影響副交感神經系統之菸鹼乙醯膽鹼受體(nAChR)促效劑。三叉神經為產生眼睛之天然淚膜的腺體及細胞提供副交感控制。在一個態樣中,本發明提供對個體治療乾眼病、增加淚液產生或減少眼部不適之方法,其藉由刺激三叉副交感路徑以促進天然淚膜產生。本發明描述包含經由鼻腔向三叉神經遞送nAChR促效劑,及對個體有效地治療乾眼病、增加淚液產生或減少眼部不適之方法。本文所描述之方法中之nAChR促效劑為具有以下結構之化合物1:,
或其醫藥學上可接受之鹽。The present invention relates to nicotinic acetylcholine receptor (nAChR) agonists that affect the parasympathetic nervous system. The trigeminal nerve provides parasympathetic control for the glands and cells that produce the natural tear film of the eye. In one aspect, the present invention provides a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual, which promotes natural tear film production by stimulating the trigeminal parasympathetic pathway. The description of the present invention includes the delivery of nAChR agonists to the trigeminal nerve through the nasal cavity, and methods for effectively treating dry eye disease, increasing tear production, or reducing eye discomfort for individuals. The nAChR agonist in the method described herein is
本文提供一種對個體治療乾眼病、增加淚液產生或減少眼部不適之方法,其包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量;其中該方法造成有效治療該有需要之個體。Provided herein is a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual, which comprises administering an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need And one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need.
本發明提供一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法,其包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides an immediate and immediate use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors or combinations thereof in individuals in need A method of long-term pharmacological stimulation, which comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and optionally selecting one or more subsequent doses.
本發明提供一種用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides a compound for a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of an individual, and one or more subsequent doses are selected as appropriate.
本發明提供一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、菸鹼乙醯膽鹼α3β4受體、菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides an immediate and long-term pharmacology for nicotinic acetylcholine α4β2 receptor, nicotinic acetylcholine α3β4 receptor, nicotinic acetylcholine α3α5β4 receptor or a combination thereof in an individual in need Compound of the method of chemical stimulation, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of
本發明提供菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中該藥物用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,其中菸鹼乙醯膽鹼受體促效劑為化合物1或其醫藥學上可接受之鹽。The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production, or reduce eye discomfort for an individual in need. The choline receptor agonist is Compound 1 or a pharmaceutically acceptable salt thereof.
本發明提供菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中藥物用於對菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激,其中菸鹼乙醯膽鹼受體促效劑為化合物1或其醫藥學上可接受之鹽,且方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of medicines, wherein the medicine is used for the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or The nicotinic acetylcholine α3α5β4 receptor or a combination thereof undergoes immediate and long-term pharmacological stimulation, wherein the nicotinic acetylcholine receptor agonist is Compound 1 or a pharmaceutically acceptable salt thereof, and the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of the individual in need, and one or more subsequent doses are selected as appropriate.
本發明提供一種醫藥調配物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,該調配物包含化合物1或其醫藥學上可接受之鹽。The present invention provides a pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need. The formulation includes Compound 1 or a pharmaceutically acceptable salt thereof.
本發明提供一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法中,該調配物包含化合物1或其醫藥學上可接受之鹽。The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need or In a method for immediate and long-term pharmacological stimulation of the combination, the formulation contains Compound 1 or a pharmaceutically acceptable salt thereof.
本發明提供一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法中,該調配物包含化合物1或其醫藥學上可接受之鹽。The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need, Or a method for immediate and long-term pharmacological stimulation of the nicotinic acetylcholine α4α6β2 receptor or a combination thereof, the formulation contains Compound 1 or a pharmaceutically acceptable salt thereof.
相關申請案之交叉參考Cross-reference of related applications
本申請案主張2018年7月10日申請之美國臨時申請案第62/696,310號;2018年11月30日申請之第62/773,996號;及2019年3月6日申請之第62/814,762號之權益,其內容以全文引用之方式併入本文中。This application claims U.S. Provisional Application No. 62/696,310 filed on July 10, 2018; No. 62/773,996 filed on November 30, 2018; and No. 62/814,762 filed on March 6, 2019 The contents of the rights and interests are incorporated into this article by citation.
本發明提供改善或重建淚膜穩態之方法。在一些實施例中,有需要之個體不具有淚膜穩態。The present invention provides a method to improve or reconstruct the tear film homeostasis. In some embodiments, individuals in need do not have tear film homeostasis.
本文提供一種對個體治療乾眼病、增加淚液產生或減少眼部不適之方法。在本文所述之一些實施例中,眼部不適與隱形眼鏡不耐相關。在本文所述之一些實施例中,有需要之個體佩戴隱形眼鏡具有不適。在本文所述之一些實施例中,方法包含改善淚膜穩態。在本文所述之一些實施例中,方法包含重建淚膜穩態。在本文所述之一些實施例中,有需要之個體不具有淚膜穩態或淚膜穩態受損。This article provides a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual. In some embodiments described herein, eye discomfort is associated with contact lens intolerance. In some embodiments described herein, individuals in need have discomfort when wearing contact lenses. In some embodiments described herein, the method includes improving tear film homeostasis. In some embodiments described herein, the method includes reconstructing tear film homeostasis. In some embodiments described herein, the individual in need does not have tear film homeostasis or tear film homeostasis is impaired.
在本文所述之一些實施例中,治療有需要之個體之乾眼病的方法包含向有需要之個體之鼻腔中投與有效量的具有以下結構之化合物1,
或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量;其中該方法造成有效治療該有需要之個體。在本文所述之一些實施例中,增加有需要之個體之淚液產生之方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量;其中該方法造成有效治療該有需要之個體。在本文所述之一些實施例中,減少有需要之個體之眼部不適之方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量;其中該方法造成有效治療該有需要之個體。In some embodiments described herein, a method of treating dry eye disease in an individual in need comprises administering an effective amount of
化合物1之專利相關資訊可見於美國專利7,098,331、美國專利7,714,001、美國專利8,063,068、美國專利8,067,443、美國專利8,604,191、美國專利9,145,396、美國專利9,981,949、美國專利8,633,222及PCT公開案WO 2017/177024中。
如本文所述之化合物1係指如下結構:。
化合物1之替代結構表示為:。化合物1亦可藉由其化學名稱提及。舉例而言,化合物1可稱為(R)-5-((E)-2-吡咯啶-3-基乙烯基)嘧啶,或其變化形式,包括5-{(E)-2-[(3R)-吡咯啶-3-基]乙烯基}嘧啶及(R,E)-5-((2-吡咯啶-3-基)乙烯基)嘧啶。The alternative structure of
本發明提供一種用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。在本文所述之一些實施例中,本發明提供一種用於治療有需要之個體之乾眼病之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。在本文所述之一些實施例中,本發明提供一種用於增加有需要之個體之淚液產生之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。在本文所述之一些實施例中,本發明提供一種用於減少有需要之個體之眼部不適之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。在本文所述之一些實施例中,該方法造成有效治療該有需要之個體。The present invention provides a compound for a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of an individual, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the present invention provides a compound for a method for treating dry eye disease in an individual in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of the individual in need, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the present invention provides a compound for a method for increasing tear production in an individual in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of the individual in need, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the present invention provides a compound for a method for reducing eye discomfort in an individual in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of an individual in need, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the method results in effective treatment of the individual in need.
乾眼病之嚴重度可經由包括以下之一系列基礎測試評估:根據視覺類比量表之乾眼評分測試、斯戈默測試(Schirmer's test)、角膜螢光素染色測試及眼表面疾病指數測試。此等測試亦可用於評估個體之流淚量或眼部不適。亦涵蓋此項技術中熟知之測試,諸如淚膜破裂時間測試。The severity of dry eye disease can be evaluated by one of the following series of basic tests: dry eye score test according to visual analog scale, Schirmer's test, corneal fluorescein stain test, and eye surface disease index test. These tests can also be used to assess an individual's tearfulness or eye discomfort. Tests well known in the art are also covered, such as tear film rupture time test.
在本文所述之一些實施例中,個體之有效治療係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之乾眼評分測試,b)斯戈默測試,c)角膜螢光素染色測試,及d)眼表面疾病指數測試。在本文所述之一些實施例中,個體之有效治療係由至少根據視覺類比量表之乾眼評分測試及斯戈默測試指示。在本文所述之一些實施例中,個體之有效治療係由至少根據視覺類比量表之乾眼評分測試、斯戈默測試及眼表面疾病指數測試指示。在本文所述之一些實施例中,個體之有效治療係由至少根據視覺類比量表之乾眼評分測試、斯戈默測試、眼表面疾病指數測試及角膜螢光素染色測試指示。在本文所述之一些實施例中,角膜螢光素染色測試係根據國家眼科研究所(National Eye Institute,NEI)分級系統。In some embodiments described herein, the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) dry eye scoring test according to the visual analog scale, b) Sgormer test, c ) Corneal luciferin staining test, and d) Eye surface disease index test. In some embodiments described herein, the effective treatment of the individual is indicated by a dry eye score test and a Sgormer test based at least on the visual analog scale. In some embodiments described herein, the effective treatment of the individual is indicated by at least a dry eye score test, a Sgormer test, and an ocular surface disease index test according to a visual analog scale. In some embodiments described herein, effective treatment of an individual is indicated by at least a dry eye score test according to a visual analogue scale, a Sgormer test, an ocular surface disease index test, and a corneal fluorescein stain test. In some embodiments described herein, the corneal fluorescein staining test is based on the National Eye Institute (NEI) grading system.
菸鹼乙醯膽鹼受體可在整個本發明中可互換地稱為nAChR。nAChR為一類五聚配位體閘控之離子通道,其對於菸鹼及乙醯膽鹼兩者具有高親和力及選擇性且包含α及β次單位之組合。特定nAChR亞型可包括α4β2菸鹼受體、α3β4菸鹼受體、α3α5β4菸鹼受體及α4α6β2菸鹼受體。The nicotinic acetylcholine receptor may be interchangeably referred to as nAChR throughout the present invention. nAChR is a type of pentameric ligand-gated ion channel that has high affinity and selectivity for both nicotine and acetylcholine and includes a combination of alpha and beta subunits. Specific nAChR subtypes may include α4β2 nicotinic receptors, α3β4 nicotinic receptors, α3α5β4 nicotinic receptors, and α4α6β2 nicotinic receptors.
本文中提及之「α7」係指同聚α7亞型,其中nAChR之五聚次單位完全由α7次單位構成。因此,結合及活化nAChR α7之nAChR促效劑為結合及活化nAChR同聚α7受體之促效劑。在本文所述之一些實施例中,nAChR促效劑不為α7受體促效劑。在本文所述之一些實施例中,nAChR促效劑不為完全α7受體促效劑。The "α7" mentioned in this article refers to the homopolymeric α7 subtype, in which the pentameric subunit of nAChR is composed entirely of α7 subunits. Therefore, nAChR agonists that bind and activate nAChR α7 are agonists that bind and activate nAChR homopolymeric α7 receptors. In some embodiments described herein, the nAChR agonist is not an α7 receptor agonist. In some embodiments described herein, the nAChR agonist is not a full α7 receptor agonist.
nAChR促效劑結合至nAChR,活化受體以產生相關生物反應,例如流淚增加或減少眼部不適或治療乾眼病之其他生物反應。The nAChR agonist binds to nAChR and activates the receptor to produce related biological responses, such as increased or reduced tearing of eye discomfort or other biological responses to treat dry eye disease.
nAChR促效劑可表徵為完全或部分促效劑,如藉由相較於在給定受體處針對乙醯膽鹼(ACh)之反應,其活化該受體以產生反應之能力所確定。一般而言,若nAChR促效劑在結合至給定受體後誘發等於或大於ACh之反應的反應,則其為完全促效劑。若nAChR促效劑在結合至受體後誘發相較於由ACh產生之反應較低的反應,則其為部分促效劑。An nAChR agonist may be characterized as a full or partial agonist, as determined by its ability to activate the receptor to produce a response compared to the response to acetylcholine (ACh) at a given receptor. In general, an nAChR agonist is a full agonist if it induces a response equal to or greater than that of ACh after binding to a given receptor. An nAChR agonist is a partial agonist if it induces a lower response than the response produced by ACh after binding to the receptor.
可例如使用適當基於細胞的分析來產生可測定受體活化之nAChR促效劑反應。經設計以在結合至nAChR促效劑且藉由nAChR促效劑活化時表現特定nAChR受體亞型及產生電流反應之細胞可用於表徵化合物之促效劑概況及因此測定之受體活化的量。一般方案之實例描述於下文。Appropriate cell-based assays can be used, for example, to generate nAChR agonist responses that can measure receptor activation. Cells designed to exhibit specific nAChR receptor subtypes and generate electrical responses when bound to nAChR agonists and activated by nAChR agonists can be used to characterize compound agonist profiles and the amount of receptor activation thus determined . Examples of general schemes are described below.
表現特定人類nAChR亞型之細胞首先暴露於ACh。ACh結合及活化受體,由此誘發電流。選擇ACh之濃度以引發受體之最大反應(例如1280微莫耳ACh)。此電流記錄為ACh反應且充當100% nAChR促效劑反應且與針對其他nAChR促效劑之反應進行比較。在洗滌之後,細胞暴露於各種濃度(例如0.1、0.3、1、3、10、30、100及300微莫耳)之nAChR促效劑。針對各nAChR濃度量測及記錄藉由暴露於nAChR促效劑誘發之電流。此nAChR促效劑反應資料接著相對於最大ACh誘發電流標準化為單位且作為nAChR促效劑濃度之對數的函數標繪。nAChR促效劑反應接著計算為ACh反應之百分比。Cells expressing specific human nAChR subtypes are first exposed to ACh. ACh binds and activates receptors, thereby inducing electrical current. The concentration of ACh is chosen to elicit the maximum response of the receptor (eg 1280 micromolar ACh). This current is recorded as an ACh reaction and acts as a 100% nAChR agonist response and is compared to reactions against other nAChR agonists. After washing, cells are exposed to nAChR agonists at various concentrations (eg, 0.1, 0.3, 1, 3, 10, 30, 100, and 300 micromolar). The current induced by nAChR agonist exposure was measured and recorded for each nAChR concentration. This nAChR agonist response data is then normalized to units of maximum ACh evoked current and plotted as a function of logarithm of nAChR agonist concentration. The nAChR agonist response is then calculated as the percentage of ACh response.
在一些情況下,測定nAChR促效劑之相對促效活性之方法包含其中ACh反應誘發自1或大於1毫莫耳ACh溶液之條件。In some cases, the method of determining the relative agonistic activity of an nAChR agonist includes conditions in which the ACh response is induced from 1 or more millimolar ACh solutions.
誘發等於或大於在相同受體類型處測定之最大ACh反應的nAChR促效劑為完全促效劑。在一些情況下,考慮實驗變化性,誘發小於100% ACh反應之反應的nAChR促效劑可仍表徵為完全促效劑。舉例而言,測試或測量方法之間的變化性及統計誤差可解釋反應結果的差異。在一些情況下,將誘發80%至120%之ACh反應的nAChR促效劑視為完全促效劑。在一些情況下,將誘發99%或更大ACh反應的nAChR促效劑視為完全促效劑。在一些情況下,將誘發95%或更大ACh反應的nAChR促效劑視為完全促效劑。在一些情況下,將誘發90%或更大ACh反應的nAChR促效劑視為完全促效劑。在一些情況下,將誘發85%或更大ACh反應的nAChR促效劑視為完全促效劑。在一些情況下,將誘發80%或更大ACh反應的nAChR促效劑視為完全促效劑。An nAChR agonist that induces a response equal to or greater than the maximum ACh response measured at the same receptor type is a full agonist. In some cases, considering experimental variability, nAChR agonists that elicit responses that are less than 100% ACh responses may still be characterized as full agonists. For example, the variability and statistical errors between test or measurement methods may explain the difference in response results. In some cases, nAChR agonists that induce 80% to 120% of the ACh response are considered to be full agonists. In some cases, nAChR agonists that induce 99% or greater ACh responses are considered to be full agonists. In some cases, nAChR agonists that induce 95% or greater ACh responses are considered full agonists. In some cases, nAChR agonists that induce 90% or more of the ACh response are considered full agonists. In some cases, nAChR agonists that induce an ACh response of 85% or more are considered to be full agonists. In some cases, nAChR agonists that induce an ACh response of 80% or more are considered to be full agonists.
考慮實驗變化性,若nAChR促效劑誘發小於100%之ACh反應,則一般將促效劑視為部分促效劑。在一些情況下,將誘發小於95%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發小於90%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發小於85%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發小於80%之ACh反應的nAChR促效劑視為部分促效劑。Considering the experimental variability, if the nAChR agonist induces an ACh response of less than 100%, the agonist is generally regarded as a partial agonist. In some cases, nAChR agonists that induce less than 95% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce less than 90% of the ACh response are considered partial agonists. In some cases, nAChR agonists that induce an ACh response of less than 85% are considered partial agonists. In some cases, nAChR agonists that induce less than 80% of the ACh response are considered partial agonists.
在一些情況下,將誘發5%至95%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發5%至90%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發5%至85%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發5%至80%之ACh反應的nAChR促效劑視為部分促效劑。In some cases, nAChR agonists that induce 5% to 95% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 5% to 90% of the ACh response are considered partial agonists. In some cases, nAChR agonists that induce 5% to 85% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 5% to 80% of the ACh response are considered partial agonists.
在一些情況下,將誘發10%至95%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發10%至90%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發10%至85%之ACh反應的nAChR促效劑視為部分促效劑。在一些情況下,將誘發10%至80%之ACh反應的nAChR促效劑視為部分促效劑。In some cases, nAChR agonists that induce 10% to 95% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 10% to 90% of the ACh response are considered partial agonists. In some cases, nAChR agonists that induce 10% to 85% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 10% to 80% of ACh responses are considered partial agonists.
在相對高促效劑濃度下產生低電活性水準之nAChR促效劑可描述為弱部分促效劑。在一些情況下,將誘發30%或更小ACh反應的nAChR促效劑視為弱部分促效劑。在一些情況下,將誘發小於25%或更小ACh反應的nAChR促效劑視為弱部分促效劑。在一些情況下,將誘發20%或更小ACh反應的nAChR促效劑視為弱部分促效劑。在一些情況下,相對高nAChR促效劑濃度為至少100微莫耳。在一些情況下,相對高nAChR促效劑濃度為至少200微莫耳。在一些情況下,相對高nAChR促效劑濃度為至少300微莫耳或更大。舉例而言,將誘發25%最大Ach誘發電流之300微莫耳濃度之nAChR促效劑視為弱部分促效劑。NAChR agonists that produce low levels of electrical activity at relatively high agonist concentrations can be described as weak partial agonists. In some cases, nAChR agonists that induce ACh responses of 30% or less are considered weak partial agonists. In some cases, nAChR agonists that induce an ACh response of less than 25% or less are considered weak partial agonists. In some cases, nAChR agonists that induce ACh responses of 20% or less are considered weak partial agonists. In some cases, the relatively high nAChR agonist concentration is at least 100 micromolar. In some cases, the relatively high nAChR agonist concentration is at least 200 micromolar. In some cases, the relatively high nAChR agonist concentration is at least 300 micromolar or greater. For example, an nAChR agonist with a concentration of 300 micromolar that induces a 25% maximum Ach evoked current is considered a weak partial agonist.
在一些實施例中,nAChR促效劑為完全促效劑。在一些實施例中,nAChR促效劑為部分促效劑。在一些實施例中,nAChR促效劑為弱部分促效劑。In some embodiments, the nAChR agonist is a full agonist. In some embodiments, the nAChR agonist is a partial agonist. In some embodiments, the nAChR agonist is a weak partial agonist.
化合物1為nAChR亞型α4β2、α3β4、α3α5β4及α4α6β2之完全促效劑。
化合物1為亞型α3β2之部分促效劑。
化合物1為亞型α7之弱部分促效劑。在一個實例中,300微莫耳濃度之化合物1檸檬酸鹽僅誘發最大ACh誘發電流之25%。
在本文所述之一些實施例中,nAChR促效劑或其醫藥學上可接受之鹽可為化合物1或其醫藥學上可接受之鹽。In some embodiments described herein, the nAChR agonist or a pharmaceutically acceptable salt thereof may be Compound 1 or a pharmaceutically acceptable salt thereof.
本發明提供一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法。本發明提供一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法。在本文所述之一些實施例中,該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides a method for nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine in individuals in need A method for immediate and long-term pharmacological stimulation of choline α4α6β2 receptor or a combination thereof. The present invention provides an immediate and immediate use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors or combinations thereof in individuals in need Method of long-term pharmacological stimulation. In some embodiments described herein, the method comprises administering to the nasal cavity of an individual in need an effective amount of a first dose of
本發明提供一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法的化合物,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides an immediate and immediate use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors or combinations thereof in individuals in need A compound of a method of long-term pharmacological stimulation, wherein the compound is
本發明提供一種化合物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法中,其中化合物為化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。The present invention provides a compound for the use of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco Alkaline acetylcholine α4α6β2 receptor or a combination thereof for immediate and long-term pharmacological stimulation, wherein the compound is
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之乾眼評分測試,b)斯戈默測試,c)角膜螢光素染色測試,及d)眼表面疾病指數測試。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由根據視覺類比量表之乾眼評分測試指示。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由斯戈默測試指示。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由角膜螢光素染色測試指示。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由眼表面疾病指數測試指示。In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The stimulation is indicated by one or more tests selected from the group consisting of: a) dry eye scoring test according to the visual analog scale, b) Sgormer test, c) corneal luciferin staining test, and d) eye surface Disease index test. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Stimulation is indicated by the dry eye score test according to the visual analog scale. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The stimulus is indicated by the Gomer test. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The stimulation is indicated by the corneal luciferin staining test. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The irritation is indicated by the eye surface disease index test.
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之乾眼評分測試,b)斯戈默測試,c)角膜螢光素染色測試,及d)眼表面疾病指數測試。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由根據視覺類比量表之乾眼評分測試指示。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由斯戈默測試指示。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由角膜螢光素染色測試指示。在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由眼表面疾病指數測試指示。In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by one or more tests selected from the group consisting of: a) dry eye score test according to the visual analog scale, b) Sgormer test, c) cornea Fluorescein staining test, and d) Eye surface disease index test. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by the dry eye score test according to the visual analog scale. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by the Gomer test. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of choline α4α6β2 receptor or a combination thereof is indicated by corneal fluorescein staining test. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of choline α4α6β2 receptor or its combination is indicated by the ocular surface disease index test.
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽選擇性地刺激菸鹼乙醯膽鹼α4β2受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽選擇性地刺激菸鹼乙醯膽鹼α3β4受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽選擇性地刺激菸鹼乙醯膽鹼α3α5β4受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽選擇性地刺激菸鹼乙醯膽鹼α4α6β2受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽為雙重促效劑且刺激菸鹼乙醯膽鹼α4β2受體及菸鹼乙醯膽鹼α3β4受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽為雙重促效劑且刺激菸鹼乙醯膽鹼α4β2受體及菸鹼乙醯膽鹼α3α5β4受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽為雙重促效劑且刺激菸鹼乙醯膽鹼α3β4受體及菸鹼乙醯膽鹼α3α5β4受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽為雙重促效劑且刺激菸鹼乙醯膽鹼α4β2受體及菸鹼乙醯膽鹼α4α6β2受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽為雙重促效劑且刺激菸鹼乙醯膽鹼α3β4受體及菸鹼乙醯膽鹼α4α6β2受體。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽為雙重促效劑且刺激菸鹼乙醯膽鹼α3α5β4受體及菸鹼乙醯膽鹼α4α6β2受體。在本文所述之一些實施例中,菸鹼乙醯膽鹼受體為外周菸鹼乙醯膽鹼受體。In some embodiments described herein,
隨後章節提供關於根據視覺類比量表之乾眼評分測試、斯戈默測試、角膜螢光素染色測試及眼表面疾病指數測試之其他細節。 乾眼評分測試Subsequent chapters provide additional details about the Dry Eye Scoring Test, Sgormer Test, Corneal Luciferin Staining Test, and Ocular Surface Disease Index Test according to the Visual Analogue Scale. Dry eye score test
根據視覺類比量表之乾眼評分測試可用於評估個體之乾眼病、流淚量或眼部不適。測試涉及使用視覺類比量表且包含100 mm水平線,其中0處之一個終點標記為「無不適」且100處之另一終點標記為「最大不適」。圖11顯示視覺類比量表之實例。要求個體藉由將豎直標記置於水平線上以指示其不適水準而對其由乾眼所致之眼部症狀評級。接著藉由在100 mm標度上鑑定個體反應在何處來獲得乾眼評分。舉例而言,可詢問個體關於其就乾眼而言之不適水準。個體接著在視覺類比量表上自評估及指示其不適水準。此數目可由臨床醫師用於測定個體之乾眼評分。The dry eye score test according to the visual analog scale can be used to assess an individual's dry eye disease, tearing volume, or eye discomfort. The test involves the use of a visual analog scale and contains a 100 mm horizontal line, where one end point at 0 is marked as "no discomfort" and the other end point at 100 is marked as "maximum discomfort". Figure 11 shows an example of a visual analog scale. Individuals are required to rate their eye symptoms caused by dry eyes by placing a vertical marker on a horizontal line to indicate their level of discomfort. The dry eye score is then obtained by identifying where the individual's response is on a 100 mm scale. For example, individuals can be asked about their discomfort level with respect to dry eyes. The individual then self-assessed and indicated their level of discomfort on the visual analogue scale. This number can be used by clinicians to determine the individual's dry eye score.
乾眼評分(以mm量測)可用於評估眼部症狀之嚴重度,及個體之特定治療的有效性。此測試具有如下優勢:以每5分鐘之頻率向個體投與,其允許測試管理員緊密監測個體症狀隨時間推移之變化。相較於指示相對較低不適水準之較低數目,較高數目指示眼部症狀更不適。乾眼評分隨時間推移減小證明眼部症狀減輕或緩解且一般指示個體病況改善。乾眼評分減小證明治療對於治療乾眼病、增加淚液產生或改善眼部不適有效。The dry eye score (measured in mm) can be used to assess the severity of eye symptoms and the effectiveness of specific treatments in the individual. This test has the advantage of being administered to the individual every 5 minutes, which allows the test administrator to closely monitor the individual's symptoms over time. Compared to a lower number indicating a relatively lower level of discomfort, a higher number indicates that the eye symptoms are more uncomfortable. The decrease in dry eye score over time demonstrates the reduction or relief of eye symptoms and generally indicates an improvement in the individual's condition. A decrease in dry eye score proves that the treatment is effective in treating dry eye disease, increasing tear production, or improving eye discomfort.
在所述之一些實施例中,有效治療係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;b)接受投與對照物之個體的乾眼評分;或c)接受投與比較化合物之個體的乾眼評分。In some of the embodiments described, effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is when the individual is administered an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;b)接受投與對照物之個體的乾眼評分;或c)接受投與比較化合物之個體的乾眼評分。In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Irritation is indicated by a statistically significant decrease in the individual's dry eye score, and the statistically significant decrease in the individual's dry eye score is the first to administer an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;b)接受投與對照物之個體的乾眼評分;或c)接受投與比較化合物之個體的乾眼評分。In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of
在本文所述之一些實施例中,個體之乾眼評分係相較於在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之乾眼評分。在本文所述之一些實施例中,個體之乾眼評分係相較於接受投與對照物之個體的乾眼評分。在本文所述之一些實施例中,個體之乾眼評分係相較於接受投與比較化合物之個體的乾眼評分。In some embodiments described herein, the individual's dry eye score is compared to the individual's dry eye score prior to administration of the first dose of
在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降至少5%、10%、15%、20%、25%、50%、75%、80%、90%、95%、100%、125%、150%、200%、250%、300%或350%。In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95% , 100%, 125%, 150%, 200%, 250%, 300% or 350%.
在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降至少3 mm、至少5 mm、至少10 mm、至少15 mm、至少20 mm、至少25 mm、至少30 mm、至少35 mm、至少40 mm、至少45 mm或至少50 mm。In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 3 mm, at least 5 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30 mm, at least 35 mm, at least 40 mm, at least 45 mm, or at least 50 mm.
在本文所述之一些實施例中,個體之乾眼評分在統計上顯著下降3 mm與10 mm之間、在3 mm與20 mm之間、在3 mm與25 mm之間、在3 mm與30 mm之間、在3 mm與35 mm之間、在3 mm與40 mm之間、在3 mm與45 mm之間、在3 mm與50 mm之間、在5 mm與10 mm之間、在5 mm與20 mm之間、在5 mm與25 mm之間、在5 mm與30 mm之間、在5 mm與35 mm之間、在5 mm與40 mm之間、在5 mm與45 mm之間、在5 mm與50 mm之間、在10 mm與15 mm之間、在10 mm與20 mm之間、在10 mm與25 mm之間、在10 mm與30 mm之間、在10 mm與35 mm之間、在10 mm與40 mm之間、在10 mm與45 mm之間、在10 mm與50 mm之間、在15 mm與20 mm之間、在20 mm與30 mm之間、在25 mm與35 mm之間、在30 mm與40 mm之間、在30 mm與45 mm或在30 mm與50 mm。In some embodiments described herein, the individual's dry eye score is statistically significantly reduced between 3 mm and 10 mm, between 3 mm and 20 mm, between 3 mm and 25 mm, between 3 mm and Between 30 mm, between 3 mm and 35 mm, between 3 mm and 40 mm, between 3 mm and 45 mm, between 3 mm and 50 mm, between 5 mm and 10 mm, Between 5 mm and 20 mm, between 5 mm and 25 mm, between 5 mm and 30 mm, between 5 mm and 35 mm, between 5 mm and 40 mm, between 5 mm and 45 between mm, between 5 mm and 50 mm, between 10 mm and 15 mm, between 10 mm and 20 mm, between 10 mm and 25 mm, between 10 mm and 30 mm, at Between 10 mm and 35 mm, between 10 mm and 40 mm, between 10 mm and 45 mm, between 10 mm and 50 mm, between 15 mm and 20 mm, between 20 mm and 30 mm Between, between 25 mm and 35 mm, between 30 mm and 40 mm, between 30 mm and 45 mm or between 30 mm and 50 mm.
在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.
在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內、10分鐘內、15分鐘內、20分鐘內、30分鐘內、45分鐘內或60分鐘內。在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降為立即的。In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is within 5 minutes, 10 minutes of administering the first dose of an effective amount of
在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持於10%內至少30分鐘。In some embodiments described herein, the statistically significant decrease in the individual's dry eye score has been maintained at 10% for at least 30 minutes since the first dose of an effective amount of
在本文所述之一些實施例中,在測定個體之乾眼評分之間,個體存在於濕度降低之環境中。在本文所述之一些實施例中,在測定個體之乾眼評分之間,個體存在於濕度降低且溫度低於或高於室溫之環境中。 斯戈默評分測試In some embodiments described herein, between measuring the individual's dry eye score, the individual is present in an environment with reduced humidity. In some embodiments described herein, between measuring the individual's dry eye score, the individual is present in an environment with reduced humidity and a temperature below or above room temperature. Sgomer score test
乾眼病影響淚液量及淚液產生。斯戈默測試可用於評估淚液產量及評估個體之乾眼病、流淚量不足或眼部不適的嚴重度。該測試量測由一隻或兩隻眼睛產生之淚液的量。該測試通常涉及首先將麻醉劑置於個體之一隻或兩隻眼睛中。此等滴劑預防眼睛回應於測試條而流淚。接著,測試管理員將一片濾紙置於下眼瞼內部且該個體閉上眼睛。在5分鐘之後,測試管理員移除濾紙且評估淚液在紙上行進了多遠。Dry eye disease affects tear volume and tear production. The Gomer test can be used to assess tear production and the severity of dry eye disease, insufficient tearing, or eye discomfort in an individual. This test measures the amount of tears produced by one or both eyes. This test usually involves first placing the anesthetic in one or both eyes of the individual. These drops prevent the eyes from weeping in response to the test strip. Next, the test administrator placed a piece of filter paper inside the lower eyelid and the individual closed their eyes. After 5 minutes, the test administrator removed the filter paper and evaluated how far the tears traveled on the paper.
一般而言,紙上之水分的量愈小,個體產生之淚液愈少。在健康眼睛中,各紙條通常含有大於10毫米水分。小於10毫米水分之斯戈默評分可指示以下病況中之一或多者:包括乾眼病、流淚量異常低或眼部不適。In general, the smaller the amount of water on the paper, the less tears the individual produces. In healthy eyes, each paper strip usually contains more than 10 mm of water. A Stommer score of less than 10 mm of water can indicate one or more of the following conditions: including dry eye disease, abnormally low tear volume, or eye discomfort.
斯戈默測試可用於評估個體中特定治療之有效性且可投與多次以監測個體症狀之嚴重度在一段時間內之任何變化。治療乾眼病、流淚量不足或眼部不適之個體中斯戈默評分隨時間推移增加證明淚液量或淚液產生增加且一般指示個體之病況改善。斯戈默評分隨時間推移增加證明治療對於治療乾眼病、增加淚液產生或改善眼部不適有效。The Gomer test can be used to assess the effectiveness of a particular treatment in an individual and can be administered multiple times to monitor any change in the severity of an individual's symptoms over a period of time. An increase in the Stommer score in individuals who treat dry eye disease, insufficient tearing, or eye discomfort demonstrates an increase in tear volume or tear production and generally indicates an improvement in the individual's condition. The increase in Sgormer score over time proves that the treatment is effective for treating dry eye disease, increasing tear production, or improving eye discomfort.
在本文所述之一些實施例中,有效治療係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的斯戈默評分;b)接受投與對照物之個體的斯戈默評分;或c)接受投與比較化合物之個體的斯戈默評分。In some embodiments described herein, the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the statistically significant increase in the individual's Sgormer score is in administering an effective amount of the compound to the individual The first dose of 1 or its pharmaceutically acceptable salt or one or more subsequent doses are selected after the determination, and the individual’s Sgormer score is compared to a) after administration of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的斯戈默評分;b)接受投與對照物之個體的斯戈默評分;或c)接受投與比較化合物之個體的斯戈默評分。In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Stimulation is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的斯戈默評分;b)接受投與對照物之個體的斯戈默評分;或c)接受投與比較化合物之個體的斯戈默評分。In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the statistically significant increase in the individual's Sgormer score is the administration of an effective amount of the compound to the individual The first dose of 1 or its pharmaceutically acceptable salt or one or more subsequent doses are selected after the determination, and the individual’s Sgormer score is compared to a) after administration of
在本文所述之一些實施例中,個體之斯戈默評分係相較於在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之斯戈默評分。在本文所述之一些實施例中,個體之斯戈默評分係相較於接受投與對照物之個體的斯戈默評分。在本文所述之一些實施例中,個體之斯戈默評分係相較於接受投與比較化合物之個體的斯戈默評分。In some embodiments described herein, the individual's Sgormer score is compared to the individual's Sgormer score prior to administration of the first dose of
在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升至少5%、10%、15%、20%、25%、50%、75%、80%、90%、95%、100%、125%、150%、200%、250%、300%或350%。在本文所述之一些實施例中,個體之斯戈默評分的增加為至少100%、200%或300%。In some embodiments described herein, the individual's Sgormer score is statistically significantly increased by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95 %, 100%, 125%, 150%, 200%, 250%, 300% or 350%. In some embodiments described herein, the increase in the individual's Sgormer score is at least 100%, 200%, or 300%.
在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升至少3 mm、至少5 mm、至少10 mm、至少15 mm、至少20 mm、至少25 mm、至少30 mm、至少35 mm、至少40 mm、至少45 mm或至少50 mm。In some embodiments described herein, the individual's Sgormer score is statistically significantly increased by at least 3 mm, at least 5 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30 mm, at least 35 mm, at least 40 mm, at least 45 mm, or at least 50 mm.
在本文所述之一些實施例中,個體之斯戈默評分之統計上顯著上升在3 mm與5 mm之間、在3 mm與10 mm之間、在3 mm與15 mm之間、在3 mm與20 mm之間、在3 mm與25 mm之間、在3 mm與30 mm之間、在5 mm與10 mm之間、在5 mm與15 mm之間、在5 mm與20 mm之間、在5 mm與25 mm之間、在5 mm與30 mm之間、在10 mm與15 mm之間、在10 mm與20 mm之間、在10 mm與25 mm之間、在10 mm與30 mm、在15 mm與20 mm之間、在15 mm與25 mm之間、在15 mm與30 mm之間、在20 mm與25 mm或在20 mm與30 mm之間。In some of the embodiments described herein, the statistical increase in the individual’s Sgormer score is significantly between 3 mm and 5 mm, between 3 mm and 10 mm, between 3 mm and 15 mm, and between 3 between mm and 20 mm, between 3 mm and 25 mm, between 3 mm and 30 mm, between 5 mm and 10 mm, between 5 mm and 15 mm, between 5 mm and 20 mm Between, between 5 mm and 25 mm, between 5 mm and 30 mm, between 10 mm and 15 mm, between 10 mm and 20 mm, between 10 mm and 25 mm, between 10 mm With 30 mm, between 15 mm and 20 mm, between 15 mm and 25 mm, between 15 mm and 30 mm, between 20 mm and 25 mm or between 20 mm and 30 mm.
在本文所述之一些實施例中,個體之斯戈默評分之統計上顯著上升係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。In some embodiments described herein, the statistically significant increase in the individual's Sgormer score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.
在本文所述之一些實施例中,個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內、10分鐘內、15分鐘內、20分鐘內、30分鐘內、45分鐘內或60分鐘內。在本文所述之一些實施例中,個體之斯戈默評分之統計上顯著上升為立即的。In some embodiments described herein, the statistically significant increase in the individual's Sgormer score is within 5 minutes, 10 minutes of administering the first dose of an effective amount of
在本文所述之一些實施例中,在測定個體之斯戈默評分之間,個體存在於濕度降低之環境中。在本文所述之一些實施例中,在測定個體之斯戈默評分之間,個體存在於濕度降低且溫度低於或高於室溫之環境中。在本文所述之一些實施例中,室溫下降低之濕度為小於40%、小於30%、小於20%、小於10%或小於5%。室溫在15℃(59℉)與25℃(77℉)之間。In some of the embodiments described herein, the individual is present in an environment with reduced humidity between the determination of the Sgormer score of the individual. In some embodiments described herein, between determining an individual's Sgormer score, the individual exists in an environment with reduced humidity and a temperature below or above room temperature. In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).
在本文所述之一些實施例中,投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。一或多個後續劑量係在第一劑量之後的一段時間之後投與。第一劑量與下一後續劑量之間的此時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。第一劑量與下一後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。一或多個後續劑量之間的時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。一或多個後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。In some embodiments described herein, administration of
在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定。In some of the embodiments described herein, the individual's Sgormer score is statistically significantly increased after the first dose of an effective amount of
在本文所述之一些實施例中,其中統計上顯著上升係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之斯戈默評分。
角膜螢光素染色測試In some of the embodiments described herein, where the statistically significant increase is based on the Sgomer score of the individual measured after administration of an effective amount of
角膜表面變化與淚流量不足及過度乾燥,以及乾眼病及眼部不適相關。角膜表面變化可包括保護表面上皮細胞之黏蛋白包衣的破壞,及/或對上皮細胞壁之損害。Corneal surface changes are associated with insufficient tear flow and excessive dryness, as well as dry eye disease and eye discomfort. Corneal surface changes may include the destruction of the mucin coating that protects the surface epithelial cells, and/or damage to the epithelial cell wall.
角膜螢光素染色測試為用於測定角膜表面健康之診斷測試且可指示角膜表面上之受損區域。正常角膜表面不吸收滴注至淚膜中之水溶性染料。然而,受損上皮細胞允許水溶性染料擴散至表面細胞中。染色受損上皮細胞之螢光素可觀測於角膜表面上,指示角膜表面上由乾燥所致之損害。The corneal fluorescein staining test is a diagnostic test used to determine the health of the corneal surface and can indicate damaged areas on the corneal surface. The normal corneal surface does not absorb the water-soluble dye dripped into the tear film. However, the damaged epithelial cells allow the water-soluble dye to diffuse into the surface cells. Luciferin staining damaged epithelial cells can be observed on the surface of the cornea, indicating damage caused by drying on the surface of the cornea.
為了投與角膜螢光素染色測試,將螢光素施加至一隻或兩隻眼睛。使螢光素穿透及染色表面細胞之間的區域。可藉由此染色觀測到滅活細胞及滅活表面組織束(絲狀纖維)。測試管理員接著使用已開發之角膜表面評分系統對觀測之損害嚴重度評級。此評分系統適用於監測隨時間推移之乾眼治療。圖9描繪用於評分系統之NEI/Industry Workshop量表。可使用其他等效標準化評分系統。測試管理員對受損之角膜表面區域分級且計算反映對角膜表面受損嚴重度的角膜評分。To administer the corneal luciferin staining test, luciferin is applied to one or both eyes. Let luciferin penetrate and stain the area between the surface cells. By this staining, inactivated cells and inactivated surface tissue bundles (filamentous fibers) can be observed. The test administrator then uses the developed corneal surface scoring system to rate the observed severity of damage. This scoring system is suitable for monitoring dry eye treatment over time. Figure 9 depicts the NEI/Industry Workshop scale used in the scoring system. Other equivalent standardized scoring systems can be used. The test administrator grades the damaged corneal surface area and calculates a corneal score that reflects the severity of damage to the corneal surface.
測試管理員可使用角膜評分來評估個體中特定治療之有效性。測試可投與多次以監測個體眼表面之嚴重度在一段時間內之任何變化。一般而言,較高數目指示相較於較低數目對角膜表面之較大損害,較低數目指示對角膜表面之較低損害水準。角膜評分隨時間推移減小證明對角膜表面之損害降低。角膜評分減小一般指示個體之病況改善。角膜評分隨時間推移減小亦證明治療對於治療乾眼病、增加淚液產生或改善眼部不適有效。Test administrators can use corneal scores to assess the effectiveness of specific treatments in individuals. The test can be administered multiple times to monitor any changes in the severity of the individual's eye surface over a period of time. In general, a higher number indicates a greater damage to the corneal surface than a lower number, and a lower number indicates a lower level of damage to the corneal surface. The decrease in corneal score over time proves that the damage to the corneal surface is reduced. A decrease in corneal score generally indicates an improvement in the individual's condition. The decrease in corneal score over time also proves that the treatment is effective for treating dry eye disease, increasing tear production, or improving eye discomfort.
在本文所述之一些實施例中,有效治療係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之角膜評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;b)接受投與對照物之個體的角膜評分;或c)接受投與比較化合物之個體的角膜評分。在本文所述之一些實施例中,角膜螢光素染色測試係根據國家眼科研究所(NEI)分級系統。In some embodiments described herein, effective treatment is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is when an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之角膜評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;b)接受投與對照物之個體的角膜評分;或c)接受投與比較化合物之個體的角膜評分。In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Irritation is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is the first dose or an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之角膜評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;b)接受投與對照物之個體的角膜評分;或c)接受投與比較化合物之個體的角膜評分。In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is when an effective amount of
在本文所述之一些實施例中,個體之角膜評分係相較於在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之角膜評分。在本文所述之一些實施例中,個體之角膜評分係相較於接受投與對照物之個體的角膜評分。在本文所述之一些實施例中,個體之角膜評分係相較於接受投與比較化合物之個體的角膜評分。In some embodiments described herein, the individual's corneal score is compared to the individual's corneal score prior to administration of the first dose of
在本文所述之一些實施例中,個體之角膜評分之統計上顯著下降至少5%、10%、15%、20%、25%、50%、75%、80%、90%、95%或100。In some embodiments described herein, the individual's corneal score is statistically significantly reduced by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95% or 100.
在本文所述之一些實施例中,個體之角膜評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。In some embodiments described herein, the statistically significant drop in the individual's corneal score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.
在本文所述之一些實施例中,個體之角膜評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內、10分鐘內、15分鐘內、20分鐘內、30分鐘內、45分鐘內或60分鐘內。在本文所述之一些實施例中,個體之角膜評分之統計上顯著下降為立即的。In some of the embodiments described herein, the statistically significant decrease in the individual's corneal score is within 5 minutes, within 10 minutes of administering the first dose of an effective amount of
在本文所述之一些實施例中,在測定個體之角膜評分之間,個體存在於濕度降低之環境中。在本文所述之一些實施例中,在測定個體之角膜評分之間,個體存在於濕度降低且溫度低於或高於室溫之環境中。在本文所述之一些實施例中,室溫下降低之濕度為小於40%、小於30%、小於20%、小於10%或小於5%。室溫在15℃(59℉)與25℃(77℉)之間。In some of the embodiments described herein, between measuring the individual's corneal score, the individual is present in an environment with reduced humidity. In some embodiments described herein, between measuring an individual's corneal score, the individual exists in an environment with reduced humidity and a temperature below or above room temperature. In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).
在本文所述之一些實施例中,投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。一或多個後續劑量係在第一劑量之後的一段時間之後投與。第一劑量與下一後續劑量之間的此時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。第一劑量與下一後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。一或多個後續劑量之間的時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。一或多個後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。In some embodiments described herein, administration of
在本文所述之一些實施例中,個體之角膜評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之角膜評分。In some embodiments described herein, the statistically significant decrease in the individual's corneal score is based on the individual's corneal score determined after administration of an effective amount of the first dose of
在本文所述之一些實施例中,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續之後測定的個體之角膜評分。
眼表面疾病指數測試In some of the embodiments described herein, where the statistically significant decrease is based on the corneal score of the individual determined after subsequent administration of an effective amount of
治療乾眼病、增加淚液產生或改善眼部不適之個體可提供用於診斷其病況及測定乾眼症狀嚴重度(經由調查表)之重要資訊。精心設計之調查表可證實再現性且應由引發回應性答案之相關問題組成。乾眼調查表之一個實例為眼表面疾病指數(OSDI),其為針對乾眼患者之12個問題的調查,已顯示為用於直接評估症狀頻率之可靠及有效的工具。評估之眼部症狀包括灼痛/刺痛、瘙癢、異物感、眼部不適、乾眼、畏光及疼痛。大部分人熟悉調查表且理解其為健康提供商收集資訊之高效方式。調查表亦減少偏差,因為無語言或視覺提示無意地影響調查對象。OSDI調查表之實例顯示於圖10中。測試管理員收集來自個體之應答且基於個體對問題的回答計算OSDI。Individuals who treat dry eye disease, increase tear production, or improve eye discomfort can provide important information for diagnosing their condition and measuring the severity of dry eye symptoms (via questionnaire). A carefully designed questionnaire confirms reproducibility and should consist of relevant questions that trigger responsive answers. An example of a dry eye questionnaire is the Ocular Surface Disease Index (OSDI), which is a survey of 12 questions for dry eye patients and has been shown to be a reliable and effective tool for directly assessing the frequency of symptoms. The eye symptoms evaluated included burning/tingling, itching, foreign body sensation, eye discomfort, dry eyes, photophobia, and pain. Most people are familiar with the questionnaire and understand that it is an efficient way for health providers to collect information. The questionnaire also reduces deviations because no words or visual cues unintentionally affect the respondents. An example of the OSDI questionnaire is shown in Figure 10. The test administrator collects responses from individuals and calculates OSDI based on the individuals' answers to questions.
OSDI評分可用於評估眼部症狀之嚴重度,及個體之特定治療的有效性。較高數目指示乾眼病之較高嚴重度。OSDI評分隨時間推移減小證明眼部症狀減輕或緩解且一般指示個體病況改善。OSDI評分減小亦證明治療對於治療乾眼病、增加淚液產生或改善眼部不適有效。The OSDI score can be used to assess the severity of ocular symptoms and the effectiveness of individual specific treatments. A higher number indicates a higher severity of dry eye disease. The decrease in OSDI score over time demonstrates the reduction or remission of ocular symptoms and generally indicates an improvement in the individual's condition. The decreased OSDI score also proves that the treatment is effective in treating dry eye disease, increasing tear production, or improving eye discomfort.
在所述之一些實施例中,有效治療係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;b)接受投與對照物之個體的OSDI評分;或c)接受投與比較化合物之個體的OSDI評分。In some of the embodiments described, effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;b)接受投與對照物之個體的OSDI評分;或c)接受投與比較化合物之個體的OSDI評分。In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Stimulation is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is the first dose or an effective amount of
在本文所述之一些實施例中,個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;b)接受投與對照物之個體的OSDI評分;或c)接受投與比較化合物之個體的OSDI評分。In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of
在本文所述之一些實施例中,個體之OSDI評分係相較於在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前的個體之OSDI評分。在本文所述之一些實施例中,個體之OSDI評分係相較於接受投與對照物之個體的OSDI評分。在本文所述之一些實施例中,個體之OSDI評分係相較於接受投與比較化合物之個體的OSDI評分。In some embodiments described herein, the individual's OSDI score is compared to the individual's OSDI score prior to administration of the first dose of
在本文所述之一些實施例中,個體之OSDI評分之統計上顯著下降至少5%、10%、15%、20%、25%、50%、75%、80%、90%、95%、100%、125%、150%、200%、250%、300%或350%。In some embodiments described herein, the individual's OSDI score is statistically significantly reduced by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95%, 100%, 125%, 150%, 200%, 250%, 300% or 350%.
在本文所述之一些實施例中,個體之OSDI評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。In some embodiments described herein, a statistically significant decrease in an individual's OSDI score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.
在本文所述之一些實施例中,個體之OSDI評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內、10分鐘內、15分鐘內、20分鐘內、30分鐘內、45分鐘內或60分鐘內。在本文所述之一些實施例中,個體之OSDI評分之統計上顯著下降為立即的。In some embodiments described herein, the statistically significant decrease in the individual's OSDI score is within 5 minutes, within 10 minutes of administering the first dose of an effective amount of
在本文所述之一些實施例中,在測定個體之OSDI評分之間,個體存在於濕度降低之環境中。在本文所述之一些實施例中,在測定個體之OSDI評分之間,個體存在於濕度降低且溫度低於或高於室溫之環境中。在本文所述之一些實施例中,室溫下降低之濕度為小於40%、小於30%、小於20%、小於10%或小於5%。室溫在15℃(59℉)與25℃(77℉)之間。In some embodiments described herein, between determining the individual's OSDI score, the individual is present in an environment with reduced humidity. In some embodiments described herein, between determining the individual's OSDI score, the individual exists in an environment where the humidity is reduced and the temperature is below or above room temperature. In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).
在本文所述之一些實施例中,投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。一或多個後續劑量係在第一劑量之後的一段時間之後投與。第一劑量與下一後續劑量之間的此時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。第一劑量與下一後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。一或多個後續劑量之間的時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。一或多個後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。In some embodiments described herein, administration of
在本文所述之一些實施例中,其中個體之OSDI評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之OSDI評分。In some embodiments described herein, wherein the statistically significant decrease in the individual's OSDI score is based on the individual's OSDI score determined after administration of an effective amount of the first dose of
在本文所述之一些實施例中,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之OSDI評分。
隨時間推移維持有效治療In some embodiments described herein, wherein the statistically significant decrease is based on the individual's OSDI score determined after administration of an effective amount of
本發明提供在一段時間內之有效治療,其中維持個體評分之統計上顯著改善。如本發明中所用且與維持個體評分(EDS、斯戈默、角膜或OSDI)之統計上顯著改善相關之術語「維持」係指統計上顯著改善不隨時間推移降至低於某一臨限值。即使個體評分在隨後的時間點改變,亦可維持統計上顯著改善。第一劑量之後的改善可在不額外給藥之情況下或在一或多個後續劑量之後維持。The present invention provides effective treatment over a period of time, where statistically significant improvements in maintaining individual scores are maintained. The term "maintenance" as used in the present invention and related to maintaining a statistically significant improvement in individual scores (EDS, Stommer, cornea, or OSDI) means that the statistically significant improvement does not fall below a certain threshold over time value. Even if the individual score changes at a later time point, statistically significant improvements can be maintained. The improvement after the first dose can be maintained without additional administration or after one or more subsequent doses.
舉例而言,乾眼評分「維持於10%內」意謂個體之乾眼評分的減小在指定時間內不降低超過10%。個體之乾眼評分的另一改善亦將視為維持統計上顯著改善(例如若乾眼評分在指定時間內進一步改善15%,則此將視為「維持於10%內」)。For example, a dry eye score "maintained within 10%" means that the individual's dry eye score does not decrease by more than 10% within a specified time. Another improvement in the individual's dry eye score will also be regarded as maintaining a statistically significant improvement (for example, some eye scores will be further improved by 15% within a specified time, then this will be considered "maintained within 10%").
在另一實例中,若在服用第一劑量之後30分鐘,個體之乾眼評分統計上顯著下降(改善),且在隨後的時間點,個體之評分為相同或更小(指示對該個體之益處),則將統計上顯著改善稱為得以維持。或者,若在隨後的時間點,個體之乾眼評分超過在服用第一劑量之後30分鐘的乾眼評分,則該個體仍可獲得治療益處且隨後測定之評分仍可為相較於先前投與第一劑量或其治療前基線評分之統計上顯著改善。In another example, if 30 minutes after taking the first dose, the individual's dry eye score is statistically significantly reduced (improved), and at a later time point, the individual's score is the same or less (indicating the individual's Benefit), the statistically significant improvement is said to be maintained. Alternatively, if at a subsequent time point, the individual's dry eye score exceeds the
應注意,構成改善之要素取決於量測之評分而不同。舉例而言,乾眼評分、角膜評分及OSDI評分之改善為評分數值的減小。對於斯戈默測試,改善通常為斯戈默評分數值的增加。It should be noted that the elements that make up the improvement vary depending on the measured score. For example, the improvement in dry eye score, corneal score, and OSDI score is a decrease in score value. For the Sgormer test, the improvement is usually an increase in the Sgormer score.
在本文所述之一些實施例中,維持個體評分(例如EDS、斯戈默、角膜或OSDI)之統計上顯著改善意謂統計上顯著改善不降低超過10%、20%、30%、40%、50%或60%。In some embodiments described herein, maintaining a statistically significant improvement in an individual’s score (eg, EDS, Sgormer, cornea, or OSDI) means that the statistically significant improvement does not decrease by more than 10%, 20%, 30%, 40% , 50% or 60%.
在本文所述之一些實施例中,個體評分(例如EDS、斯戈默、角膜或OSDI)之統計上顯著改善維持至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月。在本文所述之一些實施例中,個體評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘,其中統計上顯著改善不降低超過30%。In some embodiments described herein, the statistically significant improvement in individual scores (eg, EDS, Gomer, cornea, or OSDI) is maintained for at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, At least 6 hours, at least 8 hours, at least 1 day, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments described herein, the statistically significant improvement in the individual score is maintained for at least 30 minutes from the first dose of the effective amount of
在本文所述之一些實施例中,個體評分(例如EDS、斯戈默、角膜或OSDI)之統計上顯著改善在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後維持至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內的個體評分,統計上顯著改善不降低超過10%、20%、30%、40%、50%或60%。In some embodiments described herein, the statistical score of the individual score (eg, EDS, Stommer, cornea, or OSDI) significantly improves the first dose of
在本文所述之一些實施例中,個體評分(例如EDS、斯戈默、角膜或OSDI)之統計上顯著改善在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後維持至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應乾眼評分、角膜評分或OSDI評分,統計上顯著改善不降低超過20%。In some embodiments described herein, the statistical score of the individual score (eg, EDS, Stommer, cornea, or OSDI) significantly improves the first dose of
在本文所述之一些實施例中,個體評分(例如EDS、斯戈默、角膜或OSDI)之統計上顯著改善在投與有效量的化合物1之第一劑量之後維持至少30分鐘,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內的個體評分,統計上顯著改善不降低超過10%、20%或30%。In some of the embodiments described herein, the statistically significant improvement in individual scores (eg, EDS, Stommer, cornea, or OSDI) is maintained for at least 30 minutes after administration of the first dose of an effective amount of
在本文所述之一些實施例中,相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應斯戈默評分,在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月,個體之斯戈默評分不減小超過10%、20%、30%、40%、50%或60%。In some of the embodiments described herein, compared to the corresponding Sgormer score of an individual within 5 minutes after the administration of the first dose of an effective amount of
在本文所述之一些實施例中,相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應斯戈默評分,在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月,個體之斯戈默評分不減小超過30%。In some of the embodiments described herein, compared to the corresponding Sgormer score of an individual within 5 minutes after the administration of the first dose of an effective amount of
在本文所述之一些實施例中,相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應斯戈默評分,在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘,個體之斯戈默評分不減小超過30%、20%或10%。In some of the embodiments described herein, compared to the corresponding Sgormer score of an individual within 5 minutes after the administration of the first dose of an effective amount of
在本文所述之一些實施例中,相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應乾眼評分、角膜評分或OSDI評分,在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月,個體之乾眼評分、角膜評分或OSDI評分不增加超過10%、20%、30%、40%、50%或60%。In some embodiments described herein, compared to the corresponding dry eye score, corneal score, or OSDI score of an individual within 5 minutes after administration of an effective amount of the first dose of
在本文所述之一些實施例中,相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應乾眼評分、角膜評分或OSDI評分,在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘、至少45分鐘、至少60分鐘、至少2小時、至少4小時、至少6小時、至少8小時、至少1天、至少1週、至少1個月、至少3個月、至少6個月、至少9個月或至少12個月,個體之乾眼評分、角膜評分或OSDI評分不增加超過30%。In some embodiments described herein, compared to the corresponding dry eye score, corneal score, or OSDI score of an individual within 5 minutes after administration of an effective amount of the first dose of
在本文所述之一些實施例中,相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之對應乾眼評分、角膜評分或OSDI評分,在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘,個體之乾眼評分、角膜評分或OSDI評分不增加超過30%、20%或10%。
劑量及體積In some embodiments described herein, compared to the corresponding dry eye score, corneal score, or OSDI score of an individual within 5 minutes after administration of an effective amount of the first dose of
在本文所述之一些實施例中,投與本文所述之劑量以進行預防性及/或治療性治療。對治療性治療有效之劑量取決於疾病或病況之嚴重度及病程;先前療法;患者之健康、狀況、體重及對藥物之反應;以及治療健康提供商之判斷。治療有效量視情況藉由包括但不限於劑量遞增臨床試驗之方法來確定。In some embodiments described herein, the doses described herein are administered for prophylactic and/or therapeutic treatments. The dose effective for therapeutic treatment depends on the severity and course of the disease or condition; previous therapy; the patient's health, condition, weight, and response to the drug; and the judgment of the treatment health provider. The therapeutically effective amount is determined by methods including but not limited to dose escalation clinical trials, as appropriate.
在預防性應用中,向易罹患或另外處於特定疾病、病症或病況風險下之患者投與本文所述之醫藥調配物。此類量定義為「預防有效量或劑量」。在此用途中,量將取決於疾病、病症或病況之嚴重度及病程、先前療法、患者之健康狀況及對藥物之反應,及治療健康提供商之判斷。In prophylactic applications, the pharmaceutical formulations described herein are administered to patients susceptible to or otherwise at risk for a particular disease, disorder or condition. Such amounts are defined as "prophylactically effective amounts or doses". In this use, the amount will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drug, and the judgment of the treatment health provider.
在本文所述之一些實施例中,向個體投與之每劑化合物1之量為5-4000微克、5-1000微克、10-2000微克、10-700微克、100-700微克、100-600微克、100-500微克、200-700微克、200-600微克、200-500微克、300-600微克、300-500微克、900-4000微克、900-3000微克、900-2500微克、900-2000微克、1000-4000微克、1000-2500微克、1000-2000微克、1250-4000微克、1250-2500微克、1250-2000微克、1500-4000微克、1500-3000微克、1500-2500微克、1500-2000微克、1800-4000微克、1800-3000微克、1800-2500微克、1800-2250微克、2000-4000微克、2000-3000微克或2000-2500微克,或其醫藥學上可接受之鹽之對應量。在本文所述之一些實施例中,向個體投與之每劑化合物1之量為900-2500微克、1000-2500微克、1500-3000微克、1800-2500微克、1800-2250微克,或其醫藥學上可接受之鹽之對應量。在本文所述之一些實施例中,向個體投與之每劑化合物1之量為150-300微克、900-1200微克或2100-2400微克,或其醫藥學上可接受之鹽之對應量。在本文所述之一些實施例中,投與化合物1之醫藥學上可接受之鹽。在本文所述之一些實施例中,投與化合物1之游離鹼。In some embodiments described herein, the amount of
向個體投與之醫藥調配物之體積取決於各種因素,包括投與途徑及遞送裝置的類型。對於經鼻投與,醫藥調配物之體積應足以將有效量的藥物遞送至鼻腔。體積過小可導致藥物無法達到鼻腔。另一方面,體積不應過大以致不實用、不適或太難向個體投與。另外,體積過大可導致醫藥調配物遞送至未預期遞送之身體區域。此可導致醫藥調配物浪費或組織刺激。舉例而言,將劑量體積自200微升減少至100微升可藉由減少滴注後之鼻後滴注而減少上喉/軟齶刺激的發生率。The volume of pharmaceutical formulation administered to an individual depends on various factors, including the route of administration and the type of delivery device. For nasal administration, the volume of the pharmaceutical formulation should be sufficient to deliver an effective amount of drug to the nasal cavity. If the volume is too small, the medicine cannot reach the nasal cavity. On the other hand, the volume should not be too large to be practical, uncomfortable, or too difficult to administer to the individual. In addition, excessive volume can cause delivery of pharmaceutical formulations to areas of the body where delivery is not expected. This can result in wasted pharmaceutical formulations or tissue irritation. For example, reducing the dose volume from 200 microliters to 100 microliters can reduce the incidence of upper larynx/soft palate stimulation by reducing post-nasal instillation after instillation.
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為50-250微升、75-125微升、150-250微升或175-225微升。In some embodiments described herein,
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為約50微升、約75微升、約100微升、約125微升、約150微升、約175微升、約200微升、約225微升或約250微升。In some embodiments described herein,
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每個鼻孔之醫藥調配物之總體積為50-250微升、75-125微升、150-250微升或175-225微升。In some embodiments described herein,
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每個鼻孔之醫藥調配物之總體積為約50微升、約75微升、約100微升、約125微升、約150微升、約175微升、約200微升、約225微升或約250微升。In some embodiments described herein,
在本文所述之一些實施例中,化合物1係呈經鼻投藥之醫藥調配物投與,該醫藥調配物包含1 mg/mL與40 mg/mL之間、1 mg/mL與30 mg/mL之間、1 mg/mL與20 mg/mL之間、1 mg/mL與10 mg/mL之間、1 mg/mL與5 mg/mL之間、2 mg/mL與40 mg/mL之間、2 mg/mL與30 mg/mL之間、2 mg/mL與20 mg/mL之間、2 mg/mL與10 mg/mL之間、2 mg/mL與5 mg/mL, 5 mg/mL與40 mg/mL之間、5 mg/mL與30 mg/mL之間、5 mg/mL與20 mg/mL之間、5 mg/mL與10 mg/mL之間或5 mg/mL與15 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。In some embodiments described herein,
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,其中每劑量之化合物1或其醫藥學上可接受之鹽之濃度為0.01% (w/v)至0.5% (w/v)、0.01% (w/v)至1.0% (w/v)、0.01% (w/v)至1.5% (w/v)、0.01% (w/v)至2.0% (w/v)、0.01% (w/v)至2.5% (w/v)、0.01% (w/v)至3.0% (w/v)、0.5% (w/v)至1.0% (w/v)、0.5% (w/v)至1.5% (w/v)、0.5% (w/v)至2.0% (w/v)、0.5% (w/v)至2.5% (w/v)、0.5% (w/v)至3.0% (w/v)、1.0% (w/v)至1.5% (w/v)、1.0% (w/v)至2.0% (w/v)、1.0% (w/v)至2.5% (w/v)、1.0% (w/v)至3.0% (w/v)、1.5% (w/v)至2.0% (w/v)、1.5% (w/v)至2.5% (w/v)、1.5% (w/v)至3.0% (w/v)、2.0% (w/v)至2.5% (w/v)或2.0% (w/v)至3.0% (w/v)。In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, wherein the concentration of Compound 1 or a pharmaceutically acceptable salt thereof per dose 0.01% (w/v) to 0.5% (w/v), 0.01% (w/v) to 1.0% (w/v), 0.01% (w/v) to 1.5% (w/v), 0.01 % (w/v) to 2.0% (w/v), 0.01% (w/v) to 2.5% (w/v), 0.01% (w/v) to 3.0% (w/v), 0.5% ( w/v) to 1.0% (w/v), 0.5% (w/v) to 1.5% (w/v), 0.5% (w/v) to 2.0% (w/v), 0.5% (w/ v) to 2.5% (w/v), 0.5% (w/v) to 3.0% (w/v), 1.0% (w/v) to 1.5% (w/v), 1.0% (w/v) To 2.0% (w/v), 1.0% (w/v) to 2.5% (w/v), 1.0% (w/v) to 3.0% (w/v), 1.5% (w/v) to 2.0 % (w/v), 1.5% (w/v) to 2.5% (w/v), 1.5% (w/v) to 3.0% (w/v), 2.0% (w/v) to 2.5% ( w/v) or 2.0% (w/v) to 3.0% (w/v).
在本文所述之一些實施例中,化合物1為醫藥學上可接受之鹽。在本文所述之一些實施例中,化合物1之醫藥學上可接受之鹽為半乳糖二酸鹽(例如半-半乳糖二酸鹽二水合物)或檸檬酸鹽(例如單檸檬酸鹽)。在本文所述之一些實施例中,化合物1為游離鹼。In some embodiments described herein,
向有需要之個體投與之nAChR促效劑游離鹼之量及鹽之對應量可基於向有需要之個體投與之醫藥調配物的nAChR促效劑濃度及醫藥調配物的體積來計算。以下實例說明向個體投與之醫藥調配物之濃度及體積與nAChR促效劑鹽及游離鹼之量之間的關係。The amount of nAChR agonist free base administered to an individual in need and the corresponding amount of salt can be calculated based on the concentration of the nAChR agonist administered to the individual in need and the volume of the pharmaceutical formulation. The following examples illustrate the relationship between the concentration and volume of pharmaceutical formulation administered to an individual and the amount of nAChR agonist salt and free base.
舉例而言,2.0%化合物1半-半乳糖二酸鹽二水合物溶液等效於20 mg鹽/1 mL溶液。2.0%化合物1半-半乳糖二酸鹽二水合物溶液對應於1.1%化合物1游離鹼溶液。1.1%游離鹼溶液等效於11.1 mg/mL化合物1游離鹼。For example, a 2.0
50 µL 2.0%化合物1半-半乳糖二酸鹽二水合物溶液含有約1000 µg化合物1半-半乳糖二酸鹽二水合物,其等效於約554 µg化合物1游離鹼。同樣,100 µL 2.0%化合物1半-半乳糖二酸鹽二水合物溶液含有約2000 µg化合物1半-半乳糖二酸鹽二水合物,其等效於約1108 µg化合物1游離鹼。鹽之量及游離鹼之對應量可針對其他濃度或體積以類似方式計算。A 50 µL 2.0
在另一實例中,2.3%化合物1單檸檬酸鹽溶液等效於23.2 mg鹽/1 mL溶液。2.3%化合物1單檸檬酸鹽溶液對應於1.1%化合物1游離鹼溶液。1.1%游離鹼溶液等效於11.1 mg/mL化合物1游離鹼。In another example, a 2.3
50 µL 2.3%化合物1單檸檬酸鹽溶液含有約1161 µg化合物1單檸檬酸鹽,其等效於約554 µg化合物1游離鹼。同樣,100 µL 2.3%化合物1單檸檬酸鹽溶液含有約2322 µg化合物1單檸檬酸鹽,其等效於約1108 µg化合物1游離鹼。鹽之量及游離鹼之對應量可針對其他濃度或體積以類似方式計算。A 50 µL 2.3
鹽形式之對應量可藉由游離鹼之量乘以倍增因數來計算。倍增因數係由鹽形式之分子量除以游離鹼之分子量來計算。舉例而言,將一定量之式I化合物游離鹼轉化為單檸檬酸鹽之倍增因數為2.096。將一定量之式I化合物游離鹼轉化為半-半乳糖二酸鹽二水合物之倍增因數為1.805。The corresponding amount of salt form can be calculated by multiplying the amount of free base by a multiplication factor. The multiplication factor is calculated by dividing the molecular weight of the salt form by the molecular weight of the free base. For example, the multiplication factor for converting a certain amount of compound I free base to monocitrate is 2.096. The multiplication factor for converting a certain amount of the free base of the compound of formula I to galactose dihydrate dihydrate is 1.805.
游離鹼之對應量可藉由鹽形式之量乘以倍增因數來計算。該因數係由游離鹼之分子量除以鹽形式之分子量來計算。將一定量之式I化合物單檸檬酸鹽轉化為游離鹼之倍增因數為0.477。將一定量之式I化合物半-半乳糖二酸鹽二水合物轉化為游離鹼之倍增因數為0.554。The corresponding amount of free base can be calculated by multiplying the amount of salt form by the multiplication factor. This factor is calculated by dividing the molecular weight of the free base by the molecular weight of the salt form. The multiplication factor for converting a certain amount of the compound of formula I monocitrate into free base is 0.477. The multiplication factor for converting a certain amount of the compound of formula I hemi-galactonate dihydrate to the free base is 0.554.
本文所述之醫藥調配物係向個體之鼻腔投與。本文所述之醫藥調配物包括但不限於液體、懸浮液、氣溶膠、凝膠、軟膏、乾燥粉末、乳膏、漿液、洗劑或香膏。The pharmaceutical formulations described herein are administered to the individual's nasal cavity. The pharmaceutical formulations described herein include, but are not limited to, liquids, suspensions, aerosols, gels, ointments, dry powders, creams, slurries, lotions, or balsams.
在本文揭示之一些實施例中,化合物1或其醫藥學上可接受之鹽係向個體之鼻腔投與。本文所述之醫藥調配物包括但不限於液體、懸浮液、氣溶膠、凝膠、軟膏、乾燥粉末、乳膏、漿液、洗劑或香膏。In some embodiments disclosed herein,
在本文揭示之一些實施例中,化合物1或其醫藥學上可接受之鹽係藉由噴霧泵、注射器、滴管、瓶噴霧器、霧化泵、吸入器、粉末噴霧裝置、汽化器、貼片、藥棒、吸管或液體噴射器投與至鼻腔中。
投與時序及方法In some embodiments disclosed herein,
向個體投與劑量之排程取決於各種考慮因素,包括各劑量之有效性持續時間、藥物之藥物動力學概況及劑量對身體的影響。舉例而言,其中根據健康提供商之判斷,患者之病況未改善,投與一劑化合物1或其醫藥學上可接受之鹽可增加頻率或長期投與,以改善或另外控制或限制患者之疾病或病況的症狀。在另一實例中,若根據健康提供商之判斷,個體之病況已改善,則投與一劑化合物1或其醫藥學上可接受之鹽之頻率可降低,同時維持個體有效治療。舉例而言,投與一或多個劑量之間的時間段經延長,或向個體投與一或多個劑量之天數之間的時間段經延長。作為非限制性實例,每日投與一或多個劑量經修改以每隔一天或一週一次地投與一或多個劑量。The schedule of doses administered to an individual depends on various considerations, including the duration of effectiveness of each dose, the pharmacokinetic profile of the drug, and the effect of the dose on the body. For example, where the condition of the patient is not improved according to the judgment of the health provider, the administration of a dose of
在本文所述之一些實施例中,在第一天投藥後每天一至四次、在第一天投藥後一天一次、在第一天投藥後一天兩次或在第一天投藥後一天三次地向有需要之個體投與劑量。In some embodiments described herein, one to four times a day after the first day of administration, once a day after the first day of administration, twice a day after the first day of administration, or three times a day after the first day of administration Individuals in need are dosed.
在本文所述之一些實施例中,隨時間推移向個體投與一或多個後續劑量,其中甚至在減少隨時間推移向個體投與之化合物1或其醫藥學上可接受之鹽之量的情況下維持個體有效治療。在本文所述之一些實施例中,向個體投與之化合物1或其醫藥學上可接受之鹽之劑量頻率隨時間推移降低。舉例而言,一天兩次投與之劑量降低為一天一次投與之劑量。In some of the embodiments described herein, one or more subsequent doses are administered to the individual over time, wherein even the amount of
在本文所述之一些實施例中,給藥之間的時間長度增加。舉例而言,每4小時投與一劑量經修改為每8或12小時投與一劑量。在本文所述之一些實施例中,每劑量之化合物1之總量,或其醫藥學上可接受之鹽之對應量隨時間推移減少。舉例而言,2000微克之劑量減少為1000微克化合物1或對應量的其醫藥學上可接受之鹽,其中投與減少之劑量維持個體有效治療。在本文所述之一些實施例中,減少之劑量由減少投與化合物1或其醫藥學上可接受之鹽而提供。舉例而言,當以鼻用噴霧形式投與時,包含化合物1或其醫藥學上可接受之鹽之兩次投與或「噴霧」的劑量減少為僅投與一次「噴霧」。In some embodiments described herein, the length of time between administrations increases. For example, a dose administered every 4 hours is modified to a dose administered every 8 or 12 hours. In some embodiments described herein, the total amount of
在本文所述之一些實施例中,劑量包含向各鼻孔多次投與之化合物1或其醫藥學上可接受之鹽。在本文所述之一些實施例中,劑量包含向一個鼻孔多次投與之化合物1或其醫藥學上可接受之鹽。In some embodiments described herein, the dosage comprises
在本文所述之一些實施例中,劑量包含向各鼻孔單次投與之化合物1或其醫藥學上可接受之鹽。在本文所述之一些實施例中,劑量包含向一個鼻孔單次投與之化合物1或其醫藥學上可接受之鹽。In some embodiments described herein, the dosage comprises
在本文所述之一些實施例中,每劑量向一個鼻孔投與化合物1或其醫藥學上可接受之鹽。在本文所述之一些實施例中,每劑量向兩個鼻孔投與化合物1或其醫藥學上可接受之鹽。In some embodiments described herein,
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係投與至少28天。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係投與至少一或多個月。In some embodiments described herein,
在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係投與至少2個月、至少3個月、至少4個月、至少5個月、至少6個月、至少7個月、至少8個月、至少9個月、至少10個月、至少11個月、或至少一年。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係投與2-52週、2-40週、2-36週、2-24週、2-12週、2-8週、4-52週、4-40週、4-36週、4-24週、4-12週、4-8週、5-52週、5-40週、5-36週、5-24週、5-12週、5-8週、6-52週、6-40週、6-36週、6-24週、6-12週或6-8週。In some embodiments described herein,
在本文所述之一些實施例中,該方法包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。一或多個後續劑量係在第一劑量之後的一段時間之後投與。第一劑量與下一後續劑量之間的此時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。第一劑量與下一後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。一或多個後續劑量之間的時段為至少1小時、至少2小時、至少3小時、至少4小時、至少5小時、至少6小時、至少7小時或至少8小時。一或多個後續劑量之間的時段在1-3小時、2-4小時、3-6小時或4-8小時之間。In some embodiments described herein, the method comprises an effective amount of a first dose of
在本文所述之一些實施例中,包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量,其中該方法造成有效治療該有需要之個體。在本文所述之一些實施例中,個體之有效治療係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之乾眼評分測試及b)斯戈默測試。在一些實施例中,個體之乾眼評分係相較於在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內,且係藉由小於0.05之p值表徵。在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降至少10 mm。在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降至少5 mm。在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降至少3 mm。在本文所述之任一實施例之其他實施例中,向個體投與每劑1800-2500微克之化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之任一實施例之其他實施例中,向個體投與每劑3500-4500微克之化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑之醫藥調配物之總體積為50微升-250微升。在本文所述之一些實施例中,每劑之醫藥調配物之總體積為75微升-150微升。在本文所述之一些實施例中,每劑之醫藥調配物之總體積為150微升-250微升。在本文所述之一些實施例中,每劑之醫藥調配物之總體積為約100微升或約200微升。在本文所述之一些實施例中,經鼻投與用醫藥調配物包含1 mg /mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,經鼻投與用醫藥調配物包含5 mg /mL與25 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,經鼻投與用醫藥調配物包含2 mg /mL、10 mg/mL或20 mg/mL化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,個體之乾眼評分之統計上顯著降幅在自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始的至少30分鐘內維持於10%或20%內。在本文所述之一些實施例中,個體之乾眼評分之統計上顯著降幅在自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始的至少60分鐘內維持於10%或20%內。在本文所述之一些實施例中,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後30分鐘個體之乾眼評分在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之乾眼評分的10%內。In some embodiments described herein, a first dose comprising an effective amount of
在本文所述之一些實施例中,該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量,其中該方法造成有效治療該有需要之個體。在本文所述之一些實施例中,個體之有效治療係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之斯戈默評分測試及b)斯戈默測試。在本文所述之一些實施例中,個體之斯戈默評分係相較於在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的斯戈默評分;個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內,且係藉由小於0.05之p值表徵。在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升至少100%、200%或300%。在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升至少10 mm。在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升至少5 mm。在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升至少3 mm。在本文所述之任一實施例之其他實施例中,向個體投與每劑1800-2500微克的化合物1之醫藥學上可接受之鹽。在本文所述之任一實施例之其他實施例中,向個體投與每劑3500-4500微克的化合物1之醫藥學上可接受之鹽。在本文所述之一些實施例中,化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑之醫藥調配物之總體積為50微升-250微升。在本文所述之一些實施例中,每劑之醫藥調配物之總體積為75微升-150微升。在本文所述之一些實施例中,每劑之醫藥調配物之總體積為150微升-250微升。在本文所述之一些實施例中,每劑之醫藥調配物之總體積為約100微升或約200微升。在本文所述之一些實施例中,經鼻投與用醫藥調配物包含1 mg /mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,經鼻投與用醫藥調配物包含5 mg /mL與25 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,經鼻投與用醫藥調配物包含約2 mg/mL、10 mg/mL或20 mg/mL化合物1,或對應量的其醫藥學上可接受之鹽。在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始的至少30分鐘內維持於10%或20%內。在本文所述之一些實施例中,個體之斯戈默評分在統計上顯著上升自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始的至少60分鐘內維持於10%或20%內。在本文所述之一些實施例中,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後30分鐘個體之斯戈默評分在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之斯戈默評分的10%內。
屈光手術In some embodiments described herein, the method comprises administering to the nasal cavity of an individual in need an effective amount of a first dose of
在本文所述之一些實施例中,該個體將進行或已進行眼部屈光手術。屈光手術之實例包括雷射輔助原位角膜磨削術(LASIK)、散光性角膜切除術(AK)、屈光性角膜切除術(PRK)及角膜緣鬆解切口(LRI)。在方法、用途及所使用之組合物之一些實施例中,屈光手術為雷射輔助原位角膜磨削術(LASIK)。在方法、用途及所使用之組合物之一些實施例中,屈光手術為散光性角膜切除術(AK)。在方法、用途及所使用之組合物之一些實施例中,屈光手術為屈光性角膜切除術(PRK)。在方法、用途及所使用之組合物之一些實施例中,屈光手術為角膜緣鬆解切口(LRI)。在一些實施例中,本文所述之化合物或組合物係在手術前投與。在一些實施例中,本文所述之化合物或組合物係在手術前投與。在一些實施例中,本文所述之化合物或組合物係在手術前及手術後投與。在本文所述之一些實施例中,個體已在2週內進行眼部屈光手術或預定在2週內進行眼部屈光手術。 LASIK群體In some embodiments described herein, the individual will undergo or have undergone eye refractive surgery. Examples of refractive surgery include laser assisted in situ keratomileusis (LASIK), astigmatism keratectomy (AK), refractive keratectomy (PRK), and limbal keratolysis (LRI). In some embodiments of the method, use, and composition used, the refractive surgery is laser assisted in situ keratomileusis (LASIK). In some embodiments of the method, use, and composition used, the refractive surgery is astigmatism keratectomy (AK). In some embodiments of the method, use, and composition used, the refractive surgery is refractive keratectomy (PRK). In some embodiments of the method, use, and composition used, the refractive surgery is a limbal keratolytic incision (LRI). In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before and after surgery. In some embodiments described herein, the individual has undergone eye refractive surgery within 2 weeks or is scheduled to perform eye refractive surgery within 2 weeks. LASIK group
在一些實施例中,本文所述之化合物或組合物係在手術前投與。在一些實施例中,本文所述之化合物或組合物係在手術前投與。在一些實施例中,本文所述之化合物或組合物係在手術前及手術後投與。在本文所述之一些實施例中,個體已在2週內進行雷射原位層狀角膜塑形(Lasik)手術或預定在2週內進行Lasik手術。 角膜炎In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before and after surgery. In some embodiments described herein, the individual has undergone laser in situ lamellar keratoplasty (Lasik) surgery within 2 weeks or is scheduled to perform Lasik surgery within 2 weeks. Keratitis
正常淚膜含有多種生物活性生長因子,包括神經生長因子、表皮生長因子、轉型生長因子-β、肝細胞生長因子、血小板源性生長因子、血管內皮生長因子、纖維母細胞生長因子、角質細胞生長因子及類胰島素生長因子。當角膜感覺到刺激或壓力時,眼瞼將閉合且將產生眼淚來保護角膜及眼睛。Normal tear film contains a variety of biologically active growth factors, including nerve growth factor, epidermal growth factor, transforming growth factor-β, hepatocyte growth factor, platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor, keratinocyte growth Factor and insulin-like growth factor. When the cornea feels irritation or pressure, the eyelids will close and tears will be produced to protect the cornea and eyes.
神經營養性角膜炎造成角膜敏感性降低。患有神經營養性角膜炎(NK)之個體的角膜功能受損,因為神經支配角膜之神經無法正常運作;此等神經攜有輔助角膜功能之衝動。由於此等神經在NK中不正常運作,角膜外層(稱作上皮)可破裂,導致上皮缺陷。在更晚期神經營養性角膜炎中,稱作角膜基質之內部層亦可破裂,導致角膜薄化。此稱作基質『融化』。在晚期基質融化中,角膜可薄化至嚴重程度,其可導致眼睛內部的孔洞或開口,此可導致感染及潛在地失明。NK可導致多種併發症,包括角膜傷口癒合不佳、角膜疤痕及視力喪失。存在多種不同的可損害為角膜服務之神經的病況。Neurotrophic keratitis causes decreased corneal sensitivity. The corneal function of individuals with neurotrophic keratitis (NK) is impaired because the nerves that innervate the cornea cannot function properly; these nerves carry impulses to assist corneal function. Because these nerves do not function properly in NK, the outer layer of the cornea (called the epithelium) can rupture, leading to epithelial defects. In more advanced neurotrophic keratitis, the inner layer called the corneal stroma can also rupture, resulting in thinning of the cornea. This is called "melting" of the matrix. In late stromal melting, the cornea can thin to a severe degree, which can cause holes or openings inside the eye, which can lead to infection and potentially blindness. NK can cause a variety of complications, including poor corneal wound healing, corneal scarring, and loss of vision. There are many different conditions that can damage the nerves that serve the cornea.
多種療法可用於治療此病症,其取決於個體中病症之進展程度。最近,重組人類神經生長因子(rhNGF)(Oxervate,Dompe)已批准用於治療NK。不幸的是,此療法存在若干缺點,包括如下事實:該產品需要以2小時間隔每天投與6次,持續8週;該產品係用吸管遞送,其對於自投藥可為繁瑣的;該產品必須進行冷凍;及4週供應之成本大於$10K。A variety of therapies can be used to treat this disorder, depending on the degree of progression of the disorder in the individual. Recently, recombinant human nerve growth factor (rhNGF) (Oxervate, Dompe) has been approved for the treatment of NK. Unfortunately, this therapy has several drawbacks, including the fact that the product needs to be administered 6 times a day at 2-hour intervals for 8 weeks; the product is delivered with a straw, which can be cumbersome for self-administration; the product must Frozen; and the cost of supply for 4 weeks is greater than $10K.
本發明提供用於治療個體之角膜炎的方法、用途及組合物。在一些實施例中,角膜炎為NK。在一些實施例中,本文揭示之用於治療患有NK之個體的方法及組合物刺激天然淚膜。在一些實施例中,每天一次或兩次地向患有NK之個體投與本文提供之組合物。在一些實施例中,每天一次或兩次地向患有NK之個體投與本文提供之組合物,持續至少4週、至少5週、至少6週、至少7週或至少8週。在一些實施例中,每天兩次地向患有NK之個體投與本文提供之組合物,持續至少8週。在一些實施例中,每天兩次地向患有NK之個體鼻內投與本文提供之組合物,持續至少8週。 副作用The present invention provides methods, uses, and compositions for treating keratitis in an individual. In some embodiments, the keratitis is NK. In some embodiments, the methods and compositions disclosed herein for treating individuals with NK stimulate natural tear film. In some embodiments, the composition provided herein is administered to an individual with NK once or twice a day. In some embodiments, the composition provided herein is administered to an individual with NK once or twice a day for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks. In some embodiments, the composition provided herein is administered to an individual with NK twice a day for at least 8 weeks. In some embodiments, the composition provided herein is administered intranasally to an individual with NK twice a day for at least 8 weeks. side effect
本發明提供局部投與(鼻內)化合物1或其醫藥學上可接受之鹽之方法。局部投與具有優於全身投與之優勢,包括藉由限制可穿過血腦屏障之藥物的量來減少潛在副作用。在本文揭示之一些實施例中,投與之化合物1或其醫藥學上可接受之鹽不為全身之生體可用性。在本文揭示之一些實施例中,該方法不會造成不期望之全身副作用。在本文揭示之一些實施例中,該方法並不會造成不期望之影響精神副作用。The present invention provides a method of topical administration (intranasal) of
在本文所述之一些實施例中,個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。In some embodiments described herein, the individual does not experience one or more side effects selected from the group consisting of excessive tear production, cough, throat irritation, drip site irritation, sneezing, nasopharyngitis, nasal irritation , Toothache, dry mouth and headache.
在本文所述之一些實施例中,其中在投與第一劑量或一或多個後續劑量之5分鐘-60分鐘內,個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。In some embodiments described herein, wherein within 5-60 minutes of administration of the first dose or one or more subsequent doses, the individual will not experience one or more side effects selected from the group consisting of: overproduction Tears, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.
在本文所述之一些實施例中,過度產生眼淚係由個體之斯戈默評分升幅超過20 mm所指示。在本文所述之一些實施例中,過度產生眼淚係由以將不實用或非所需的量過度流淚指示。舉例而言,以將干擾個體之眼妝,或將導致個體擦去或經一組織吸收過量眼淚的量流淚皆為不實用及非所需的效應。 濕度In some embodiments described herein, excessive tear production is indicated by an increase in the individual's Sgormer score of more than 20 mm. In some embodiments described herein, excessive tear production is indicated by excessive tearing in an amount that will not be practical or undesirable. For example, tearing in amounts that will interfere with the individual's eye makeup or cause the individual to wipe off or absorb excessive tears through a tissue are both unpractical and undesirable effects. humidity
術語濕度可指相對濕度,其為給定溫度下之水蒸氣分壓與水之平衡蒸氣壓之比。相對濕度取決於所關注之系統之溫度及壓力。在低溫下需要較少水蒸氣以達到高相對濕度;在溫曖或熱空氣中需要更多水蒸氣以達到高相對濕度。在本文所述之一些實施例中,個體在測定個體評分(乾眼、斯戈默、角膜、OSDI)之間存在於相對濕度降低之環境中。The term humidity may refer to relative humidity, which is the ratio of the partial pressure of water vapor at a given temperature to the equilibrium vapor pressure of water. The relative humidity depends on the temperature and pressure of the system of interest. At low temperatures, less water vapor is required to achieve high relative humidity; more warm water or hot air is required to achieve high relative humidity. In some embodiments described herein, the individual is present in a reduced relative humidity environment between the determination of individual scores (dry eye, gosmer, cornea, OSDI).
在使用特定測試測定個體評分之間,個體可存在或暴露於經人工創造以不利地刺激個體之環境。舉例而言,個體可處於溫度、濕度、氣流經控制以創造不良條件之房間中。在另一實例中,個體可佩戴除濕鏡且其眼睛可經低相對濕度刺激。Between using specific tests to determine individual scores, the individual may be present or exposed to an environment created artificially to adversely stimulate the individual. For example, an individual may be in a room where temperature, humidity, and airflow are controlled to create undesirable conditions. In another example, an individual may wear a dehumidifying mirror and his eyes may be stimulated by low relative humidity.
在本文所述之一些實施例中,在測定個體之乾眼評分之間,在測定個體之斯戈默評分之間,在測定個體之角膜評分之間,及在測定個體之OSDI評分之間,個體存在於濕度降低之環境中。在本文所述之一些實施例中,在測定個體之乾眼評分之間,在測定個體之斯戈默評分之間,在測定個體之角膜評分之間,及在測定個體之OSDI評分之間,個體存在於濕度降低且溫度低於或高於室溫之環境中。在本文所述之一些實施例中,室溫下降低之相對濕度為小於40%、小於30%、小於20%、小於10%或小於5%。室溫在15℃(59℉)與25℃(77℉)之間。In some embodiments described herein, between measuring the individual's dry eye score, between measuring the individual's Sgormer score, between measuring the individual's corneal score, and between measuring the individual's OSDI score, The individual exists in an environment with reduced humidity. In some embodiments described herein, between measuring the individual's dry eye score, between measuring the individual's Sgormer score, between measuring the individual's corneal score, and between measuring the individual's OSDI score, The individual exists in an environment with reduced humidity and a temperature below or above room temperature. In some embodiments described herein, the reduced relative humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).
在本文所述之一些實施例中,室溫下降低之濕度為小於40%、小於30%、小於20%、小於10%或小於5%。室溫在15℃(59℉)與25℃(77℉)之間。 Cmax血漿濃度In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F). Cmax plasma concentration
本文所述之方法及用途包括局部鼻內投與。由於所揭示之方法及用途為局部鼻內投與,相較於自全身投與形式(例如攝入口服調配物)達成之濃度,循環血漿中nAChR促效劑或其醫藥學上可接受之鹽之濃度較低。nAChR促效劑之低血漿濃度避免與全身循環之nAChR促效劑相關之潛在非所需副作用,諸如噁心、睡眠障礙、便秘、胃腸氣積、嘔吐、皮膚病(如皮疹及瘙癢)、頭痛、腹痛、消化不良、胃食道逆流病及口乾。The methods and uses described herein include topical intranasal administration. Since the disclosed method and use is for local intranasal administration, compared to the concentration achieved from the systemic administration form (eg ingestion of oral formulations), the circulating plasma nAChR agonist or its pharmaceutically acceptable salt The concentration is lower. The low plasma concentration of nAChR agonists avoids potential undesirable side effects associated with systemic circulating nAChR agonists, such as nausea, sleep disorders, constipation, gastrointestinal gas, vomiting, skin diseases (such as rashes and itching), headaches, Abdominal pain, indigestion, gastroesophageal reflux disease and dry mouth.
一種表徵個體中nAChR促效劑或其醫藥學上可接受之鹽之血漿濃度的方法為量測在向個體投與nAChR促效劑或其醫藥學上可接受之鹽之後及在投與第二劑量之前,nAChR促效劑或其醫藥學上可接受之鹽達成之Cmax-最大或峰值血清濃度。測定Cmax之方法為此項技術中已知的。用於測定式I化合物之藥物動力學概況,包括測定Cmax之方案的非限制性實例提供於實例4中。A method for characterizing the plasma concentration of an nAChR agonist or its pharmaceutically acceptable salt in an individual is to measure after administering the nAChR agonist or its pharmaceutically acceptable salt to the individual and after administering the second Prior to the dose, the Cmax-maximum or peak serum concentration achieved by the nAChR agonist or its pharmaceutically acceptable salt. Methods for determining Cmax are known in the art. A non-limiting example of a protocol for determining the pharmacokinetics of the compound of Formula I, including the determination of Cmax is provided in Example 4.
在本文所述之一些實施例中,針對個體計算Cmax。在本文所述之一些實施例中,Cmax計算自兩個或更多位個體之平均Cmax。在本文所述之一些實施例中,Cmax計算自亞群之平均Cmax。In some embodiments described herein, Cmax is calculated for individuals. In some embodiments described herein, Cmax is calculated from the average Cmax of two or more individuals. In some embodiments described herein, Cmax is calculated from the average Cmax of the subgroup.
在本文所述之一些實施例中,有需要之個體之nAChR促效劑或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL、小於4 ng/mL、小於3 ng/mL或小於2 ng/mL。In some embodiments described herein, the plasma Cmax of nAChR agonists or pharmaceutically acceptable salts of individuals in need is less than 5 ng/mL, less than 4 ng/mL, less than 3 ng/mL or Less than 2 ng/mL.
在本文所述之一些實施例中,有需要之個體之nAChR促效劑或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL、小於4 ng/mL、小於3 ng/mL或小於2 ng/mL;且其中向有需要之個體投與包含以下之劑量:10微克至150微克、10微克至100微克、10微克至50微克、50微克至150微克、50微克至100微克、100微克至1500微克、100微克至600微克、150微克至300微克、200微克至400微克、400微克至600微克、750微克至1200微克、900微克至1200微克或2100至2400微克之nAChR促效劑,或對應量的其醫藥學上可接受之鹽。In some embodiments described herein, the plasma Cmax of nAChR agonists or pharmaceutically acceptable salts of individuals in need is less than 5 ng/mL, less than 4 ng/mL, less than 3 ng/mL or Less than 2 ng/mL; and in which the doses containing the following are administered to individuals in need: 10 μg to 150 μg, 10 μg to 100 μg, 10 μg to 50 μg, 50 μg to 150 μg, 50 μg to 100 μg, 100 μg to 1500 μg, 100 μg to 600 μg, 150 μg to 300 μg, 200 μg to 400 μg, 400 μg to 600 μg, 750 μg to 1200 μg, 900 μg to 1200 μg, or 2100 to 2400 μg Agent, or a corresponding amount of its pharmaceutically acceptable salt.
在本文所述之一些實施例中,有需要之個體之化合物1或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL、小於4 ng/mL、小於3 ng/mL或小於2 ng/mL;且其中向有需要之個體投與包含以下之劑量:100微克至1500微克、100微克至600微克、200微克至400微克、400微克至600微克或750微克至1200微克之化合物1,或對應量的其醫藥學上可接受之鹽。In some embodiments described herein, the plasma Cmax of
在本文所述之一些實施例中,有需要之個體之化合物1或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL、小於4 ng/mL、小於3 ng/mL或小於2 ng/mL;且其中向有需要之個體投與包含以下之劑量:150-300微克、900-1200微克或2100-2400微克,或對應量的其醫藥學上可接受之鹽。In some embodiments described herein, the plasma Cmax of
在本文所述之一些實施例中,有需要之個體之化合物1或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL;且其中向有需要之個體投與包含以下之劑量:150-300微克、900-1200微克或2100-2400微克,或對應量的其醫藥學上可接受之鹽。In some embodiments described herein, the plasma Cmax of
在本文所述之一些實施例中,個體之乾眼評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之乾眼評分。In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is based on the individual's dry eye determined after the administration of the first dose of an effective amount of
在本文所述之一些實施例中,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之乾眼評分。In some of the embodiments described herein, wherein the statistically significant decrease is based on the dry eye score of the individual determined after administration of an effective amount of one or more subsequent doses of
在本文所述之一些實施例中,該方法不包含向個體投與正向異位調節劑。In some embodiments described herein, the method does not include administering a positive ectopic modulator to the individual.
在本文所述之一些實施例中,比較化合物為Restasis®或Xiidra®。In some embodiments described herein, the comparative compound is Restasis® or Xiidra®.
本發明提供菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中該藥物用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,其中菸鹼乙醯膽鹼受體促效劑為化合物1或其醫藥學上可接受之鹽。The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production, or reduce eye discomfort for an individual in need. The choline receptor agonist is
本發明提供菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中藥物用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行藥理學刺激,其中菸鹼乙醯膽鹼受體促效劑為化合物1或其醫藥學上可接受之鹽。The invention provides the use of a nicotinic acetylcholine receptor agonist, which is used to manufacture a medicament, wherein the medicament is used for the nicotinic acetylcholine α4β2 receptor in an individual in need, or the nicotinic acetylcholine The base α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof performs pharmacological stimulation, wherein the nicotinic acetylcholine receptor agonist is
本發明提供菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中藥物用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行藥理學刺激,其中菸鹼乙醯膽鹼受體促效劑為化合物1或其醫藥學上可接受之鹽。The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of a medicament, wherein the medicament is used for the nicotinic acetylcholine α4β2 receptor in an individual in need, or the nicotinic acetylcholine Alkali α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, wherein the nicotinic acetylcholine receptor agonist is
本發明提供一種醫藥調配物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,該調配物包含化合物1或其醫藥學上可接受之鹽。The present invention provides a pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need. The formulation includes
本發明提供一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行藥理學刺激,其中調配物包含化合物1或其醫藥學上可接受之鹽。The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need or The combination is subjected to pharmacological stimulation, wherein the formulation contains
本發明提供一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行藥理學刺激,該調配物包含化合物1或其醫藥學上可接受之鹽。The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need, Or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, the formulation contains
在整個本發明中,在治療乾眼病、增加淚液產生及減少眼部不適之方法之情境內論述之各種實施例亦可適用於與用於製造藥物之化合物、用於各種方法之化合物及醫藥調配物相關之實施例。另外,在治療乾眼病、增加淚液產生及減少眼部不適之方法的情境內論述之各種實施例亦可適用於與對菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行藥理學刺激之方法相關之實施例。在對菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行藥理學刺激之方法的情境內論述之各種實施例亦可適用於與用於製造藥物之化合物、用於各種方法之化合物及醫藥調配物相關之實施例。Throughout the present invention, the various embodiments discussed in the context of methods for treating dry eye disease, increasing tear production, and reducing eye discomfort can also be applied to compounds used in the manufacture of drugs, compounds used in various methods, and pharmaceutical formulations Examples related to things. In addition, the various embodiments discussed in the context of a method for treating dry eye disease, increasing tear production, and reducing eye discomfort can also be applied to the receptor for nicotinic acetylcholine α4β2 or nicotinic acetylcholine α3β4. Examples of methods for pharmacological stimulation of the body, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof. Pharmacology of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor, or a combination thereof The various embodiments discussed in the context of stimulation methods can also be applied to embodiments related to compounds used in the manufacture of drugs, compounds used in various methods, and pharmaceutical formulations.
如本文用於描述個體評分之統計上顯著變化可計算自個體評分之增加或減少。測定個體評分變化是否統計上顯著及兩個資料集是否彼此顯著不同之非限制性實例包括基於ANCOVA模型之計算,及統計假設檢驗,諸如t-檢驗及非參數威爾科克森(Wilcoxon)秩和檢驗。涵蓋此項技術中熟知的其他模型及統計假設檢驗。Statistically significant changes as used herein to describe individual scores can be calculated from the increase or decrease in individual scores. Non-limiting examples of determining whether individual score changes are statistically significant and whether the two data sets are significantly different from each other include calculations based on the ANCOVA model, and statistical hypothesis tests, such as t-tests and nonparametric Wilcoxon ranks And inspection. Covers other models and statistical hypothesis testing well known in the art.
在整個本發明中,揭示之化合物1之量係指存在於調配物中之化合物1游離形式的量。如本文所用之術語「對應量」係指獲得調配物中所列舉之化合物1游離形式的量所需的化合物1之醫藥學上可接受之鹽的量。熟習此項技術者瞭解如何考量化合物之游離形式與鹽形式之間的分子量差,計算化合物之鹽的「對應量」,諸如化合物1之醫藥學上可接受之鹽的對應量。舉例而言,175.24 g化合物1游離鹼將對應於316.34 g半-半乳糖二酸鹽二水合物鹽或367.36 g單檸檬酸鹽。Throughout the present invention, the amount of
如本文所使用,術語「約」係與術語「大致地」同義地使用。說明性地,關於量使用術語「約」指示值略微超出列舉值,例如±0.1%至20%、±0.1%至10%、±0.1%至5%或±0.1%至2%。 例示性實施例As used herein, the term "about" is used synonymously with the term "substantially." Illustratively, the use of the term "about" to indicate an amount slightly exceeds the enumerated value, such as ±0.1% to 20%, ±0.1% to 10%, ±0.1% to 5%, or ±0.1% to 2%. Illustrative embodiment
實施例I-1. 一種對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法,其包含
向有需要之個體之鼻腔中投與有效量的具有以下結構之化合物1,
或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量;
其中該方法造成有效治療該有需要之個體。Example I-1. A method for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, which comprises administering an effective amount of
實施例I-2. 一種化合物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法,
其中該化合物為具有以下結構之化合物1,
或其醫藥學上可接受之鹽;
其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。Example I-2. A compound for a method for treating dry eye disease, increasing tear production or reducing eye discomfort in an individual in need thereof, wherein the compound is
實施例I-3. 如實施例I-2所使用之化合物,其中該方法造成有效治療該有需要之個體。Example I-3. The compound as used in Example I-2, wherein the method results in effective treatment of the individual in need.
實施例I-4. 如實施例I-1之方法或如實施例I-3所使用之化合物,其中個體之有效治療係藉由選自由以下組成之群的一或多種測試指示: a)根據視覺類比量表之乾眼評分測試, b)斯戈默測試, c)根據國家眼科研究所(NEI)分級系統之角膜螢光素染色測試,及 d)眼表面疾病指數測試。Example I-4. The method as in Example I-1 or the compound used in Example I-3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.
實施例I-5. 如實施例I-4之方法或所使用之化合物,其中有效治療係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;
b)接受投與對照物之個體的乾眼評分;或
c)接受投與比較化合物之個體的乾眼評分。Example I-5. As in the method of Example I-4 or the compound used, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is Measured after administering an effective amount of the first dose of
實施例I-6. 如實施例I-5之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少15%。Example I-6. As in the method of Example I-5 or the compound used, the statistically significant reduction in the individual's dry eye score is at least 15%.
實施例I-7. 如實施例I-5或實施例I-6之方法或所使用之化合物,其中個體之乾眼評分在統計上顯著下降10 mm與20 mm之間。Example I-7. As in the method of Example I-5 or Example I-6 or the compound used, the dry eye score of the individual statistically decreased between 10 mm and 20 mm.
實施例I-8. 如實施例I-5至I-7中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少10 mm。Example I-8. The method or the compound used as in any one of Examples I-5 to I-7, wherein the individual's dry eye score statistically decreases by at least 10 mm.
實施例I-9. 如實施例I-5至I-8中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少3 mm。Example I-9. The method or compound used in any one of Examples I-5 to I-8, wherein the statistically significant reduction in the individual's dry eye score is at least 3 mm.
實施例I-10. 如實施例I-5至I-9中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-10. The method or the compound used as in any one of Examples I-5 to I-9, wherein the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or more The p value of small, 0.005 or less or 0.001 or less is characterized.
實施例I-11. 如實施例I-5至I-10中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-11. The method or the compound used as in any one of Examples I-5 to I-10, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of
實施例I-12. 如實施例I-5至I-11中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-12. The method or the compound used as in any one of Examples I-5 to I-11, wherein the statistical evaluation of the individual's dry eye score significantly improves the self-administered effective amount of
實施例I-13. 如實施例I-5至I-11中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之乾眼評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之乾眼評分不增加超過10%。Example I-13. The method or the compound used as in any one of Examples I-5 to I-11, wherein compared to the administration of an effective amount of
實施例I-14. 如實施例I-12或I-13之方法或所使用之化合物,其中在測定個體之乾眼評分之間,個體存在於濕度降低之環境中。Example I-14. The method as in Example I-12 or I-13 or the compound used, in which the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.
實施例I-15. 如實施例I-1至I-14中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example I-15. The method or the compound used as in any one of Examples I-1 to I-14, wherein
實施例I-16. 如實施例I-5至I-15中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之乾眼評分。Example I-16. The method or the compound used as in any one of Examples I-5 to I-15, wherein the statistically significant decrease in the individual's dry eye score is based on administering an effective amount of
實施例I-17. 如實施例I-5至I-15中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之乾眼評分。Example I-17. The method or the compound used as in any one of Examples I-5 to I-15, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例I-18. 如實施例I-4至I-17中任一項之方法或所使用之化合物,其中有效治療係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之至少一隻眼睛之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之相同眼睛的斯戈默評分;
b)接受投與對照物之個體的斯戈默評分;或
c)接受投與比較化合物之個體的斯戈默評分。Example I-18. The method or compound used as in any one of Examples I-4 to I-17, wherein the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the individual's The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of
實施例I-19. 如實施例I-18之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少15%。Example I-19. As in the method of Example I-18 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 15%.
實施例I-20. 如實施例I-18或I-19之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升10 mm與20 mm之間。Example I-20. The method as in Example I-18 or I-19 or the compound used, wherein the individual's Sgormer score statistically significantly increased between 10 mm and 20 mm.
實施例I-21. 如實施例I-18或I-19之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少3 mm。Example I-21. The method as in Example I-18 or I-19 or the compound used, wherein the individual's Sgormer score statistically significantly increased by at least 3 mm.
實施例I-22. 如實施例I-18或I-19之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少10 mm。Example I-22. As in the method of Example I-18 or I-19 or the compound used, the individual's Sgormer score statistically significantly increased by at least 10 mm.
實施例I-23. 如實施例I-18至I-22中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-23. The method or the compound used in any one of Examples I-18 to I-22, wherein the statistically significant increase in the individual's Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.
實施例I-24. 如實施例I-18至I-23中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-24. The method or the compound used as in any one of Examples I-18 to I-23, wherein the statistically significant increase in the individual's Sgormer score is when administering an effective amount of
實施例I-25. 如實施例I-18至I-24中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-25. The method or the compound used as in any one of Examples I-18 to I-24, wherein the statistical improvement of the individual's Sgormer score significantly improves the self-administered effective amount of
實施例I-26. 如實施例I-18至I-24中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之斯戈默評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之斯戈默評分不減小超過10%。Example I-26. The method or the compound used as in any one of Examples I-18 to I-24, wherein compared to the administration of an effective amount of
實施例I-27. 如實施例I-18至I-26中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example I-27. The method or the compound used as in any one of Examples I-18 to I-26, wherein
實施例I-28. 如實施例I-18至I-27中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係基於在投與第一劑量之後測定的個體之斯戈默評分。Example I-28. The method or the compound used as in any one of Examples I-18 to I-27, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.
實施例I-29. 如實施例I-18至I-27中任一項之方法或所使用之化合物,其中統計上顯著上升係基於在投與化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之斯戈默評分。Example I-29. The method or the compound used as in any one of Examples I-18 to I-27, wherein the statistically significant increase is based on the administration of
實施例I-30. 如實施例I-4至29中任一項之方法或所使用之化合物,其中有效治療係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;
b)接受投與對照物之個體的角膜評分;或
c)接受投與比較化合物之個體的角膜評分。Example I-30. The method or the compound used as in any one of Examples I-4 to 29, wherein the effective treatment is indicated by a statistically significant decrease in the individual's corneal score, and wherein the individual's corneal score is statistically The significant decrease is determined after administering an effective amount of the first dose of
實施例I-31. 如實施例I-30之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降至少15%。Example I-31. As in the method of Example I-30 or the compound used, the statistically significant decrease in the individual's corneal score is at least 15%.
實施例I-32. 如實施例I-30或I-31之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-32. The method or the compound used as in Example I-30 or I-31, wherein the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例I-33. 如實施例I-30至I-32中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-33. The method or the compound used as in any one of Examples I-30 to I-32, wherein the statistically significant decrease in the individual's corneal score is when an effective amount of
實施例I-34. 如實施例I-30至I-33中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-34. The method or the compound used as in any one of Examples I-30 to I-33, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of
實施例I-35. 如實施例I-30至I-33中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之角膜評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之角膜評分不增加超過10%。Example I-35. The method or the compound used as in any one of Examples I-30 to I-33, wherein compared to the administration of an effective amount of
實施例I-36. 如實施例I-34或I-35之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example I-36. The method as in Example I-34 or I-35 or the compound used, in which the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例I-37. 如實施例I-30至I-36中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example I-37. The method or the compound used as in any one of Examples I-30 to I-36, wherein
實施例I-38. 如實施例I-30至I-37中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之角膜評分。Example I-38. The method or the compound used as in any one of Examples I-30 to I-37, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of
實施例I-39. 如實施例I-30至I-37中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之角膜評分。Example I-39. The method or the compound used as in any one of Examples I-30 to I-37, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例I-40. 如實施例I-4至I-39中任一項之方法或所使用之化合物,其中有效治療係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;
b)接受投與對照物之個體的OSDI評分;或
c)接受投與比較化合物之個體的OSDI評分。Example I-40. The method or the compound used as in any one of Examples I-4 to I-39, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the individual's OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of
實施例I-41. 如實施例I-40之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降至少15%。Example I-41. As in the method of Example I-40 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.
實施例I-42. 如實施例I-40或I-41之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-42. The method or the compound used as in Example I-40 or I-41, wherein the statistically significant decrease in the individual's OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例I-43. 如實施例I-40至I-42中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-43. The method or the compound used as in any one of Examples I-40 to I-42, wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of
實施例I-44. 如實施例I-40至I-43中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-44. The method or the compound used as in any one of Examples I-40 to I-43, wherein the statistically significant improvement in the individual's OSDI score improves the self-administered effective amount of
實施例I-45. 如實施例I-40至I-43中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之OSDI評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之OSDI評分不增加超過10%。Embodiment I-45. The method or the compound used as in any one of Embodiments I-40 to I-43, wherein compared to the administration of an effective amount of
實施例I-46. 如實施例I-44或I-45之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example I-46. The method or the compound used as in Example I-44 or I-45, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例I-47. 如實施例I-40至I-46中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example I-47. The method or the compound used as in any one of Examples I-40 to I-46, wherein
實施例I-48. 如實施例I-40至I-47中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之OSDI評分。Example I-48. The method or the compound used as in any one of Examples I-40 to I-47, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of
實施例I-49. 如實施例I-40至I-47中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之OSDI評分。Example I-49. The method or the compound used as in any one of Examples I-40 to I-47, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例I-50. 一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法,其包含
向有需要之個體之鼻腔中投與有效量的具有以下結構之化合物1,
或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量。Example I-50. A nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor or a combination thereof in an individual in need A method for immediate and long-term pharmacological stimulation, which comprises administering an effective amount of
實施例I-51. 一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行立即及長期藥理學刺激之方法的化合物,
其中該化合物為具有以下結構之化合物1,
或其醫藥學上可接受之鹽;
其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。Example I-51. A nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor or a combination thereof in an individual in need A compound for immediate and long-term pharmacological stimulation, wherein the compound is
實施例I-52. 如實施例I-50之方法或如實施例I-51所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由選自由以下組成之群的一或多種測試指示: a)根據視覺類比量表之乾眼評分測試, b)斯戈默測試, c)根據國家眼科研究所(NEI)分級系統之角膜螢光素染色測試,及 d)眼表面疾病指數測試。Example I-52. The method as in Example I-50 or the compound as used in Example I-51, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 receptor in the individual , Or the pharmacological stimulation of the nicotinic acetylcholine α3α5β4 receptor or a combination thereof is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.
實施例I-53. 如實施例I-52之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;
b)接受投與對照物之個體的乾眼評分;或
c)接受投與比較化合物之個體的乾眼評分。Example I-53. The method or the compound used in Example I-52, wherein the nicotinic acetylcholine α4β2 receptor in the individual, or the nicotinic acetylcholine α3β4 receptor, or nicotinic acetylacetate The pharmacological stimulation of the choline α3α5β4 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is when the individual is administered an effective amount of
實施例I-54. 如實施例I-53之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少15%。Example I-54. As in the method of Example I-53 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 15%.
實施例I-55. 如實施例I-53或I-54之方法或所使用之化合物,其中個體之乾眼評分在統計上顯著下降10 mm與20 mm之間。Example I-55. As in the method of Example I-53 or I-54 or the compound used, the individual's dry eye score statistically decreased between 10 mm and 20 mm.
實施例I-56. 如實施例I-53或I-54之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少10 mm。Example I-56. As in the method of Example I-53 or I-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 10 mm.
實施例I-57. 如實施例I-53或I-54之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少3 mm。Example I-57. As in the method of Example I-53 or I-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 3 mm.
實施例I-58. 如實施例I-53或I-54之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-58. The method or the compound used as in Example I-53 or I-54, wherein the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or less, 0.005 or A p value of less or 0.001 or less is characterized.
實施例I-59. 如實施例I-53至I-58中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-59. The method or the compound used as in any one of Examples I-53 to I-58, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of
實施例I-60. 如實施例I-53至I-59中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-60. The method or the compound used as in any one of Examples I-53 to I-59, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of
實施例I-61. 如實施例I-53至I-59中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之乾眼評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之乾眼評分不增加超過10%。Embodiment I-61. The method or the compound used as in any one of Embodiments I-53 to I-59, wherein compared to the administration of an effective amount of
實施例I-62. 如實施例I-60或I-61之方法或所使用之化合物,其中在測定個體之乾眼評分之間,個體存在於濕度降低之環境中。Example I-62. The method as in Example I-60 or I-61 or the compound used, wherein the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.
實施例I-63. 如實施例I-53至I-62中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example I-63. The method or the compound used as in any one of Examples I-53 to I-62, wherein
實施例I-64. 如實施例I-53至I-63中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之乾眼評分。Example I-64. The method or the compound used as in any one of Examples I-53 to I-63, wherein the statistically significant decrease in the individual's dry eye score is based on administering an effective amount of
實施例I-65. 如實施例I-53至I-63中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之乾眼評分。Example I-65. The method or the compound used as in any one of Examples I-53 to I-63, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例I-66. 如實施例I-52至I-65中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之至少一隻眼睛之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之相同眼睛的斯戈默評分;
b)接受投與對照物之個體的斯戈默評分;或
c)接受投與比較化合物之個體的斯戈默評分。Embodiment I-66. The method or the compound used as in any one of Embodiments I-52 to I-65, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof, is indicated by a statistically significant increase in the individual's Sgormer score, and the statistics of the Sgormer score in at least one eye of the individual The significant increase is determined after administering an effective amount of the first dose of
實施例I-67. 如實施例I-66之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少15%。Example I-67. As in the method of Example I-66 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 15%.
實施例I-68. 如實施例I-66或I-67之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升10 mm與20 mm之間。Example I-68. As in the method of Example I-66 or I-67 or the compound used, the Sgormer score of the individual statistically increased between 10 mm and 20 mm.
實施例I-69. 如實施例I-66或I-67之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少3 mm。Example I-69. As in the method of Example I-66 or I-67 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 3 mm.
實施例I-70. 如實施例I-66或I-67之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少10 mm。Example I-70. As in the method of Example I-66 or I-67 or the compound used, the individual's Sgormer score increases statistically significantly by at least 10 mm.
實施例I-71. 如實施例I-66至I-70中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-71. The method or the compound used as in any one of Examples I-66 to I-70, wherein the statistically significant increase in the individual's Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.
實施例I-72. 如實施例I-66至I-71中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-72. The method or the compound used as in any one of Examples I-66 to I-71, wherein the statistically significant increase in the individual's Sgormer score is when administering an effective amount of
實施例I-73. 如實施例I-66至I-72中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-73. The method or the compound used as in any one of Examples I-66 to I-72, wherein the statistical increase in the individual’s Sgormer score significantly improves the self-administered effective amount of
實施例I-74. 如實施例I-66至I-72中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之斯戈默評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之斯戈默評分不減小超過10%。Embodiment I-74. The method or the compound used as in any one of Embodiments I-66 to I-72, wherein compared to the administration of an effective amount of
實施例I-75. 如實施例I-66至I-74中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Embodiment I-75. The method or the compound used as in any one of Embodiments I-66 to I-74, wherein administration of
實施例I-76. 如實施例I-66至I-75中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係基於在投與第一劑量之後測定的個體之斯戈默評分。Example I-76. The method or the compound used as in any one of Examples I-66 to I-75, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.
實施例I-77. 如實施例I-66至I-75中任一項之方法或所使用之化合物,其中統計上顯著上升係基於在投與化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之斯戈默評分。Example I-77. The method or the compound used as in any one of Examples I-66 to I-75, wherein the statistically significant increase is based on the administration of
實施例I-78. 如實施例I-52至I-77中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;
b)接受投與對照物之個體的角膜評分;或
c)接受投與比較化合物之個體的角膜評分。Embodiment I-78. The method or the compound used as in any one of Embodiments I-52 to I-77, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof, is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is administered to the individual An effective amount of the first dose of
實施例I-79. 如實施例I-78之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降至少15%。Example I-79. As in the method of Example I-78 or the compound used, a statistically significant decrease in the individual's corneal score is at least 15%.
實施例I-80. 如實施例I-78或I-79之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-80. The method or the compound used as in Example I-78 or I-79, wherein the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例I-81. 如實施例I-78至I-80中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-81. The method or the compound used as in any one of Examples I-78 to I-80, wherein the statistically significant decrease in the individual's corneal score is when an effective amount of
實施例I-82. 如實施例I-78至I-81中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-82. The method or the compound used as in any one of Examples I-78 to I-81, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of
實施例I-83. 如實施例I-78至I-81中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之角膜評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之角膜評分不增加超過10%。Embodiment I-83. The method or the compound used as in any one of Embodiments I-78 to I-81, wherein compared to the administration of an effective amount of
實施例I-84. 如實施例I-82或I-83之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example I-84. The method or the compound used as in Example I-82 or I-83, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例I-85. 如實施例I-78至I-84中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example I-85. The method or the compound used as in any one of Examples I-78 to I-84, wherein
實施例I-86. 如實施例I-78至I-85中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之角膜評分。Example I-86. The method or the compound used as in any one of Examples I-78 to I-85, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of
實施例I-87. 如實施例I-78至I-85中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續之後測定的個體之角膜評分。Example I-87. The method or the compound used as in any one of Examples I-78 to I-85, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例I-88. 如實施例I-52至I-87中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合之藥理學刺激係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;
b)接受投與對照物之個體的OSDI評分;或
c)接受投與比較化合物之個體的OSDI評分。Embodiment I-88. The method or the compound used as in any one of Embodiments I-52 to I-87, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof, is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is when administered to the individual The effective amount of the first dose of
實施例I-89. 如實施例I-88之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降至少15%。Example I-89. As in the method of Example I-88 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.
實施例I-90. 如實施例I-88或I-89之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example I-90. The method or compound used as in Example I-88 or I-89, wherein the statistically significant decrease in the individual's OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例I-91. 如實施例I-88至I-90中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example I-91. The method or the compound used as in any one of Examples I-88 to I-90, wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of
實施例I-92. 如實施例I-88至I-91中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example I-92. The method or the compound used as in any one of Examples I-88 to I-91, wherein the statistically significant improvement of the individual's OSDI score improves the self-administered effective amount of
實施例I-93. 如實施例I-88至I-91中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之OSDI評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之OSDI評分不增加超過10%。Embodiment I-93. The method or the compound used as in any one of Embodiments I-88 to I-91, wherein compared to the administration of an effective amount of
實施例I-94. 如實施例I-92或I-93之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example I-94. The method as in Example I-92 or I-93 or the compound used, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例I-95. 如實施例I-88至I-94中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Embodiment I-95. The method or the compound used as in any one of Embodiments I-88 to I-94, wherein administration of
實施例I-96. 如實施例I-88至I-95中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之OSDI評分。Example I-96. The method or the compound used as in any one of Examples I-88 to I-95, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of
實施例I-97. 如實施例I-88至I-95中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之OSDI評分。Example I-97. The method or the compound used as in any one of Examples I-88 to I-95, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例I-98. 如實施例I-50至I-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α4β2受體受到藥理學刺激。Example I-98. The method or the compound used as in any one of Examples I-50 to I-97, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated.
實施例I-99. 如實施例I-50至I-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α3β4受體受到藥理學刺激。Embodiment I-99. The method or the compound used as in any one of Embodiments I-50 to I-97, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated.
實施例I-100. 如實施例I-50至I-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α3α5β4受體受到藥理學刺激。Embodiment I-100. The method or the compound used as in any one of Embodiments I-50 to I-97, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated.
實施例I-101. 如實施例I-1至I-100中任一項之方法或所使用之化合物,其中每劑量5-4000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Embodiment I-101. The method or the compound used in any one of Embodiments I-1 to I-100, wherein 5-4000 micrograms of
實施例I-102. 如實施例I-1至I-100中任一項之方法或所使用之化合物,其中每劑量900-3000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Embodiment I-102. The method or the compound used as in any one of Embodiments I-1 to I-100, wherein 900-3000 micrograms of
實施例I-103. 如實施例I-1至I-100中任一項之方法或所使用之化合物,其中每劑量1000-2500微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Embodiment I-103. The method or the compound used as in any one of Embodiments I-1 to I-100, wherein 1000-2500 micrograms of
實施例I-104. 如實施例I-1至I-100中任一項之方法或所使用之化合物,其中每劑量1500-3000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Embodiment I-104. The method or the compound used as in any one of Embodiments I-1 to I-100, wherein each dose of 1500-3000 micrograms of
實施例I-105. 如實施例I-1至I-104中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為50-250微升。Embodiment I-105. The method or the compound used as in any one of Embodiments I-1 to I-104, wherein
實施例I-106. 如實施例I-1至I-104中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為150-250微升。Embodiment I-106. The method or the compound used as in any one of Embodiments I-1 to I-104, wherein
實施例I-107. 如實施例I-1至I-106中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,該醫藥調配物包含1 mg/mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。Embodiment I-107. The method or the compound used as in any one of Embodiments I-1 to I-106, wherein
實施例I-108. 如實施例I-105至I-107中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每個鼻孔投與之醫藥調配物的總體積為50-250微升。Embodiment I-108. The method or the compound used as in any one of Embodiments I-105 to I-107, wherein
實施例I-109. 如實施例I-1至I-108中任一項之方法或所使用之化合物,其中化合物1為醫藥學上可接受之鹽。Embodiment I-109. The method or the compound used as in any one of Embodiments I-1 to I-108, wherein
實施例I-110. 如實施例I-1至I-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後每天一至四次地向有需要之個體投與。Example I-110. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need one to four times a day after the first day of administration.
實施例I-111. 如實施例I-1至I-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天一次地向有需要之個體投與。Example I-111. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need once a day after the first day of administration.
實施例I-112. 如實施例I-1至I-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天兩次地向有需要之個體投與。Example I-112. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need twice a day after the first day of administration.
實施例I-113. 如實施例I-1至I-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天三次地向有需要之個體投與。Example I-113. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need three times a day after the first day of administration.
實施例I-114. 如實施例I-1至I-109中任一項之方法或所使用之化合物,其中
a)向個體投與之化合物1或其醫藥學上可接受之鹽之劑量頻率隨時間推移降低,或
b)每劑量之化合物1之總量,或其醫藥學上可接受之鹽之對應量隨時間推移減少。Embodiment I-114. The method or the compound used as in any one of Embodiments I-1 to I-109, wherein
a) The frequency of doses of
實施例I-115. 如實施例I-114之方法或所使用之化合物,其中各劑量包含向該個體之鼻腔中投與超過一次化合物1或其醫藥學上可接受之鹽,且其中隨時間推移來減少每劑量之化合物1之總量或其醫藥學上可接受之鹽之對應量係藉由減少向該個體之鼻腔中投與化合物1或其醫藥學上可接受之鹽的次數來實現。Example I-115. The method or compound used as in Example I-114, wherein each dose comprises administering
實施例I-116. 如實施例I-1至I-115中任一項之方法或所使用之化合物,其中劑量包含向一個或兩個鼻孔多次投與化合物1或其醫藥學上可接受之鹽。Embodiment I-116. The method or the compound used as in any one of Embodiments I-1 to I-115, wherein the dose comprises multiple administrations of
實施例I-117. 如實施例I-1至I-115中任一項之方法或所使用之化合物,其中劑量包含向一個或兩個鼻孔單次投與化合物1或其醫藥學上可接受之鹽。Embodiment I-117. The method or the compound used as in any one of Embodiments I-1 to I-115, wherein the dosage comprises a single administration of
實施例I-118. 如實施例I-1至I-117中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係每劑量向一個鼻孔投與。Embodiment I-118. The method or the compound used as in any one of Embodiments I-1 to I-117, wherein
實施例I-119. 如實施例I-1至I-117中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係每劑量向兩個鼻孔投與。Example I-119. The method or the compound used as in any one of Examples I-1 to I-117, wherein
實施例I-120. 如實施例I-1至I-119中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係投與至少28天。Embodiment I-120. The method or the compound used as in any one of Embodiments I-1 to I-119, wherein
實施例I-121. 如實施例I-1至I-119中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係投與至少3個月。Embodiment I-121. The method or the compound used as in any one of Embodiments I-1 to I-119, wherein
實施例I-122. 如實施例I-1至I-121中任一項之方法或所使用之化合物,其中該個體已在2週內進行Lasik手術或預定在2週內進行Lasik手術。Embodiment I-122. The method or the compound used as in any one of Embodiments I-1 to I-121, wherein the individual has undergone Lasik surgery within 2 weeks or is scheduled to undergo Lasik surgery within 2 weeks.
實施例I-123. 如實施例I-1至I-122中任一項之方法或所使用之化合物,其中該個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。Embodiment I-123. The method or the compound used as in any one of Embodiments I-1 to I-122, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, Cough, throat irritation, drip irritation, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.
實施例I-124. 如實施例I-123之方法或所使用之化合物,其中在投與第一劑量或一或多個後續劑量之5分鐘-60分鐘內,個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。Example I-124. The method or the compound used as in Example I-123, wherein within 5-60 minutes of administration of the first dose or one or more subsequent doses, the individual does not experience One or more side effects of the group: excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, irritation of the nose, toothache, dry mouth and headache.
實施例I-125. 如實施例I-1至I-124中任一項之方法或所使用之化合物,其中過度產生眼淚係由個體之斯戈默評分升幅超過20 mm所指示。Example I-125. The method or the compound used as in any one of Examples I-1 to I-124, wherein excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm.
實施例I-126. 如實施例I-1至I-125中任一項之方法或所使用之化合物,其中該方法不包含向個體投與正向異位調節劑。Embodiment I-126. The method or the compound used as in any one of Embodiments I-1 to I-125, wherein the method does not include administering a positive ectopic modulator to the individual.
實施例I-127. 一種菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中該藥物用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,其中菸鹼乙醯膽鹼受體促效劑為具有以下結構之化合物1, 或其醫藥學上可接受之鹽。Example I-127. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production or reduce eye discomfort for individuals in need, The nicotinic acetylcholine receptor agonist is compound 1 with the following structure , Or a pharmaceutically acceptable salt thereof.
實施例I-128. 一種菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中該藥物用於刺激有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合,其中菸鹼乙醯膽鹼受體促效劑為具有以下結構之化合物1,
或其醫藥學上可接受之鹽。Example I-128. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or Nicotine acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist is a compound having the following
實施例I-129. 一種醫藥調配物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,該調配物包含具有以下結構之化合物1,
或其醫藥學上可接受之鹽。Embodiment I-129. A pharmaceutical formulation for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, the formulation comprises
實施例I-130. 如實施例I-129之醫藥調配物,其中該用途包含如實施例I-1至I-128中任一項所定義之方法。Embodiment I-130. The pharmaceutical formulation of Embodiment I-129, wherein the use comprises the method as defined in any one of Embodiments I-1 to I-128.
實施例I-131. 一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體,或菸鹼乙醯膽鹼α3β4受體,或菸鹼乙醯膽鹼α3α5β4受體或其組合進行藥理學刺激,該調配物包含具有以下結構之化合物1,
或其醫藥學上可接受之鹽。Example I-131. A pharmaceutical formulation for the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 in an individual in need Receptor or a combination thereof for pharmacological stimulation, the formulation contains
實施例I-132. 如實施例I-131所使用之醫藥調配物,其中該調配物包含如實施例I-1至I-130,或II-1至II-4中任一項所定義之化合物。Embodiment I-132. The pharmaceutical formulation as used in Embodiment I-131, wherein the formulation comprises as defined in any one of Embodiments I-1 to I-130, or II-1 to II-4 Compound.
實施例II-1. 如實施例I-1至I-126中任一項之方法或所使用之化合物,其中有需要之個體之化合物1或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL。Example II-1. The method or the compound used as in any one of Examples I-1 to I-126, wherein the plasma Cmax of
實施例II-2. 如實施例I-1至I-126或II-1中任一項之方法或所使用之化合物,其中每劑量150-300微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example II-2. The method or the compound used in any one of Examples I-1 to I-126 or II-1, wherein each dose of 150-300 micrograms of
實施例II-3. 如實施例I-1至I-126或II-1中任一項之方法或所使用之化合物,其中每劑量900-1200微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example II-3. The method or the compound used as in any one of Examples I-1 to I-126 or II-1, wherein 900-1200 micrograms of
實施例II-4. 如實施例I-1至I-126或II-1中任一項之方法或所使用之化合物,其中每劑量900-1200微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example II-4. The method or the compound used as in any one of Examples I-1 to I-126 or II-1, wherein 900-1200 micrograms of
實施例III-1. 一種對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法,其包含
向有需要之個體之鼻腔中投與有效量的具有以下結構之化合物1,
或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量;
其中該方法造成有效治療該有需要之個體。Example III-1. A method for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, which comprises administering an effective amount of
實施例III-2. 一種化合物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法,
其中該化合物為具有以下結構之化合物1,
或其醫藥學上可接受之鹽;
其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。Example III-2. A compound for a method for treating dry eye disease, increasing tear production, or reducing eye discomfort in an individual in need thereof, wherein the compound is
實施例III-3. 如實施例III-2所使用之化合物,其中該方法造成有效治療該有需要之個體。Example III-3. The compound as used in Example III-2, wherein the method results in effective treatment of the individual in need.
實施例III-4. 如實施例III-1之方法或如實施例III-3所使用之化合物,其中個體之有效治療係藉由選自由以下組成之群的一或多種測試指示: a)根據視覺類比量表之乾眼評分測試, b)斯戈默測試, c)根據國家眼科研究所(NEI)分級系統之角膜螢光素染色測試,及 d)眼表面疾病指數測試。Example III-4. The method as in Example III-1 or the compound as in Example III-3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.
實施例III-5. 如實施例III-4之方法或所使用之化合物,其中有效治療係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;
b)接受投與對照物之個體的乾眼評分;或
c)接受投與比較化合物之個體的乾眼評分。Example III-5. The method or compound used as in Example III-4, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is Measured after administering an effective amount of the first dose of
實施例III-6. 如實施例III-5之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少15%。Example III-6. The method as in Example III-5 or the compound used, wherein the individual's dry eye score is statistically significantly reduced by at least 15%.
實施例III-7. 如實施例III-5或III-6之方法或所使用之化合物,其中個體之乾眼評分在統計上顯著下降10 mm與20 mm之間。Example III-7. The method as in Example III-5 or III-6 or the compound used, wherein the individual's dry eye score statistically decreased between 10 mm and 20 mm.
實施例III-8. 如實施例III-5至III-7中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少10 mm。Example III-8. The method or the compound used as in any one of Examples III-5 to III-7, wherein the statistically significant decrease in the individual's dry eye score is at least 10 mm.
實施例III-9. 如實施例III-5至III-8中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少3 mm。Example III-9. The method or the compound used as in any one of Examples III-5 to III-8, wherein the statistically significant decrease in the individual's dry eye score is at least 3 mm.
實施例III-10. 如實施例III-5至III-9中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-10. The method or the compound used as in any one of Examples III-5 to III-9, wherein the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or more The p value of small, 0.005 or less or 0.001 or less is characterized.
實施例III-11. 如實施例III-5至III-10中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-11. The method or the compound used as in any one of Examples III-5 to III-10, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of
實施例III-12. 如實施例III-5至III-11中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-12. The method or the compound used as in any one of Examples III-5 to III-11, wherein the statistical evaluation of the individual's dry eye score significantly improves the self-administered effective amount of
實施例III-13. 如實施例III-5至III-11中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之乾眼評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之乾眼評分不增加超過10%。Example III-13. The method or the compound used in any one of Examples III-5 to III-11, wherein compared to the administration of an effective amount of
實施例III-14. 如實施例III-12或III-13之方法或所使用之化合物,其中在測定個體之乾眼評分之間,個體存在於濕度降低之環境中。Example III-14. As in the method of Example III-12 or III-13 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.
實施例III-15. 如實施例III-1至III-14中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-15. The method or the compound used as in any one of Examples III-1 to III-14, wherein
實施例III-16. 如實施例III-5至III-15中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之乾眼評分。Example III-16. The method or compound used in any one of Examples III-5 to III-15, wherein the statistically significant decrease in the individual's dry eye score is based on the administration of an effective amount of
實施例III-17. 如實施例III-5至III-15中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之乾眼評分。Example III-17. The method or the compound used in any one of Examples III-5 to III-15, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例III-18. 如實施例III-4至III-17中任一項之方法或所使用之化合物,其中有效治療係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之至少一隻眼睛之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之相同眼睛的斯戈默評分;
b)接受投與對照物之個體的斯戈默評分;或
c)接受投與比較化合物之個體的斯戈默評分。Example III-18. The method or compound used in any one of Examples III-4 to III-17, wherein the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the individual's The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of
實施例III-19. 如實施例I-18之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少15%。Example III-19. As in the method of Example I-18 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 15%.
實施例III-20. 如實施例III-18或III-19之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升10 mm與20 mm之間。Example III-20. As in the method of Example III-18 or III-19 or the compound used, the Sgormer score of the individual increases statistically significantly between 10 mm and 20 mm.
實施例III-21. 如實施例III-18或III-19之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少3 mm。Example III-21. As in the method of Example III-18 or III-19 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 3 mm.
實施例III-22. 如實施例III-18或III-19之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少10 mm。Example III-22. As in the method of Example III-18 or III-19 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 10 mm.
實施例III-23. 如實施例III-18至III-22中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-23. The method or compound used in any one of Examples III-18 to III-22, wherein the statistically significant increase in the individual’s Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.
實施例III-24. 如實施例III-18至III-23中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-24. The method or the compound used in any one of Examples III-18 to III-23, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of
實施例III-25. 如實施例III-18至III-24中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-25. The method or the compound used in any one of Examples III-18 to III-24, wherein the individual's Sgormer score statistically significantly improves the self-administered effective amount of
實施例III-26. 如實施例III-18至III-24中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之斯戈默評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之斯戈默評分不減小超過10%。Example III-26. The method or the compound used as in any one of Examples III-18 to III-24, wherein compared to the administration of an effective amount of
實施例III-27. 如實施例III-18至III-26中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-27. The method or the compound used as in any one of Examples III-18 to III-26, wherein
實施例III-28. 如實施例III-18至III-27中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係基於在投與第一劑量之後測定的個體之斯戈默評分。Example III-28. The method or the compound used as in any one of Examples III-18 to III-27, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.
實施例III-29. 如實施例III-18至III-27中任一項之方法或所使用之化合物,其中統計上顯著上升係基於在投與化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之斯戈默評分。Example III-29. The method or compound used in any one of Examples III-18 to III-27, wherein the statistically significant increase is based on the administration of
實施例III-30. 如實施例III-4至III-29中任一項之方法或所使用之化合物,其中有效治療係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;
b)接受投與對照物之個體的角膜評分;或
c)接受投與比較化合物之個體的角膜評分。Example III-30. The method or compound used in any one of Examples III-4 to III-29, wherein the effective treatment is indicated by a statistically significant drop in the individual's corneal score, and wherein the individual's corneal score The statistically significant decrease is determined after administering an effective amount of the first dose of
實施例III-31. 如實施例III-30之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降至少15%。Example III-31. As in the method of Example III-30 or the compound used, the individual's corneal score statistically decreased by at least 15%.
實施例III-32. 如實施例III-30或III-31之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-32. The method or compound used in Example III-30 or III-31, wherein the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例III-33. 如實施例III-30至III-32中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-33. The method or the compound used in any one of Examples III-30 to III-32, wherein the statistically significant decrease in the individual's corneal score is due to the administration of an effective amount of
實施例III-34. 如實施例III-30至III-33中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-34. The method or the compound used in any one of Examples III-30 to III-33, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of
實施例III-35. 如實施例III-30至III-33中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之角膜評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之角膜評分不增加超過10%。Example III-35. The method or the compound used as in any one of Examples III-30 to III-33, wherein compared to the administration of an effective amount of
實施例III-36. 如實施例III-34或III-35之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example III-36. As in the method of Example III-34 or III-35 or the compound used, between the determination of the individual's corneal score, the individual is present in an environment with reduced humidity.
實施例III-37. 如實施例III-30至III-36中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-37. The method or the compound used as in any one of Examples III-30 to III-36, wherein
實施例III-38. 如實施例III-30至III-37中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之角膜評分。Example III-38. The method or the compound used in any one of Examples III-30 to III-37, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of
實施例III-39. 如實施例III-30至III-37中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續之後測定的個體之角膜評分。Example III-39. The method or the compound used as in any of Examples III-30 to III-37, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例III-40. 如實施例III-4至III-39中任一項之方法或所使用之化合物,其中有效治療係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;
b)接受投與對照物之個體的OSDI評分;或
c)接受投與比較化合物之個體的OSDI評分。Example III-40. The method or the compound used in any one of Examples III-4 to III-39, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the individual's OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of
實施例III-41. 如實施例III-40之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降至少15%。Example III-41. As in the method of Example III-40 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.
實施例III-42. 如實施例III-40或III-41之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-42. The method or compound used in Example III-40 or III-41, wherein the statistically significant decrease in the individual’s OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例III-43. 如實施例III-40至III-42中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-43. The method or the compound used in any one of Examples III-40 to III-42, wherein the statistically significant decrease in the individual's OSDI score is the administration of an effective amount of
實施例III-44. 如實施例III-40至III-43中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-44. The method or the compound used in any one of Examples III-40 to III-43, wherein the statistically significant improvement in the individual's OSDI score improves the self-administered effective amount of
實施例III-45. 如實施例III-40至III-43中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之OSDI評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之OSDI評分不增加超過10%。Example III-45. The method or the compound used in any one of Examples III-40 to III-43, wherein compared to the administration of an effective amount of
實施例III-46. 如實施例III-44或III-45之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example III-46. As in the method of Example III-44 or III-45 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例III-47. 如實施例III-40至III-46中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-47. The method or the compound used as in any one of Examples III-40 to III-46, wherein
實施例III-48. 如實施例III-40至III-47中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之OSDI評分。Example III-48. The method or compound used in any one of Examples III-40 to III-47, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of
實施例III-49. 如實施例III-40至III-47中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之OSDI評分。Example III-49. The method or the compound used as in any one of Examples III-40 to III-47, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例III-50. 一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法,其包含
向有需要之個體之鼻腔中投與有效量的具有以下結構之化合物1,
或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量。Example III-50. For use in individuals in need of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco Method for immediate and long-term pharmacological stimulation of the base acetylcholine α4α6β2 receptor or a combination thereof, which comprises administering an effective amount of
實施例III-51. 一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法的化合物,
其中該化合物為具有以下結構之化合物1,
或其醫藥學上可接受之鹽;
其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。Example III-51. For use in individuals in need of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco Alkaline acetylcholine α4α6β2 receptor or a combination thereof for immediate and long-term pharmacological stimulation of the compound, wherein the compound is
實施例III-52. 如實施例III-50之方法或如實施例III-51所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由選自由以下組成之群的一或多種測試指示: a)根據視覺類比量表之乾眼評分測試, b)斯戈默測試, c)根據國家眼科研究所(NEI)分級系統之角膜螢光素染色測試,及 d)眼表面疾病指數測試。Example III-52. The compound as in the method of Example III-50 or the compound used in Example III-51, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 receptor in the individual , Or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof, the pharmacological stimulation is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.
實施例III-53. 如實施例III-52之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;
b)接受投與對照物之個體的乾眼評分;或
c)接受投與比較化合物之個體的乾眼評分。Example III-53. The method as in Example III-52 or the compound used in which the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylate in the individual The pharmacological stimulation of the choline α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and the statistically significant decrease in the individual's dry eye score is Determined after administering an effective amount of the first dose of
實施例III-54. 如實施例III-53之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少15%。Example III-54. As in the method of Example III-53 or the compound used, the statistically significant reduction in the individual's dry eye score is at least 15%.
實施例III-55. 如實施例III-53或III-54之方法或所使用之化合物,其中個體之乾眼評分在統計上顯著下降10 mm與20 mm之間。Example III-55. As in the method of Example III-53 or III-54 or the compound used, the individual's dry eye score statistically decreased between 10 mm and 20 mm.
實施例III-56. 如實施例III-53或III-54之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少10 mm。Example III-56. As in the method of Example III-53 or III-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 10 mm.
實施例III-57. 如實施例III-53或III-54之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少3 mm。Example III-57. As in the method of Example III-53 or III-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 3 mm.
實施例III-58. 如實施例III-53或III-54之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-58. As in the method of Example III-53 or III-54 or the compound used, the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or less, 0.005 or A p value of less or 0.001 or less is characterized.
實施例III-59. 如實施例III-53至III-58中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-59. The method or the compound used as in any one of Examples III-53 to III-58, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of
實施例III-60. 如實施例III-53至III-59中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-60. The method or the compound used in any one of Examples III-53 to III-59, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of
實施例III-61. 如實施例III-53至III-59中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之乾眼評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之乾眼評分不增加超過10%。Example III-61. The method or the compound used as in any one of Examples III-53 to III-59, wherein compared to the first step of administering an effective amount of
實施例III-62. 如實施例III-60或III-61之方法或所使用之化合物,其中在測定個體之乾眼評分之間,個體存在於濕度降低之環境中。Example III-62. The method as in Example III-60 or III-61 or the compound used, where the individual exists in an environment with reduced humidity between the determination of the individual's dry eye score.
實施例III-63. 如實施例III-53至III-62中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-63. The method or the compound used as in any one of Examples III-53 to III-62, wherein
實施例III-64. 如實施例III-53至III-63中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之乾眼評分。Example III-64. The method or the compound used as in any one of Examples III-53 to III-63, wherein the statistically significant decrease in the individual's dry eye score is based on the administration of an effective amount of
實施例III-65. 如實施例III-53至III-63中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之乾眼評分。Example III-65. The method or the compound used in any one of Examples III-53 to III-63, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例III-66. 如實施例III-52至III-65中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之至少一隻眼睛之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之相同眼睛的斯戈默評分;
b)接受投與對照物之個體的斯戈默評分;或
c)接受投與比較化合物之個體的斯戈默評分。Embodiment III-66. The method or the compound used in any one of Embodiments III-52 to III-65, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant increase in the individual’s Sgormer score, and of which the individual’s The statistically significant increase in the Sgomer score of at least one eye is after administering an effective amount of the first dose of
實施例III-67. 如實施例III-66之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少15%。Example III-67. As in the method of Example III-66 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 15%.
實施例III-68. 如實施例III-66或III-67之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升10 mm與20 mm之間。Example III-68. As in the method of Example III-66 or III-67 or the compound used, the Sgormer score of the individual statistically increased significantly between 10 mm and 20 mm.
實施例III-69. 如實施例III-66或III-67之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少3 mm。Example III-69. As in the method of Example III-66 or III-67 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 3 mm.
實施例III-70. 如實施例III-66或III-67之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少10 mm。Example III-70. As in the method of Example III-66 or III-67 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 10 mm.
實施例III-71. 如實施例III-66至III-70中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-71. The method or compound used in any one of Examples III-66 to III-70, wherein the statistically significant increase in the individual’s Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.
實施例III-72. 如實施例III-66至III-71中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-72. The method or the compound used in any one of Examples III-66 to III-71, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of
實施例III-73. 如實施例III-66至III-72中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-73. The method or the compound used as in any one of Examples III-66 to III-72, wherein the statistical increase in the individual’s Sgormer score significantly improves the self-administered effective amount of
實施例III-74. 如實施例III-66至III-72中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之斯戈默評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之斯戈默評分不減小超過10%。Example III-74. The method or the compound used as in any one of Examples III-66 to III-72, wherein compared to the administration of an effective amount of
實施例III-75. 如實施例III-66至III-74中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-75. The method or the compound used as in any one of Examples III-66 to III-74, wherein
實施例III-76. 如實施例III-66至III-75中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係基於在投與第一劑量之後測定的個體之斯戈默評分。Example III-76. The method or the compound used as in any of Examples III-66 to III-75, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.
實施例III-77. 如實施例III-66至III-75中任一項之方法或所使用之化合物,其中統計上顯著上升係基於在投與化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之斯戈默評分。Example III-77. The method or the compound used as in any of Examples III-66 to III-75, wherein the statistically significant increase is based on the administration of
實施例III-78. 如實施例III-52至III-77中任一項之方法或所使用之化合物,其中個體中之α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;
b)接受投與對照物之個體的角膜評分;或
c)接受投與比較化合物之個體的角膜評分。Example III-78. The method or the compound used in any one of Examples III-52 to III-77, in which the α4β2 receptor in an individual, or the nicotinic acetylcholine α3β4 receptor, or nicotine The pharmacological stimulation of acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and the statistically significant decrease in the individual's corneal score is Measured after administering an effective amount of the first dose of
實施例III-79. 如實施例III-78之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降至少15%。Example III-79. As in the method of Example III-78 or the compound used, the statistically significant reduction in the individual's corneal score is at least 15%.
實施例III-80. 如實施例III-78或III-79之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-80. As in the method of Example III-78 or III-79 or the compound used, the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例III-81. 如實施例III-78至III-80中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-81. The method or the compound used in any one of Examples III-78 to III-80, wherein the statistically significant decrease in the individual's corneal score is when an effective amount of
實施例III-82. 如實施例III-78至III-81中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-82. The method or the compound used in any one of Examples III-78 to III-81, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of
實施例III-83. 如實施例III-78至III-81中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之角膜評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之角膜評分不增加超過10%。Example III-83. The method or the compound used as in any one of Examples III-78 to III-81, wherein compared to the administration of an effective amount of
實施例III-84. 如實施例III-82或III-83之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example III-84. As in the method of Example III-82 or III-83 or the compound used, between the determination of the individual's corneal score, the individual exists in an environment with reduced humidity.
實施例III-85. 如實施例III-78至III-84中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-85. The method or the compound used as in any of Examples III-78 to III-84, wherein
實施例III-86. 如實施例III-78至III-85中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之角膜評分。Example III-86. The method or the compound used in any one of Examples III-78 to III-85, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of
實施例III-87. 如實施例III-78至III-85中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續之後測定的個體之角膜評分。Example III-87. The method or the compound used as in any one of Examples III-78 to III-85, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例III-88. 如實施例III-52至III-87中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;
b)接受投與對照物之個體的OSDI評分;或
c)接受投與比較化合物之個體的OSDI評分。Embodiment III-88. The method or the compound used in any one of Embodiments III-52 to III-87, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant decrease in the individual’s OSDI score, and the individual’s OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of
實施例III-89. 如實施例III-88之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降至少15%。Example III-89. As in the method of Example III-88 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.
實施例III-90. 如實施例III-88或III-89之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係藉由0.05或更小、0.01或更小、0.005或更小或0.001或更小之p值表徵。Example III-90. The method or compound used in Example III-88 or III-89, wherein the statistically significant decrease in the individual's OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.
實施例III-91. 如實施例III-88至III-90中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example III-91. The method or compound used in any one of Examples III-88 to III-90, wherein the statistically significant decrease in the individual’s OSDI score is when an effective amount of
實施例III-92. 如實施例III-88至III-91中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example III-92. The method or the compound used in any one of Examples III-88 to III-91, wherein the statistically significant improvement of the individual's OSDI score improves the self-administered effective amount of
實施例III-93. 如實施例III-88至III-91中任一項之方法或所使用之化合物,其中相較於投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後5分鐘內個體之OSDI評分,投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後至少30分鐘個體之OSDI評分不增加超過10%。Example III-93. The method or the compound used as in any one of Examples III-88 to III-91, wherein compared to the first step of administering an effective amount of
實施例III-94. 如實施例III-92或III-93之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example III-94. As in the method of Example III-92 or III-93 or the compound used, the individual exists in an environment with reduced humidity between the determination of the individual's corneal score.
實施例III-95. 如實施例III-88至III-94中任一項之方法或所使用之化合物,其中投與化合物1或其醫藥學上可接受之鹽包含有效量的化合物1或其醫藥學上可接受之鹽之第一劑量及一或多個後續劑量。Example III-95. The method or the compound used as in any one of Examples III-88 to III-94, wherein
實施例III-96. 如實施例III-88至III-95中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量之後測定的個體之OSDI評分。Example III-96. The method or compound used in any one of Examples III-88 to III-95, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of
實施例III-97. 如實施例III-88至III-95中任一項之方法或所使用之化合物,其中統計上顯著下降係基於在投與有效量的化合物1或其醫藥學上可接受之鹽之一或多個後續劑量之後測定的個體之OSDI評分。Example III-97. The method or the compound used as in any one of Examples III-88 to III-95, wherein the statistically significant decrease is based on the administration of an effective amount of
實施例III-98. 如實施例III-50至III-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α4β2受體受到藥理學刺激。Example III-98. The method or the compound used in any one of Examples III-50 to III-97, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated.
實施例III-99. 如實施例III-50至III-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α3β4受體受到藥理學刺激。Example III-99. The method or the compound used in any one of Examples III-50 to III-97, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated.
實施例III-100. 如實施例III-50至III-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α3α5β4受體受到藥理學刺激。Embodiment III-100. The method or the compound used as in any one of Embodiments III-50 to III-97, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated.
實施例III-101. 如實施例III-1至III-100中任一項之方法或所使用之化合物,其中每劑量5-4000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example III-101. The method or the compound used in any one of Examples III-1 to III-100, wherein each dose of 5-4000 micrograms of
實施例III-102. 如實施例III-1至III-100中任一項之方法或所使用之化合物,其中每劑量900-3000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example III-102. The method or the compound used as in any of Examples III-1 to III-100, wherein each dose of 900-3000 micrograms of
實施例III-103. 如實施例III-1至III-100中任一項之方法或所使用之化合物,其中每劑量1000-2500微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example III-103. The method or the compound used in any one of Examples III-1 to III-100, wherein 1000-2500 micrograms of
實施例III-104. 如實施例III-1至III-100中任一項之方法或所使用之化合物,其中每劑量1500-3000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example III-104. The method or the compound used in any one of Examples III-1 to III-100, wherein each dose of 1500-3000 micrograms of
實施例III-105. 如實施例III-1至III-104中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為50-250微升。Example III-105. The method or the compound used in any one of Examples III-1 to III-104, wherein
實施例III-106. 如實施例III-1至III-104中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為150-250微升。Example III-106. The method or the compound used as in any of Examples III-1 to III-104, wherein
實施例III-107. 如實施例III-1至III-106中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,該醫藥調配物包含1 mg/mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。Example III-107. The method or the compound used as in any one of Examples III-1 to III-106, wherein
實施例III-108. 如實施例III-105至III-107中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每個鼻孔投與之醫藥調配物的總體積為50-250微升。Example III-108. The method or the compound used in any one of Examples III-105 to III-107, wherein
實施例III-109. 如實施例III-1至III-108中任一項之方法或所使用之化合物,其中化合物1為醫藥學上可接受之鹽。Example III-109. The method or the compound used as in any one of Examples III-1 to III-108, wherein
實施例III-110. 如實施例III-1至III-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後每天一至四次地向有需要之個體投與。Example III-110. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need one to four times a day after the first day of administration.
實施例III-111. 如實施例III-1至III-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天一次地向有需要之個體投與。Example III-111. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need once a day after the first day of administration.
實施例III-112. 如實施例III-1至III-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天兩次地向有需要之個體投與。Example III-112. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need twice a day after the first day of administration.
實施例III-113. 如實施例III-1至III-109中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天三次地向有需要之個體投與。Example III-113. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need three times a day after the first day of administration.
實施例III-114. 如實施例III-1至III-109中任一項之方法或所使用之化合物,其中
a)向個體投與之化合物1或其醫藥學上可接受之鹽之劑量頻率隨時間推移降低,或
b)每劑量之化合物1之總量,或其醫藥學上可接受之鹽之對應量隨時間推移減少。Example III-114. The method or the compound used as in any one of Examples III-1 to III-109, wherein
a) The frequency of doses of
實施例III-115. 如實施例III-114之方法或所使用之化合物,其中各劑量包含向該個體之鼻腔中投與超過一次化合物1或其醫藥學上可接受之鹽,且
其中隨時間推移來減少每劑量之化合物1之總量或其醫藥學上可接受之鹽之對應量係藉由減少向該個體之鼻腔中投與化合物1或其醫藥學上可接受之鹽的次數來實現。Example III-115. The method as in Example III-114 or the compound used, wherein each dose includes more than one administration of
實施例III-116. 如實施例III-1至III-115中任一項之方法或所使用之化合物,其中劑量包含向一個或兩個鼻孔多次投與化合物1或其醫藥學上可接受之鹽。Example III-116. The method or the compound used as in any one of Examples III-1 to III-115, wherein the dose includes multiple administrations of
實施例III-117. 如實施例III-1至III-115中任一項之方法或所使用之化合物,其中劑量包含向一個或兩個鼻孔單次投與化合物1或其醫藥學上可接受之鹽。Example III-117. The method or the compound used as in any one of Examples III-1 to III-115, wherein the dose comprises a single administration of
實施例III-118. 如實施例III-1至III-117中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係每劑量向一個鼻孔投與。Example III-118. The method or the compound used as in any one of Examples III-1 to III-117, wherein
實施例III-119. 如實施例III-1至III-117中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係每劑量向兩個鼻孔投與。Example III-119. The method or the compound used as in any one of Examples III-1 to III-117, wherein
實施例III-120. 如實施例III-1至III-119中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係投與至少28天。Example III-120. The method or the compound used as in any one of Examples III-1 to III-119, wherein
實施例III-121. 如實施例III-1至III-119中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係投與至少3個月。Example III-121. The method or the compound used as in any one of Examples III-1 to III-119, wherein
實施例III-122. 如實施例III-1至III-121中任一項之方法或所使用之化合物,其中該個體已在2週內進行Lasik手術或預定在2週內進行Lasik手術。Example III-122. The method or the compound used as in any one of Examples III-1 to III-121, wherein the individual has undergone Lasik surgery within 2 weeks or is scheduled to undergo Lasik surgery within 2 weeks.
實施例III-123. 如實施例III-1至III-122中任一項之方法或所使用之化合物,其中該個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。Example III-123. The method or the compound used as in any one of Examples III-1 to III-122, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, Cough, throat irritation, drip irritation, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.
實施例III-124. 如實施例III-123之方法或所使用之化合物,其中在投與第一劑量或一或多個後續劑量之5分鐘-60分鐘內,個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。Example III-124. The method as in Example III-123 or the compound used, wherein within 5 minutes to 60 minutes of the administration of the first dose or one or more subsequent doses, the individual does not experience One or more side effects of the group: excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, irritation of the nose, toothache, dry mouth and headache.
實施例III-125. 如實施例III-1至III-124中任一項之方法或所使用之化合物,其中過度產生眼淚係由個體之斯戈默評分升幅超過20 mm所指示。Example III-125. The method or the compound used as in any one of Examples III-1 to III-124, wherein excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm.
實施例III-126. 如實施例III-1至III-125中任一項之方法或所使用之化合物,其中該方法不包含向個體投與正向異位調節劑。Embodiment III-126. The method as in any of Embodiments III-1 to III-125 or the compound used, wherein the method does not include the administration of a positive ectopic modulator to the individual.
實施例III-127. 如實施例III-1至III-126中任一項之方法或所使用之化合物,其中有需要之個體之化合物1或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL。Example III-127. The method or the compound used in any one of Examples III-1 to III-126, wherein the plasma Cmax of
實施例III-128. 如實施例III-1至III-127中任一項之方法或所使用之化合物,其中每劑量150-300微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example III-128. The method or the compound used in any one of Examples III-1 to III-127, wherein 150-300 micrograms of
實施例III-129. 如實施例III-1至III-127中任一項之方法或所使用之化合物,其中每劑量900-1200微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example III-129. The method or the compound used in any one of Examples III-1 to III-127, wherein 900-1200 micrograms of
實施例III-130. 如實施例III-50至III-97中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α4α6β2受體受到藥理學刺激。Embodiment III-130. The method or the compound used in any one of Embodiments III-50 to III-97, wherein at least the nicotinic acetylcholine α4α6β2 receptor is pharmacologically stimulated.
實施例III-131. 如實施例III-1至III-130中任一項之方法或所使用之化合物,其中醫藥學上可接受之鹽為化合物1之半-半乳糖二酸鹽。Example III-131. The method or the compound used as in any one of Examples III-1 to III-130, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of
實施例III-132. 如實施例III-1至III-130中任一項之方法或所使用之化合物,其中醫藥學上可接受之鹽為化合物1之檸檬酸鹽。Embodiment III-132. The method or the compound used as in any one of Embodiments III-1 to III-130, wherein the pharmaceutically acceptable salt is the citrate salt of
實施例III-133.一種菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中該藥物用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,其中菸鹼乙醯膽鹼受體促效劑為具有以下結構之化合物1, 或其醫藥學上可接受之鹽。Example III-133. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production or reduce eye discomfort for individuals in need, The nicotinic acetylcholine receptor agonist is compound 1 with the following structure , Or a pharmaceutically acceptable salt thereof.
實施例III-134. 一種菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中藥物用於刺激有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合,其中菸鹼乙醯膽鹼受體促效劑為具有以下結構之化合物1,
或其醫藥學上可接受之鹽。Example III-134. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or tobacco Alkaline acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist has the following
實施例III-135. 一種醫藥調配物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,該調配物包含具有以下結構之化合物1,
或其醫藥學上可接受之鹽。Example III-135. A pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, the formulation comprises
實施例III-136. 一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行藥理學刺激,該調配物包含具有以下結構之化合物1,
或其醫藥學上可接受之鹽。Example III-136. A pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 in individuals in need Receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, the formulation contains
實施例III-137. 如實施例III-135或III-136之醫藥調配物,其中該用途包含如實施例III-1至III-132中任一項所定義之方法。Embodiment III-137. The pharmaceutical formulation as in Embodiment III-135 or III-136, wherein the use includes the method as defined in any one of Embodiments III-1 to III-132.
實施例III-138. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含5-4000微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-138. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 5-4000 micrograms of
實施例III-139. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含900-3000微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-139. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 900-3000 micrograms of
實施例III-140. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含1000-2500微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-140. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 1000-2500 micrograms of
實施例III-141. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含1500-3000微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-141. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 1500-3000 micrograms of
實施例III-142. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含150-300微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-142. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 150-300 micrograms of
實施例III-143. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含900-1200微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-143. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 900-1200 micrograms of
實施例III-144. 如實施例III-135至III-137中任一項之醫藥調配物,其每劑量包含900-1200微克化合物1,或對應量的其醫藥學上可接受之鹽。Example III-144. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 900-1200 micrograms of
實施例III-145. 如實施例III-135至III-144中任一項之醫藥調配物,其中每劑量之醫藥調配物之體積為50-250微升。Embodiment III-145. The pharmaceutical formulation according to any one of embodiments III-135 to III-144, wherein the volume of the pharmaceutical formulation per dose is 50-250 microliters.
實施例III-146. 如實施例III-135至III-144中任一項之醫藥調配物,其中每劑量之醫藥調配物之體積為150-250微升。Embodiment III-146. The pharmaceutical formulation of any one of Embodiments III-135 to III-144, wherein the volume of the pharmaceutical formulation per dose is 150-250 microliters.
實施例III-147. 如實施例III-135至III-146中任一項之醫藥調配物,其包含1 mg /mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。Example III-147. The pharmaceutical formulation according to any one of Examples III-135 to III-146, which contains
實施例III-148. 如實施例III-135至III-147中任一項之醫藥調配物,其中化合物1為醫藥學上可接受之鹽。Example III-148. The pharmaceutical formulation according to any one of Examples III-135 to III-147, wherein
實施例III-149. 如實施例III-135至III-148中任一項之醫藥調配物,其中醫藥學上可接受之鹽為化合物1之半-半乳糖二酸鹽。Embodiment III-149. The pharmaceutical formulation according to any one of Embodiments III-135 to III-148, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of
實施例III-150. 如實施例III-135至III-148中任一項之醫藥調配物,其中醫藥學上可接受之鹽為化合物1之檸檬酸鹽。Embodiment III-150. The pharmaceutical formulation of any one of Embodiments III-135 to III-148, wherein the pharmaceutically acceptable salt is the citrate salt of
實施例IV-1. 一種對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法,其包含Example IV-1. A method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, which includes
向有需要之個體之鼻腔中投與有效量的具有以下結構之化合物1,或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量;其中該方法造成有效治療該有需要之個體。An effective amount of
實施例IV-2. 一種化合物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適之方法,其中該化合物為具有以下結構之化合物1,或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。Example IV-2. A compound for a method for treating dry eye disease, increasing tear production or reducing eye discomfort in an individual in need thereof, wherein the compound is
實施例IV-3. 如實施例IV-2所使用之化合物,其中該方法造成有效治療該有需要之個體。Example IV-3. The compound as used in Example IV-2, wherein the method results in effective treatment of the individual in need.
實施例IV-4. 如實施例IV-1之方法或如實施例IV-3所使用之化合物,其中個體之有效治療係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之乾眼評分測試,b)斯戈默測試,c)根據國家眼科研究所(NEI)分級系統之角膜螢光素染色測試,及d)眼表面疾病指數測試。Example IV-4. The method as in Example IV-1 or the compound as in Example IV-3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) according to vision The dry eye score test on the analog scale, b) Sgormer test, c) corneal fluorescein stain test according to the National Institute of Ophthalmology (NEI) grading system, and d) ocular surface disease index test.
實施例IV-5. 如實施例IV-4之方法或所使用之化合物,其中有效治療係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;b)接受投與對照物之個體的乾眼評分;或c)接受投與比較化合物之個體的乾眼評分。Example IV-5. As in the method of Example IV-4 or the compound used, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is Determined after administering an effective amount of the first dose of
實施例IV-6. 如實施例IV-5之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少15%。Example IV-6. As in the method of Example IV-5 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 15%.
實施例IV-7. 如實施例IV-5或IV-6之方法或所使用之化合物,其中個體之乾眼評分在統計上顯著下降10 mm與20 mm之間。Example IV-7. The method as in Example IV-5 or IV-6 or the compound used, wherein the individual's dry eye score statistically decreased between 10 mm and 20 mm.
實施例IV-8. 如實施例IV-5至IV-7中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少3 mm。Example IV-8. The method or the compound used as in any of Examples IV-5 to IV-7, wherein the statistically significant decrease in the individual's dry eye score is at least 3 mm.
實施例IV-9. 如實施例IV-5至IV-8中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example IV-9. The method or the compound used as in any one of Examples IV-5 to IV-8, wherein the statistically significant decrease in the individual's dry eye score is when an effective amount of
實施例IV-10. 如實施例IV-5至IV-9中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example IV-10. The method or the compound used in any one of Examples IV-5 to IV-9, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of
實施例IV-11. 如實施例IV-10之方法或所使用之化合物,其中在測定個體之乾眼評分之間,個體存在於濕度降低之環境中。Example IV-11. As in the method of Example IV-10 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.
實施例IV-12. 如實施例IV-4至IV-11中任一項之方法或所使用之化合物,其中有效治療係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之至少一隻眼睛之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之相同眼睛的斯戈默評分;b)接受投與對照物之個體的斯戈默評分;或c)接受投與比較化合物之個體的斯戈默評分。Example IV-12. The method or the compound used in any one of Examples IV-4 to IV-11, wherein the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the individual's The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of
實施例IV-13. 如實施例IV-12之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少15%。Example IV-13. As in the method of Example IV-12 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 15%.
實施例IV-14. 如實施例IV-12或IV-13之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升10 mm與20 mm之間。Example IV-14. As in the method of Example IV-12 or IV-13 or the compound used, the Sgormer score of the individual increases statistically significantly between 10 mm and 20 mm.
實施例IV-15. 如實施例IV-12或IV-13之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少3 mm。Example IV-15. As in the method of Example IV-12 or IV-13 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 3 mm.
實施例IV-16. 如實施例IV-12至IV-15中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著上升係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example IV-16. The method or the compound used as in any one of Examples IV-12 to IV-15, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of
實施例IV-17. 如實施例IV-12至IV-16中任一項之方法或所使用之化合物,其中個體之斯戈默評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example IV-17. The method or the compound used in any one of Examples IV-12 to IV-16, wherein the statistical increase in the individual's Sgormer score significantly improves the self-administered effective amount of
實施例IV-18. 如實施例IV-4至IV-17中任一項之方法或所使用之化合物,其中有效治療係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於
a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;b)接受投與對照物之個體的角膜評分;或c)接受投與比較化合物之個體的角膜評分。Example IV-18. The method or compound used in any one of Examples IV-4 to IV-17, wherein the effective treatment is indicated by a statistically significant drop in the individual's corneal score, and wherein the individual's corneal score The statistically significant decrease is determined after administering an effective amount of the first dose of
實施例IV-19. 如實施例IV-18之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降至少15%。Example IV-19. As in the method of Example IV-18 or the compound used, the individual's corneal score statistically decreased by at least 15%.
實施例IV-20. 如實施例IV-18至IV-19中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example IV-20. The method or the compound used in any one of Examples IV-18 to IV-19, wherein the statistically significant decrease in the individual's corneal score is the administration of an effective amount of
實施例IV-21. 如實施例IV-18至IV-20中任一項之方法或所使用之化合物,其中個體之角膜評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example IV-21. The method or the compound used in any one of Examples IV-18 to IV-20, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of
實施例IV-22. 如實施例IV-21之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example IV-22. As in the method of Example IV-21 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例IV-23. 如實施例IV-4至IV-22中任一項之方法或所使用之化合物,其中有效治療係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;b)接受投與對照物之個體的OSDI評分;或c)接受投與比較化合物之個體的OSDI評分。Example IV-23. The method or compound used in any one of Examples IV-4 to IV-22, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the individual's OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of
實施例IV-24. 如實施例IV-23之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降至少15%。Example IV-24. As in the method of Example IV-23 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.
實施例IV-25. 如實施例IV-23至IV-24中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example IV-25. The method or the compound used in any one of Examples IV-23 to IV-24, wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of
實施例IV-26. 如實施例IV-23至IV-25中任一項之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example IV-26. The method or compound used in any one of Examples IV-23 to IV-25, wherein the statistically significant improvement of the individual's OSDI score improves the self-administered effective amount of
實施例IV-27. 如實施例IV-26之方法或所使用之化合物,其中在測定個體之角膜評分之間,個體存在於濕度降低之環境中。Example IV-27. As in the method of Example IV-26 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.
實施例IV-28. 一種用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法,其包含向有需要之個體之鼻腔中投與有效量的具有結構之化合物1或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量。Example IV-28. A method for nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco in an individual in need Alkaline acetylcholine α4α6β2 receptor or a combination thereof for immediate and long-term pharmacological stimulation, which comprises administering an effective amount of a structure to the nasal cavity of an individual in need The first dose of
實施例IV-29. 一種化合物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行立即及長期藥理學刺激之方法中,其中化合物為具有結構之化合物1或其醫藥學上可接受之鹽;其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量,及視情況選用之一或多個後續劑量。Example IV-29. A compound for use in an individual in need of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor , Or a method for immediate and long-term pharmacological stimulation of nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the compound has a
實施例IV-30. 如實施例IV-28之方法或如實施例IV-29所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由選自由以下組成之群的一或多種測試指示:a)根據視覺類比量表之乾眼評分測試,b)斯戈默測試,c)根據國家眼科研究所(NEI)分級系統之角膜螢光素染色測試,及d)眼表面疾病指數測試。Example IV-30. The method as in Example IV-28 or the compound used in Example IV-29, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 receptor in the individual , Or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination of pharmacological stimuli is indicated by one or more tests selected from the group consisting of: a) according to visual analogue Table of dry eye score test, b) Sgormer test, c) corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) grading system, and d) eye surface disease index test.
實施例IV-31. 如實施例IV-30之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之乾眼評分之統計上顯著下降指示,且其中個體之乾眼評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,其中個體之乾眼評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的乾眼評分;b)接受投與對照物之個體的乾眼評分;或c)接受投與比較化合物之個體的乾眼評分。Example IV-31. The method or the compound used in Example IV-30, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine in the individual The pharmacological stimulation of the choline α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and the statistically significant decrease in the individual's dry eye score is Determined after administering an effective amount of the first dose of
實施例IV-32. 如實施例IV-31之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少15%。Example IV-32. As in the method of Example IV-31 or the compound used, the statistically significant reduction in the individual's dry eye score is at least 15%.
實施例IV-33. 如實施例IV-31或IV-32之方法或所使用之化合物,其中個體之乾眼評分在統計上顯著下降10 mm與20 mm之間。Example IV-33. As in the method of Example IV-31 or IV-32 or the compound used, the individual's dry eye score statistically decreased between 10 mm and 20 mm.
實施例IV-34. 如實施例IV-31或IV-32之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降至少3 mm。Example IV-34. As in the method of Example IV-31 or IV-32 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 3 mm.
實施例IV-35. 如實施例IV-31至IV-34中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著下降係在投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量的5分鐘內。Example IV-35. The method or the compound used as in any one of Examples IV-31 to IV-34, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of
實施例IV-36. 如實施例IV-31至IV-35中任一項之方法或所使用之化合物,其中個體之乾眼評分之統計上顯著改善自投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量開始維持至少30分鐘。Example IV-36. The method or the compound used in any one of Examples IV-31 to IV-35, wherein the statistical evaluation of the individual's dry eye score significantly improves the self-administered effective amount of
實施例IV-37. 如實施例IV-30至IV-36中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之斯戈默評分之統計上顯著上升指示,且其中個體之至少一隻眼睛之斯戈默評分之統計上顯著上升係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之斯戈默評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體之相同眼睛的斯戈默評分;b)接受投與對照物之個體的斯戈默評分;或c)接受投與比較化合物之個體的斯戈默評分。Example IV-37. The method or the compound used in any one of Examples IV-30 to IV-36, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant increase in the individual’s Sgormer score, and of which the individual’s The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of
實施例IV-38. 如實施例IV-37之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少15%。Example IV-38. As in the method of Example IV-37 or the compound used, the Sgormer score of the individual statistically increased by at least 15%.
實施例IV-39. 如實施例IV-37或IV-38之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升10 mm與20 mm之間。Example IV-39. As in the method of Example IV-37 or IV-38 or the compound used, the Sgormer score of the individual statistically increased significantly between 10 mm and 20 mm.
實施例IV-40. 如實施例IV-37或IV-38之方法或所使用之化合物,其中個體之斯戈默評分在統計上顯著上升至少3 mm。Example IV-40. As in the method of Example IV-37 or IV-38 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 3 mm.
實施例IV-41. 如實施例IV-30至IV-40中任一項之方法或所使用之化合物,其中個體中之α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之角膜評分之統計上顯著下降指示,且其中個體之角膜評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之乾眼評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的角膜評分;b)接受投與對照物之個體的角膜評分;或c)接受投與比較化合物之個體的角膜評分。Example IV-41. The method or the compound used in any one of Examples IV-30 to IV-40, in which the α4β2 receptor in an individual, or the nicotinic acetylcholine α3β4 receptor, or nicotine The pharmacological stimulation of acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and the statistically significant decrease in the individual's corneal score is Determined after administering an effective amount of the first dose of
實施例IV-42. 如實施例IV-41之方法或所使用之化合物,其中個體之角膜評分之統計上顯著下降至少15%。Example IV-42. As in the method of Example IV-41 or the compound used, a statistically significant drop in the individual's corneal score is at least 15%.
實施例IV-43. 如實施例IV-30至IV-42中任一項之方法或所使用之化合物,其中個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合之藥理學刺激係由個體之OSDI評分之統計上顯著下降指示,且其中個體之OSDI評分之統計上顯著下降係在向個體投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量或視情況選用之一或多個後續劑量之後測定,且其中個體之OSDI評分係相較於a)在投與化合物1或其醫藥學上可接受之鹽之第一劑量之前個體的OSDI評分;b)接受投與對照物之個體的OSDI評分;或c)接受投與比較化合物之個體的OSDI評分。Example IV-43. The method or the compound used in any one of Examples IV-30 to IV-42, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant decrease in the individual’s OSDI score, and the individual’s OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of
實施例IV-44. 如實施例IV-43之方法或所使用之化合物,其中個體之OSDI評分之統計上顯著下降至少15%。Example IV-44. As in the method of Example IV-43 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.
實施例IV-45. 如實施例IV-28至IV-44中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α4β2受體受到藥理學刺激。Example IV-45. The method or the compound used in any one of Examples IV-28 to IV-44, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated.
實施例IV-46. 如實施例IV-28至IV-44中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α3β4受體受到藥理學刺激。Example IV-46. The method or the compound used in any one of Examples IV-28 to IV-44, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated.
實施例IV-47. 如實施例IV-28至IV-44中任一項之方法或所使用之化合物,其中至少菸鹼乙醯膽鹼α3α5β4受體受到藥理學刺激。Example IV-47. The method or the compound used in any one of Examples IV-28 to IV-44, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated.
實施例IV-48. 如實施例IV-1至IV-47中任一項之方法或所使用之化合物,其中每劑量5-4000微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example IV-48. The method or the compound used in any one of Examples IV-1 to IV-47, wherein 5-4000 micrograms of
實施例IV-49. 如實施例IV-1至IV-48中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每劑醫藥調配物之總體積為150-250微升。Example IV-49. The method or the compound used in any one of Examples IV-1 to IV-48, wherein
實施例IV-50. 如實施例IV-1至IV-49中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,該醫藥調配物包含1 mg/mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。Example IV-50. The method or the compound used in any one of Examples IV-1 to IV-49, wherein
實施例IV-51. 如實施例IV-49至IV-50中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係呈經鼻投藥之醫藥調配物投與,且每個鼻孔投與之醫藥調配物的總體積為50-250微升。Example IV-51. The method or compound used in any one of Examples IV-49 to IV-50, wherein
實施例IV-52. 如實施例IV-1至IV-51中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後每天一至四次地向有需要之個體投與。Example IV-52. The method or the compound used in any one of Examples IV-1 to IV-51, wherein the dose is administered to an individual in need one to four times a day after the first day of administration.
實施例IV-53. 如實施例IV-1至IV-51中任一項之方法或所使用之化合物,其中劑量係在第一天投藥後一天一次地向有需要之個體投與。Example IV-53. The method or the compound used in any one of Examples IV-1 to IV-51, wherein the dose is administered to an individual in need once a day after the first day of administration.
實施例IV-54. 如實施例IV-1至IV-51中任一項之方法或所使用之化合物,其中a)向個體投與之化合物1或其醫藥學上可接受之鹽之劑量頻率隨時間推移降低,或b)每劑量之化合物1之總量,或其醫藥學上可接受之鹽之對應量隨時間推移減少。Example IV-54. The method or the compound used as in any one of Examples IV-1 to IV-51, wherein a) the dosage frequency of
實施例IV-55. 如實施例IV-54之方法或所使用之化合物,其中各劑量包含向該個體之鼻腔中投與超過一次化合物1或其醫藥學上可接受之鹽,且其中隨時間推移來減少每劑量之化合物1之總量或其醫藥學上可接受之鹽之對應量係藉由減少向該個體之鼻腔中投與化合物1或其醫藥學上可接受之鹽的次數來實現。Example IV-55. As in the method of Example IV-54 or the compound used, wherein each dose includes administration of
實施例IV-56. 如實施例IV-1至IV-55中任一項之方法或所使用之化合物,其中劑量包含向一個或兩個鼻孔多次投與化合物1或其醫藥學上可接受之鹽。Example IV-56. The method or the compound used as in any one of Examples IV-1 to IV-55, wherein the dose includes multiple administrations of
實施例IV-57. 如實施例IV-1至IV-55中任一項之方法或所使用之化合物,其中劑量包含向一個或兩個鼻孔單次投與化合物1或其醫藥學上可接受之鹽。Example IV-57. The method or the compound used as in any one of Examples IV-1 to IV-55, wherein the dose includes a single administration of
實施例IV-58. 如實施例IV-1至IV-57中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係投與至少28天。Example IV-58. The method or compound used in any one of Examples IV-1 to IV-57, wherein
實施例IV-59.如實施例IV-1至IV-57中任一項之方法或所使用之化合物,其中化合物1或其醫藥學上可接受之鹽係投與至少3個月。Embodiment IV-59. The method or the compound used as in any of Embodiments IV-1 to IV-57, wherein
實施例IV-60. 如實施例IV-1至IV-59中任一項之方法或所使用之化合物,其中該個體已在2週內進行Lasik手術或預定在2週內進行Lasik手術。Example IV-60. The method or the compound used in any one of Examples IV-1 to IV-59, wherein the individual has undergone Lasik surgery within 2 weeks or is scheduled to perform Lasik surgery within 2 weeks.
實施例IV-61. 如實施例IV-1至IV-60中任一項之方法或所使用之化合物,其中該個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。Example IV-61. The method or compound used in any one of Examples IV-1 to IV-60, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, Cough, throat irritation, drip irritation, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.
實施例IV-62. 如實施例IV-61之方法或所使用之化合物,其中在投與第一劑量或一或多個後續劑量之5分鐘-60分鐘內,個體不會經歷選自由以下組成之群的一或多種副作用:過度產生眼淚、咳嗽、喉部刺激、滴注部位刺激、打噴嚏、鼻咽炎、鼻部刺激、牙痛、口乾及頭痛。Example IV-62. The method as in Example IV-61 or the compound used, wherein within 5 minutes to 60 minutes of the administration of the first dose or one or more subsequent doses, the individual will not experience One or more side effects of the group: excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, irritation of the nose, toothache, dry mouth and headache.
實施例IV-63.如實施例IV-1至IV-62中任一項之方法或所使用之化合物,其中過度產生眼淚係由個體之斯戈默評分升幅超過20 mm所指示。Example IV-63. The method or the compound used as in any of Examples IV-1 to IV-62, wherein excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm.
實施例IV-64. 如實施例IV-1至IV-63中任一項之方法或所使用之化合物,其中該方法不包含向個體投與正向異位調節劑。Example IV-64. The method or the compound used in any one of Examples IV-1 to IV-63, wherein the method does not include the administration of a positive ectopic modulator to the individual.
實施例IV-65. 如實施例IV-1至IV-64中任一項之方法或所使用之化合物,其中有需要之個體之化合物1或其醫藥學上可接受之鹽的血漿Cmax為小於5 ng/mL。Example IV-65. The method or the compound used in any one of Examples IV-1 to IV-64, wherein the plasma Cmax of
實施例IV-66. 如實施例IV-1至IV-65中任一項之方法或所使用之化合物,其中每劑量150-300微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example IV-66. The method or the compound used in any one of Examples IV-1 to IV-65, wherein 150-300 micrograms of
實施例IV-67. 如實施例IV-1至IV-65中任一項之方法或所使用之化合物,其中每劑量900-1200微克化合物1,或對應量的其醫藥學上可接受之鹽係投與至個體。Example IV-67. The method or the compound used in any one of Examples IV-1 to IV-65, wherein 900-1200 micrograms of
實施例IV-68. 如實施例IV-1至IV-67中任一項之方法或所使用之化合物,其中醫藥學上可接受之鹽為化合物1之半-半乳糖二酸鹽。Example IV-68. The method or the compound used in any one of Examples IV-1 to IV-67, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of
實施例IV-69. 如實施例IV-1至IV-67中任一項之方法或所使用之化合物,其中醫藥學上可接受之鹽為化合物1之檸檬酸鹽。Example IV-69. The method or the compound used in any one of Examples IV-1 to IV-67, wherein the pharmaceutically acceptable salt is the citrate salt of
實施例IV-70. 一種菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中該藥物用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,其中菸鹼乙醯膽鹼受體促效劑為具有結構之化合物1或其醫藥學上可接受之鹽。Example IV-70. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production, or reduce eye discomfort for individuals in need, The nicotinic acetylcholine receptor agonist has a
實施例IV-71. 一種菸鹼乙醯膽鹼受體促效劑之用途,其用於製造藥物,其中藥物用於刺激有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合,其中菸鹼乙醯膽鹼受體促效劑為具有結構之化合物1或其醫藥學上可接受之鹽。Example IV-71. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or smoke Alkaline acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist is structured
實施例IV-72. 一種醫藥調配物,其用於對有需要之個體治療乾眼病、增加淚液產生或減少眼部不適,該調配物包含具有結構之化合物1或其醫藥學上可接受之鹽。Example IV-72. A pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, the formulation comprises a
實施例IV-73. 一種醫藥調配物,其用於對有需要之個體中之菸鹼乙醯膽鹼α4β2受體、或菸鹼乙醯膽鹼α3β4受體、或菸鹼乙醯膽鹼α3α5β4受體、或菸鹼乙醯膽鹼α4α6β2受體或其組合進行藥理學刺激,該調配物包含具有結構之化合物1或其醫藥學上可接受之鹽。Example IV-73. A pharmaceutical formulation for the use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 in individuals in need Receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, the formulation contains a
實施例IV-74. 如實施例IV-72或IV-73之醫藥調配物,其中該用途包含如實施例IV-1至IV-69中任一項所定義之方法。Example IV-74. The pharmaceutical formulation as in Example IV-72 or IV-73, wherein the use includes the method as defined in any one of Examples IV-1 to IV-69.
實施例IV-75. 如實施例IV-72至IV-74中任一項之醫藥調配物,其每劑量包含5-4000微克化合物1,或對應量的其醫藥學上可接受之鹽。Example IV-75. The pharmaceutical formulation according to any one of Examples IV-72 to IV-74, which contains 5-4000 micrograms of
實施例IV-76. 如實施例IV-72至IV-75中任一項之醫藥調配物,其中每劑量之醫藥調配物之體積為50-250微升。Embodiment IV-76. The pharmaceutical formulation of any of embodiments IV-72 to IV-75, wherein the volume of the pharmaceutical formulation per dose is 50-250 microliters.
實施例IV-77. 如實施例IV-72至IV-76中任一項之醫藥調配物,其包含1 mg /mL與40 mg/mL之間的化合物1,或對應量的其醫藥學上可接受之鹽。Example IV-77. The pharmaceutical formulation as in any of Examples IV-72 to IV-76, which contains
實施例IV-78. 如實施例IV-72至IV-77中任一項之醫藥調配物,其中醫藥學上可接受之鹽為化合物1之半-半乳糖二酸鹽。Example IV-78. The pharmaceutical formulation according to any one of Examples IV-72 to IV-77, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of
實施例IV-79. 如實施例IV-72至IV-77中任一項之醫藥調配物,其中醫藥學上可接受之鹽為化合物1之檸檬酸鹽。
實例實例 1 : 化合物 1 半 - 半乳糖二酸鹽二水合物對人類 nAChR 之促效及拮抗特性 Example IV-79. The pharmaceutical formulation of any one of Examples IV-72 to IV-77, wherein the pharmaceutically acceptable salt is the citrate salt of
此實例描述進行以表徵化合物1半-半乳糖二酸鹽二水合物在表現於爪蟾屬卵母細胞中之人類神經元菸鹼乙醯膽鹼受體(nAChR) α3β4、α3α5β4、α4β2及α7處之作用的實驗。
縮寫清單
ACh 乙醯膽鹼
nAChR 菸鹼乙醯膽鹼受體
SEM 平均值之標準誤差
5 材料及方法
5.1 測試化合物
所有實驗使用cDNA表現方法對表現於爪蟾屬卵母細胞中之人類nAChR進行。爪蟾屬卵母細胞係使用標準程序製備及注射。All experiments were performed on human nAChR expressed in Xenopus oocytes using the cDNA expression method. Xenopus oocyte cell lines were prepared and injected using standard procedures.
簡言之,自雌性有爪蟾蜍收穫卵巢,該等有爪蟾蜍已藉由在4℃下冷卻及含三卡因甲磺酸鹽(MS-222,濃度為150 mg/L)之碳酸氫鈉(300 mg/L)深度麻醉。一旦麻醉,遵循日內瓦州動物權利規則對動物去頭及除髓。一小塊卵巢經分離以用於立即製備,而其餘部分係置於4℃下之無菌Barth溶液中,該溶液含有(以mM計) NaCl 88、KCl 1、NaHCO3
2.4、HEPES 10、MgSO4
.7H2
O 0.82、Ca(NO3
)2
.4H2
O 0.33、CaCl2
.6H2
O 0.41,在pH 7.4下,且補充有20 µg /ml康黴素、100單位/毫升青黴素。所有記錄均在18℃下進行且細胞用含有(以mM計)以下之OR2培養基澆注:NaCl 88、KCl 2.5、HEPES 5、CaCl2
.2H2
O 1.8、MgCl2
.6H2
O 1,pH 7.4。
5.4.2 電生理記錄Briefly, ovaries were harvested from female clawed toads, which had been cooled by 4°C and sodium bicarbonate containing tricaine mesylate (MS-222, concentration 150 mg/L) (300 mg/L) deep anesthesia. Once anesthetized, animals are deheaded and marrowed in accordance with the animal rights rules of the Canton of Geneva. A small piece of ovary is isolated for immediate preparation, while the rest is placed in a sterile Barth solution at 4°C, which contains (in mM) NaCl 88,
由ACh或其他促效劑誘發之電流係使用裝備有標準雙電極電壓鉗組態(TEVC)之自動過程記錄。資料係使用根據Matlab(Mathworks Inc.)運行之HiQScreen專用資料獲取及分析軟體擷取及分析。 5.4.3 促效劑製備The current induced by ACh or other agonists is recorded using an automatic process equipped with a standard two-electrode voltage clamp configuration (TEVC). The data was acquired and analyzed using HiQScreen special data acquisition and analysis software running according to Matlab (Mathworks Inc.). 5.4.3 Preparation of agonists
ACh係製備為水中之濃儲備溶液(10-1 M)且接著在記錄培養基中稀釋以獲得所需測試濃度。化合物係以儲備溶液(1 mM)形式溶解於OR2中且在實驗當天進行最終稀釋至所需濃度。ACh is prepared as a concentrated stock solution (10 -1 M) in water and then diluted in recording medium to obtain the desired test concentration. The compound was dissolved in OR2 as a stock solution (1 mM) and was finally diluted to the desired concentration on the day of the experiment.
化合物1半-半乳糖二酸鹽之測試濃度為(以微莫耳計) 0.1、0.3、1、3、10、30、100及300。氯化乙醯膽鹼之測試濃度為1280微莫耳。
5.4.4 資料分析及統計The tested concentrations of
對於統計分析,值係使用Excel (Microsoft)或Matlab (Mathworks Inc.)計算。為了獲得伴以標準差之平均量測值,所有實驗均使用至少三個細胞進行。 5.4.5 實驗程序For statistical analysis, the values are calculated using Excel (Microsoft) or Matlab (Mathworks Inc.). To obtain an average measurement with standard deviation, all experiments were performed using at least three cells. 5.4.5 Experimental procedures
注射編碼人類α3β4、α3α5β4、α4β2之cDNA係在至少95個卵母細胞中進行,使用專用自動注射裝置(Hogg等人, J. Neurosci. Methods, 2008)進行且在至少兩天後檢查受體表現。卵母細胞戳有兩個電極且其膜電位在整個實驗中維持(除非有所指示)於-80 mV。 測定人類nAChR處之假定促效活性的方案Injection of cDNA encoding human α3β4, α3α5β4, α4β2 was performed in at least 95 oocytes, using a dedicated automatic injection device (Hogg et al., J. Neurosci. Methods, 2008) and the recipient performance was checked at least two days later . The oocyte has two electrodes and its membrane potential is maintained at -80 mV throughout the experiment (unless indicated). Protocol to determine putative agonistic activity at human nAChR
方案序列開始於自負載盤取用卵母細胞(步驟1)及探測針對短暫ACh測試脈衝(1280 µM)之保持電流及反應的步驟4-5。顯示穩定電流之細胞接著洗滌90秒(步驟9)。記錄序列開始於步驟10且化合物以2分鐘時間間隔連續施加10秒(步驟12)。對於α7受體化合物,施加減少至5秒。針對化合物數目及細胞數目(步驟15)重複過程自身(步驟14)。The protocol sequence begins with steps 4-5 of taking oocytes from the load tray (step 1) and detecting the holding current and response to a short ACh test pulse (1280 µM). The cells showing steady current are then washed for 90 seconds (step 9). The recording sequence starts at
為了評估化合物1半-半乳糖二酸鹽二水合物之促效特性,使用短暫暴露於化合物1半-半乳糖二酸鹽二水合物之一系列生長濃度的方案。To evaluate the potency properties of
為了測定化合物之可能的拮抗特性,化合物之預施加及共施加,細胞對ACh之反應(接近EC50
)的方案首先單獨且接著在暴露於測試化合物之後應用。在人類α3β4、α3α5β4、α4β2及α7菸鹼受體處測定化合物1半-半乳糖二酸鹽二水合物之拮抗特性。
7 結果To determine the possible antagonistic properties of the compound, the compound is applied pre-and co-applied, the cellular response to ACh (near EC 50) of the first embodiment separately and then after exposure to the test compound application. The antagonistic properties of
化合物1半-半乳糖二酸鹽二水合物在α3β4、α3α5β4、α4β2及α7受體處之促效作用的測定展現此化合物在10至100 μM範圍內充當此等受體處之促效劑。然而,在受體亞型之功能中觀測到顯著差異。亦即,化合物1半-半乳糖二酸鹽二水合物為人類α7受體處之不佳促效劑,在300 μM處僅誘發最大ACh誘發電流之24%。相比之下,來自α4β2之資料展現化合物1半-半乳糖二酸鹽二水合物誘發大於最大ACh反應約2倍之電流。此外,暴露於化合物1半-半乳糖二酸鹽二水合物增強後續ACh誘發電流。α3β4及α3α5β4處記錄之資料展現化合物1半-半乳糖二酸鹽二水合物充當此等受體處之促效劑,誘發最大ACh誘發電流之約94%。The measurement of the agonistic effect of
進行以測定化合物1半-半乳糖二酸鹽二水合物在人類α3β4、α3α5β4、α4β2及α7 nAChR處之假定促效活性的實驗確認化合物1半-半乳糖二酸鹽二水合物在所考慮受體處充當促效劑。然而,值得注意的是,相較於內源性配位體乙醯膽鹼(ACh),化合物1半-半乳糖二酸鹽二水合物在雜聚α4β2受體處誘發更大電流,且亦對於此受體亞型展示於較高效能下。Experiments were conducted to determine the hypothetical agonistic activity of
測定化合物1半-半乳糖二酸鹽二水合物之拮抗活性係在低濃度範圍內使用累積暴露進行。針對化合物1半-半乳糖二酸鹽二水合物獲得之結果展現此化合物以濃度依賴性方式抑制α3α5β4及α4β2受體且抑制不完全且對於最高測試濃度達成平線區。相比之下,未在此等實驗中測試之範圍內在α3β4或α7受體處觀測到顯著抑制。The determination of the antagonistic activity of
α3β4、α3α5β4、α4β2及α7 nAChR進行之脫敏實驗展現受體亞型功能之顯著差異。儘管α3β4及α7受體對持續暴露於至多300 nM濃度之化合物1半-半乳糖二酸鹽二水合物不敏感,但在α3α5β4及α4β2受體處觀測到顯著抑制。然而,抑制在測試之最高濃度處達成平線區水準表明此化合物僅可在實驗條件內引起部分脫敏。在α3β4、α3α5β4、α4β2及α7 nAChR處進行之脫敏實驗展現可在此等不同受體亞型之間觀測到顯著差異。Desensitization experiments conducted with α3β4, α3α5β4, α4β2, and α7 nAChR showed significant differences in receptor subtype function. Although α3β4 and α7 receptors were not sensitive to continuous exposure to
此等資料說明人類nAChR於爪蟾屬卵母細胞中之表現為測試針對給定化合物之功能性促效及拮抗活性提供有效模型且促效劑在比活化所需更低的濃度下引起受體脫敏。These data indicate that the performance of human nAChR in Xenopus oocytes provides an effective model for testing the functional agonistic and antagonistic activity against a given compound and that the agonist causes receptors at lower concentrations than required for activation Desensitization.
化合物1半-半乳糖二酸鹽二水合物在α3β4受體處幾乎充當完全促效劑。EC50在42.09±5.36 µM處。
化合物1半-半乳糖二酸鹽二水合物在α3α5β4受體處幾乎充當完全促效劑。EC50在32.15±2.16 µM處。
化合物1半-半乳糖二酸鹽二水合物在α4β2受體處充當比ACh更強力之促效劑。EC50在48.82±17.41 µM處。
化合物1半-半乳糖二酸鹽二水合物為α7受體處比ACh更強力之促效劑。應注意,鑒於由化合物1半-半乳糖二酸鹽二水合物誘發之小部分電流,EC50僅為評估。EC50在1261±500 µM處。
測試化合物1半-半乳糖二酸鹽二水合物在人類α3β4 nAChR處之拮抗特性,然而,由於觀測到ACh誘發電流之極小抑制,未嘗試符合此等結果。The antagonistic properties of
測試化合物1半-半乳糖二酸鹽二水合物在人類α3α5β4 nAChR處之拮抗特性,且相較於α3β4,在人類α3α5β4 nAChR處觀測到具有平穩階段之明顯抑制。The antagonistic properties of
測試化合物1半-半乳糖二酸鹽二水合物在人類α4β2 nAChR處之拮抗特性,且相較於α3β4,亦在人類α4β2 nAChR處觀測到具有平穩階段之明顯抑制。The
測試化合物1半-半乳糖二酸鹽二水合物在人類α7 nAChR處之拮抗特性,且未觀測到α7 nAChR處之顯著抑制。實例 2 : 化合物 1 半 - 半乳糖二酸鹽二水合物經 2 週 , 在低、中及高劑量濃度下之 2 期 臨床研究 The antagonistic properties of
此實例描述用於評估相較於安慰劑,化合物1半-半乳糖二酸鹽二水合物鼻用噴霧對乾眼病之病徵及症狀之安全性及有效性的研究。結果證明化合物1半-半乳糖二酸鹽二水合物(0.2%、1.0%、2.0%)鼻用噴霧在診斷患有乾眼病之個體中誘發水性淚液產生及減少乾眼病之症狀。
概要
當以鼻內噴霧形式遞送時,化合物1半-半乳糖二酸鹽二水合物可促進鼻淚反射活化且因此表示改善乾眼病之病徵及症狀的新穎候選物。When delivered in the form of an intranasal spray,
此研究將利用人工創造之不利環境模型來評估乾眼症狀。人工創造之不利環境由藉由調節濕度、溫度、氣流、照明條件及視覺任務分配而使環境條件標準化之房間組成。乾眼患者暴露於人工創造之不利環境至多兩小時,在此期間可在暴露之前、期間及之後評估主觀及客觀參數。人工創造之不利環境表示乾眼患者遇到的每日情況,諸如強制熱風供暖系統、飛機旅行及電腦使用且允許此等變數之標準化。 總體研究設計This study will use artificially created adverse environmental models to assess dry eye symptoms. The artificially created unfavorable environment consists of rooms that standardize environmental conditions by regulating humidity, temperature, airflow, lighting conditions, and visual task assignment. Dry eye patients are exposed to an artificially created adverse environment for up to two hours, during which subjective and objective parameters can be evaluated before, during, and after exposure. The artificially created unfavorable environment represents the daily conditions encountered by patients with dry eyes, such as forced hot air heating systems, aircraft travel and computer use and allows the standardization of these variables. Overall study design
此為2期、多中心、隨機化、雙盲、安慰劑對照研究,其經設計以評估化合物1半-半乳糖二酸鹽二水合物鼻用噴霧對患有乾眼病之成年參與者的安全性及功效。大致160個具有個體報告之乾眼病史且符合所有其他研究合格性標準之至少22歲的個體將隨機分組以在問診1及問診2時接受化合物1半-半乳糖二酸鹽二水合物或安慰劑施用。
將要求在施用時段期間提早終止之參與者在研究出口之前完成安全性評估(若參與者同意)。將不替換自研究提早終止之參與者。研究群體 Participants who terminate early during the administration period will be required to complete a safety assessment (if the participant agrees) before the study exit. Participants who have terminated the study early will not be replaced. Research community
據估計,大約160個參與者(每組大約40個)將在美國的至多3個地點登記。個體將隨機分組以接受以下四個劑量分配中之一者:
在各鼻孔中以100微升(µL)鼻內噴霧形式遞送之安慰劑(媒劑)
在各鼻孔中以100 µL鼻內噴霧形式遞送之0.11%化合物1游離鹼(0.2%化合物1半-半乳糖二酸鹽二水合物)
在各鼻孔中以100 µL鼻內噴霧形式遞送之0.55%化合物1游離鹼(1.0%化合物1半-半乳糖二酸鹽二水合物)
在各鼻孔中以100 µL鼻內噴霧形式遞送之1.1%化合物1游離鹼(2.0%化合物1半-半乳糖二酸鹽二水合物)It is estimated that approximately 160 participants (approximately 40 per group) will register at up to 3 locations in the United States. Individuals will be randomly grouped to receive one of the following four dose distributions:
Ÿ Placebo (vehicle) delivered as a 100 microliter (µL) intranasal spray in each nostril
Ÿ 0.11
個體將在問診1及問診2時投與化合物1半-半乳糖二酸鹽二水合物/安慰劑。The individual will be administered
所有個體必須為至少22歲,為任何性別,且為任何人種,且必須滿足所有納入標準及不滿足任何排除標準。關於納入及排除標準,參見上文概述。All individuals must be at least 22 years old, of any gender, and of any ethnic origin, and must meet all inclusion criteria and do not meet any exclusion criteria. For inclusion and exclusion criteria, see the summary above.
退出標準:若在研究期間之任何時間,個體安全已受損,則個體可退出研究。個體可在任何時候自研究撤回同意書。任何個體可在研究過程中出於非順應性或任何有效的醫療原因而中止。主要功效量度 Withdrawal criteria: If the individual’s safety has been compromised at any time during the study, the individual may withdraw from the study. Individuals may withdraw consent from the study at any time. Any individual may be discontinued during the study due to non-compliance or any effective medical reason. Main efficacy measure
將測試以下主要終點:
問診1時之斯戈默測試
問診2時之EDS
安全性量度:不良事件(AE)。
其他量度:眼部不適量表、尿妊娠測試(第1天)調配物
安慰劑(化合物1半-半乳糖二酸鹽二水合物媒劑鼻用噴霧)
0.11%化合物1游離鹼(0.2%化合物1半-半乳糖二酸鹽二水合物)
0.55%化合物1游離鹼(1.0%化合物1半-半乳糖二酸鹽二水合物)
1.1%化合物1游離鹼(2.0%化合物1半-半乳糖二酸鹽二水合物)分配排程 The following main endpoints will be tested:
Ÿ Stommer test at the 1st time of consultation
Ÿ EDS at 2 o'clock
Safety measures: adverse events (AE).
Other measures: eye discomfort scale, urine pregnancy test (day 1)Formulation
Ÿ Placebo (nasal spray of
在問診1時,合格個體將隨機分組且研究藥物之第一劑量將在辦公室中投與。在問診2時,個體將在人工創造之不利環境暴露期間接受其第二劑量。At
化合物1半-半乳糖二酸鹽二水合物/安慰劑將以無菌水溶液形式在磷酸鹽緩衝鹽水中之所需濃度(取決於劑量組分配)下調配,且呈現於用橡膠塞密封之單次用玻璃瓶中。產品不含防腐劑且僅預期供鼻內使用。若產品混濁或若存在粒子,則不應使用。化合物1半-半乳糖二酸鹽二水合物溶液必須在不稀釋的情況下投與。參與者進入程序
如由納入標準所定義之參與者將視為進入此研究。 Participants as defined by the inclusion criteria will be considered to enter this study.
在參與者參與試驗之前(亦即,在研究相關程序之前),將與各潛在參與者討論該研究且希望參與之參與者必須經管制且使用機構審查委員會(IRB)批准之知情同意書(ICF)提供書面知情同意書。ICF必須為已由結構合理的IRB批准之最新版本。Before the participant participates in the trial (that is, before the research-related procedures), the study will be discussed with each potential participant and the participant who wishes to participate must be regulated and use the Informed Consent Form (ICF) approved by the Institutional Review Board (IRB) ) Provide written informed consent. The ICF must be the latest version approved by the well-structured IRB.
清除間隔:禁止之藥物、治療及活動係概述於排除標準中。Clearance interval: Prohibited drugs, treatments and activities are outlined in the exclusion criteria.
最終研究進入之程序:個體必須滿足所有納入標準且不滿足任何排除標準。分配至治療組之方法 Final research entry procedure: The individual must meet all inclusion criteria and not meet any exclusion criteria. Assignment to treatment group
將向合格之各個體分配篩選編號。所有篩選編號將在一地點以嚴格數值序列分配且將不跳過或省略編號。若在問診1時符合所有納入及排除標準,則各合格個體將接著分配一隨機分組編號。Screening numbers will be assigned to qualified individuals. All screening numbers will be assigned in a strict numerical sequence at one location and the numbers will not be skipped or omitted. If all the inclusion and exclusion criteria are met at the time of
隨機分組排程將提供至各研究場地。隨機分組排程將由場地分層,使得大致相等數目之個體將分至各場地之四個治療組中之每一者。場地工作人員將向患者分配標記有對應隨機分組編號之研究套組。隨機分組編號將記錄於患者之源文件及電子病歷報告表(eCRF)上。研究人員將在隨機分組過程中及在整個研究中經遮蔽。並行療法 Random group scheduling will be provided to each research site. The randomization schedule will be stratified by the venue so that approximately equal numbers of individuals will be assigned to each of the four treatment groups at each venue. The site staff will assign the patient to the study set marked with the corresponding random group number. The random group number will be recorded on the patient's source file and electronic medical record report form (eCRF). Researchers will be masked during randomization and throughout the study. Concurrent therapy
使用任何並行藥物、處方或非處方將連同服用藥物之原因一起記錄於個體之源文件及對應eCRF上。不允許同時入選另一研究性藥物或裝置研究。禁止之藥物 / 治療 The use of any concurrent medication, prescription or over-the-counter will be recorded on the individual's source file and corresponding eCRF along with the reason for taking the medication. It is not allowed to be enrolled in another study drug or device study at the same time. Prohibited drugs / treatment
在研究期間不允許之藥物/治療概述於排除標準中。逃避藥物 Drugs/treatments not allowed during the study are outlined in the exclusion criteria. Drug evasion
此研究不需要逃避藥物。特殊飲食或活動 This study does not require drug evasion. Special diet or activity
此研究不需要特殊飲食或活動。關於研究目標在各研究問診時待執行之程序 No special diet or activities are required for this study. Procedures for research objectives to be executed during each research consultation
將執行以下程序(關於描述,參見下文標題為檢查程序、測試、設備及技術之章節)。問診 1 ( 第 1 天 ) :篩選及斯戈默測試評估 篩選 知情同意書/健康資訊便攜性及責任法案(HIPAA)同意書 人口統計資料、醫療/藥物治療及眼部病史 合格性標準 OSDI© EDS (視覺類比量表) 眼部不適量表 BCVA 裂隙燈活組織檢視法 角膜螢光素染色 斯戈默測試(程序將在角膜螢光素染色之後進行) 在鼻刺激下之斯戈默測試(棉花棒;在鼻刺激下之斯戈默測試將在第一斯戈默測試之後10分鐘進行) 鼻內檢查 尿妊娠測試(若可行) 伴隨藥物治療 AE詢問治療 ( 斯戈默測試評估 ) 治療前程序: The following procedures will be performed (for the description, see the section below titled Inspection Procedures, Tests, Equipment and Technology).inquiry 1 ( First 1 day ) : Screening and Sgormer Test Evaluation filter Ÿ Informed consent/Consent of Health Information Portability and Accountability Act (HIPAA) Ÿ Demographics, medical/medical treatment and eye history Ÿ Eligibility criteria Ÿ OSDI© Ÿ EDS (Visual Analogue Scale) Ÿ Eye Discomfort Scale Ÿ BCVA Ÿ Slit lamp biopsy Ÿ Corneal fluorescein staining Ÿ Gomer test (the procedure will be performed after corneal luciferin staining) Ÿ Sgormer test under nasal irritation (Cotton swab; Sgormer test under nasal irritation will be performed 10 minutes after the first Sgormer test) Ÿ Intranasal examination Ÿ Urine pregnancy test (if feasible) Ÿ Concomitant medication Ÿ AE inquirytreatment ( Skimer Test Evaluation ) Pre-treatment procedures:
隨機分組:合格參與者將分至以下治療組中之一者:
在各鼻孔中以100 µL鼻內噴霧形式遞送之安慰劑(媒劑)
在各鼻孔中以100 µL鼻內噴霧形式遞送之0.11%化合物1游離鹼(0.2%化合物1半-半乳糖二酸鹽二水合物)
在各鼻孔中以100 µL鼻內噴霧形式遞送之0.55%化合物1游離鹼(1.0%化合物1半-半乳糖二酸鹽二水合物)
在各鼻孔中以100 µL鼻內噴霧形式遞送之1.1%化合物1游離鹼(2.0%化合物1半-半乳糖二酸鹽二水合物)治療程序
:
指示個體進行研究性藥物/安慰劑投與
用研究性藥物/安慰劑治療治療後程序:
治療後斯戈默測試(緊接在研究性藥物投與之後進行)
BCVA
裂隙燈活組織檢視法
鼻內內窺鏡檢查
伴隨藥物治療
AE詢問
問診2之參與者安排問診 2 ( 第 15+4 天 ) :人工創造之不利環境
醫療/藥物治療及眼部病史更新
EDS
眼部不適量表
暴露於人工創造之不利環境大約120分鐘
在進入人工創造之不利環境時及此後每5分鐘收集之EDS。
在進入人工創造之不利環境時及此後每5分鐘收集之眼部不適量表。
指示個體進行研究性藥物/安慰劑投與
用研究性藥物/安慰劑治療
在使用眼部不適量表,參與者在人工創造之不利環境暴露期間的兩個或更多個連續時間點於至少一隻眼睛中報告≥3之眼部不適評分後,將投與研究性藥物/安慰劑治療(若參與者在時間=0時一隻眼睛之眼部不適評級為3,則其必須在兩次連續量測中針對該眼睛報告眼部不適評級4)。參與者將每隔5分鐘在施用結束之後1分鐘重新繼續症狀評估。
BCVA
裂隙燈活組織檢視法
鼻內檢查
尿妊娠測試(若可行)
伴隨藥物治療
AE詢問
研究出口預定問診 Randomization: Qualified participants will be assigned to one of the following treatment groups:
Ÿ Placebo (vehicle) delivered as a 100 µL intranasal spray in each nostril
Ÿ 0.11
參看下文標題為問診及量測排程之章節。非預定問診 See the section below titled Interview and Measurement Schedule. Unscheduled consultation
可進行此等問診以確保個體安全性。在非預定問診時進行之所有程序將記錄於源文件中及非預定問診eCRF頁上。eCRF中指示之任何未進行之程序應表示為「未進行(Not done)」。These consultations can be conducted to ensure individual safety. All procedures performed during an unscheduled consultation will be recorded in the source file and on the unscheduled consultation eCRF page. Any unprocessed procedures indicated in the eCRF should be indicated as "Not done".
可在非預定問診時進行之評估包括: 裂隙燈活組織檢視法; 視力; 鼻內檢查; 尿妊娠測試(若可行); 評估AE; 評估並行藥物及/或治療;及 由調查員判斷必需之任何其他評估。方案順應性 Assessments that can be performed during unscheduled consultations include: Ÿ slit lamp biopsy; Ÿ vision; Ÿ intranasal examination; Ÿ urine pregnancy test (if feasible); Ÿ assessment of AE; Ÿ assessment of concurrent medication and/or treatment; and Ÿ Any other assessment as judged by the investigator is necessary. Program compliance
將指示個體關於研究藥物將在問診1及2時如何投與且提供詳細書面說明書以供審閱。Individuals will be instructed on how the study drug will be administered at
給藥順應性將基於問診1及2時使用/未使用之研究藥物。個體處置 Dosage compliance will be based on the study drug used/unused at
完成個體為尚未自研究中止之個體。Completed individuals are those who have not been discontinued from the study.
個體可歸因於以下各者而在其完成研究之前的任何時間中止: AE; 當醫療上需要時解遮蔽; 方案違反; 管理原因(例如不能繼續、失訪); 研究終止; 個體選擇(例如撤回同意書);及 其他The individual may be discontinued at any time before completing the study due to the following: Ÿ AE; Ÿ Unmask when medically necessary; Ÿ program violation; Ÿ Management reasons (for example, unable to continue, lost to follow-up); Ÿ Research termination; Ÿ Individual choice (eg withdrawal of consent); and Ÿ Other
附註:另外,任何個體可出於任何合理的醫療原因而中止。Note: In addition, any individual may be suspended for any reasonable medical reason.
個體中止通知及中止原因將清楚地記錄於eCRF上。The notice of individual suspension and the reason for suspension will be clearly recorded on eCRF.
將不替換中止個體。研究終止 Suspended individuals will not be replaced. Study termination
研究可在任何時候停止。研究持續時間 Research can be stopped at any time. Study duration
個別個體參與將涉及大約2週(14天)內之2次問診監測及品質保證 Individual participation will involve 2 consultations and quality assurance in about 2 weeks (14 days)
在研究過程期間,監測者或指定人員將進行常規現場視察以檢查方案順應性、評估研究藥物可追究性、個體安全性及確保研究係根據相關的監管要求進行。個體醫療記錄之審查將以充分維持個體保密性的方式進行。研究監測之其他細節將概述於監測計劃中。During the research process, monitors or designated personnel will conduct routine on-site inspections to check protocol compliance, assess study drug traceability, individual safety, and ensure that research is conducted in accordance with relevant regulatory requirements. The review of individual medical records will be conducted in a way that maintains the confidentiality of the individual. Other details of the research monitoring will be outlined in the monitoring plan.
監管當局可進行現場檢驗及/或審計,其可包括源資料檢查。因此,檢驗及/或審計將需要直接存取原始源資料。所有檢驗及審計將在地方、州及聯邦法律適用之程度上考慮資料保護以及個體保密性而進行。不良事件 The supervisory authority may conduct on-site inspections and/or audits, which may include source data inspections. Therefore, inspection and/or auditing will require direct access to the original source material. All inspections and audits will be conducted taking into account data protection and individual confidentiality to the extent applicable by local, state, and federal laws. Adverse events
AE係定義為與在人體中使用藥物相關之任何不良醫療事件,無論該事件是否視為藥物相關。AE因此可為在開始向個體投配研究藥物之後出現之任何不利及非預期病徵(例如異常實驗室發現)、症狀或疾病,而不對因果關係進行任何判斷。在投與研究藥物之後惡化之任何預先存在之醫學病況亦將視為新AE。AE is defined as any adverse medical event related to the use of drugs in the human body, regardless of whether the event is considered to be drug-related. AE can therefore be any adverse and unexpected symptoms (eg, abnormal laboratory findings), symptoms, or disease that occur after starting to administer the study drug to the individual without any judgment of causality. Any pre-existing medical conditions that deteriorate after administration of the study drug will also be considered a new AE.
研究藥物包括正進行評估之研究性藥物及安慰劑。Study drugs include research drugs and placebos that are being evaluated.
關於AE之文件製作應關於性質、起始日期、結束日期、嚴重度、與研究藥物之關係、採取之行動、嚴重性及由調查員觀測或在間接詢問後由個體報告之任何病徵或症狀之結果來進行。嚴重度 The documentation about AE should be about the nature, start date, end date, severity, relationship with study drug, action taken, severity, and any signs or symptoms observed by the investigator or reported by the individual after indirect inquiry The results are carried out. Severity
AE之嚴重度係定義為如由調查員所測定或由患者/個體向其報告之AE強度程度的定性評估。嚴重度評估無關於與研究藥物之關係或事件嚴重性而進行且應根據以下標度評估:The severity of AE is defined as the qualitative assessment of the degree of AE intensity as determined by the investigator or reported to it by the patient/individual. Severity assessments are conducted without regard to the relationship with the study drug or the severity of the event and should be evaluated according to the following scale:
輕度 :事件對個體而言為明顯的,但易於容忍且不干擾個體之每日活動。 Mild : The event is obvious to the individual, but is easily tolerated and does not interfere with the individual's daily activities.
中度 :事件為麻煩的,可能需要額外療法,且可干擾個體之每日活動。 Moderate : The event is troublesome, may require additional therapy, and may interfere with the individual's daily activities.
重度 :事件為不能忍受的,需要額外療法或更改療法,且干擾個體之每日活動。與研究藥物之關係 Severe : The event is intolerable, requires additional or altered therapy, and interferes with the individual's daily activities. Relationship with research drugs
各AE與研究產品之關係應由調查員(以盲法方式)使用此等解釋來確定:The relationship between each AE and the research product should be determined by the investigator (in a blinded manner) using these interpretations:
確定 : 當存在良好原因及足夠文件以展現研究產品與AE之間的直接因果關係時 Identify : When there is a good cause and sufficient documentation to demonstrate the direct causal relationship between the research product and AE
很可能 : 當存在良好原因及足夠文件以在似乎合理、可設想、可能但未必高度可能之意義上假定因果關係時 Most likely : when there are good reasons and sufficient documentation to assume causality in the sense that it seems reasonable, conceivable, possible but not necessarily highly likely
有可能 : 當存在足夠資訊以在並非不可能及並非不太可能之意義上接受因果關係之可能性,儘管關聯歸因於例如遺漏資料或證據不足而不確定或有疑問時 Possible : When there is sufficient information to accept the possibility of causality in the sense that it is not impossible and not unlikely, even though the association is due to, for example, missing data or insufficient evidence and is uncertain or in doubt
無 :當存在足夠資訊以接受無因果關係(在不可能及不大可能之意義上)時 None : When there is enough information to accept a non-causal relationship (in the sense of impossible and unlikely)
未分類 :當因果關係出於歸因於證據不足、資料衝突或文件不佳之任何原因而不可評定時預期性 Unclassified: When causality attributable to the lack of evidence for any of the causes of poor data or documents not conflict when assessing prospective
AE之預期性應基於關於研究藥物之現有安全性資訊使用此等解釋來確定:The anticipation of AE should be based on existing safety information about the study drug using these interpretations to determine:
未預期 :未列於調查員手冊(IB)中或未列於已觀測之特異性或嚴重度下之AE。 Unexpected : AE not listed in the Investigator's Handbook (IB) or not under the specificity or severity observed.
預期 : 列於IB中已觀測之特異性及嚴重度下之AE。 Expected : AE listed in the specificity and severity observed in IB.
不適用 : 與研究藥物無關之任何AE。 Not applicable : Any AE not related to the study drug.
在IB中提及為在一類藥物之情況下出現或由藥物之藥理學特性而預料,但未特定提及為在調查中之特定藥物之情況下出現之AE係視為未預期的。調查員應起初對AE之預期性進行分類,但最終分類以醫學監察員之判定為準。嚴重不良事件 Mentioned in IB as occurring in the case of a class of drugs or expected from the pharmacological properties of the drug, but not specifically mentioned as appearing in the case of the specific drug under investigation is considered unexpected. The investigator should initially classify the AE's expectations, but the final classification is subject to the medical inspector's judgment. Serious adverse event
若在調查員看來,AE導致以下結果中之任一者,則將其視為嚴重的(SAE): 死亡 危及生命之AEIf, in the eyes of the investigator, AE causes any of the following results, it is considered serious (SAE): Ÿ death Ÿ Life-threatening AE
附註:若在調查員看來,AE之出現將患者或個體置於死亡之即時風險下,則將其視為「危及生命的」。其不包括若以更嚴重形式出現,則有可能引起死亡之AE。 住院或延長現有住院Note: If it appears to the investigator that the occurrence of AE places the patient or individual at immediate risk of death, it is considered "life-threatening". It does not include AEs that may cause death if they occur in a more serious form. Ÿ Hospitalization or extension of existing hospitalization
附註:術語「住院」係指任何入院(即使小於24小時)。對於慢性或長期住院病人,入院包括在醫院內轉移至急症/重症護理住院病人病房。住院不包括:急診;門診/當日/非臥床手術;觀察/短暫停留病房;康復設施;臨終關懷設施;療養院;或臨床研究/1期單位。Note: The term "hospitalization" refers to any admission (even if less than 24 hours). For chronic or long-term inpatients, admission includes transfer to emergency/intensive care inpatient wards within the hospital. Hospitalization does not include: emergency department; outpatient/same day/ambulatory surgery; observation/short stay in ward; rehabilitation facility; hospice facility; nursing home; or clinical research/1 phase unit.
附註:術語「延長現有住院」係指任何延長住院而超出由於調查員或治療醫師所確定之初始入院所預期或所需之停留。 持續性或顯著無能力或執行正常生活功能之能力的重大破壞Note: The term "extension of existing hospitalization" refers to any extended hospitalization that exceeds the expected or required stay for the initial admission determined by the investigator or treating physician. Ÿ Sustained or significant incapacity or significant disruption of normal life functions
附註:尤其與視覺威脅相關之SAE將解釋為對個體眼睛之任何潛在減損或損害(例如出血、視網膜剝離、中央角膜潰瘍或視神經損傷)。 先天性異常/天生缺陷。Note: SAE, especially related to visual threats, will be interpreted as any potential loss or damage to the individual's eyes (such as bleeding, retinal detachment, central corneal ulcer, or optic nerve damage). Ÿ Congenital anomalies/born defects.
當基於適當醫學判斷,可危及患者或個體且可需要醫療或手術干預以預防此定義中所列之結果之一時,可能不導致死亡、危及生命且需要住院之重大醫療事件可視為嚴重。報告不良事件之程序 When, based on appropriate medical judgment, a patient or individual may be endangered and medical or surgical intervention may be required to prevent one of the results listed in this definition, a major medical event that may not result in death, life-threatening and requires hospitalization may be considered serious. Procedures for reporting adverse events
所有AE及其結果必須向調查員及IRB/IEC報告,如由IRB/IEC、聯邦、州或地方法規及健康管理當局所要求,且記錄於適當eCRF上。All AEs and their results must be reported to the investigator and IRB/IEC, as required by the IRB/IEC, federal, state or local regulations, and health management authorities, and recorded on the appropriate eCRF.
所有『疑似』及『未預期』之AE應向調查員及IRB/IEC報告,如由IRB/IEC、聯邦、州或地方法規及健康管理當局所要求。All "suspicious" and "unexpected" AEs should be reported to investigators and IRB/IEC, as required by IRB/IEC, federal, state or local regulations and health management authorities.
為了確保個體安全,不管與研究藥物之關係,所有SAE必須立即報告。與SAE相關之所有資訊必須記錄於適當CRF上。除了CRF上報告之資訊以外,調查員亦有義務追求及獲得調查員所要求之資訊。經歷SAE之所有個體必須隨訪且報告結果。To ensure individual safety, all SAEs must report immediately regardless of the relationship with the study drug. All information related to SAE must be recorded on the appropriate CRF. In addition to the information reported on the CRF, the investigator is also obliged to pursue and obtain the information requested by the investigator. All individuals undergoing SAE must be followed up and report the results.
若發生SAE,調查員必須在其檔案中獲得及維持來自協助個體治療及隨訪之同事的所有相關的醫療記錄、資訊及醫學判斷;提供完全病歷,其包括關於事件是否疑似與研究藥物使用相關之陳述;且告知SAE之IRB在其指南內報告SAE。對研究藥物解遮蔽之程序 If SAE occurs, the investigator must obtain and maintain all relevant medical records, information, and medical judgments from colleagues who assist the individual in treatment and follow-up in their files; provide a complete medical record, including information about whether the event is suspected to be related to the use of study drugs Statement; and inform SAE's IRB to report SAE in its guidelines. Procedures for unmasking research drugs
涉及進行研究之所有個體、調查員及研究人員將關於治療分配經遮蔽。當醫療上需要時,調查員可能需要確定個體已分至何治療組。解遮蔽個體將中止研究。個體在不良事件之後的隨訪之類型及持續時間 All individuals, investigators, and researchers involved in conducting the study will be covered regarding treatment allocation. When medically necessary, the investigator may need to determine to which treatment group the individual has been assigned. Unmasking the individual will stop the study. Type and duration of individual follow-up after adverse events
調查員將追蹤未解決的AE至解決,直至個體失訪或直至AE以其他方式分類。解決意謂個體已返回至基線健康狀態或調查員不預期AE之任何進一步的改善或惡化。若患者失訪,則調查員應進行3次合理的嘗試以經由電話、郵件或保證郵件來聯繫患者。所有隨訪將記錄於個體之源文件中。在最後一次預定聯繫時鑑別之非嚴重AE必須伴以注意到的狀態記錄於AE eCRF上。The investigator will track unresolved AEs until resolution, until the individual is lost to follow-up or until AEs are classified in other ways. Resolution means that the individual has returned to baseline health or the investigator does not expect any further improvement or deterioration of AE. If the patient is lost to follow-up, the investigator should make 3 reasonable attempts to contact the patient by phone, mail or guarantee mail. All follow-up visits will be recorded in the source file of the individual. The non-serious AE identified at the last scheduled contact must be recorded on the AE eCRF with the status noted.
若調查員意識到關於現有SAE之任何新資訊(亦即,解決、狀況變化或新治療),則必須在意識到新資訊之24小時內完成新SAE/非預期報告表且發傳真。原始SAE表不改變。報告應描述事件已解決或繼續且如何處理該事件。分析之統計假設及方法 分析群體 If the investigator is aware of any new information about the existing SAE (ie, resolution, status change, or new treatment), then the new SAE/unexpected report form must be completed and faxed within 24 hours of being aware of the new information. The original SAE table is unchanged. The report should describe how the incident has been resolved or continued and how to handle the incident.Statistical assumptions and methods of analysis Analysis group
將考慮以下分析群體:The following analysis groups will be considered:
治療意向群體-治療意向(ITT)群體包括所有隨機分組個體。ITT群體中之個體將以隨機分組形式分析。Treatment Intention Group-The treatment intent (ITT) group includes all randomly grouped individuals. Individuals in the ITT group will be analyzed in random groups.
符合方案群體-符合方案(PP)群體包括ITT群體中不具有顯著方案偏差且完成研究之個體。方案偏差將在資料庫鎖定及解遮蔽之前評估。PP群體中之個體將以經治療形式分析。Compliant protocol groups-Compliant protocol (PP) groups include individuals in the ITT population who do not have significant protocol deviations and complete the study. Plan deviations will be evaluated before the database is locked and unmasked. Individuals in the PP group will be analyzed in the form of treatment.
安全群體-安全群體包括接受至少一個劑量之研究產品的所有個體。安全群體中之個體將以經治療形式分析。Safe group-The safe group includes all individuals who receive at least one dose of the research product. Individuals in the safe group will be analyzed in the form of treatment.
將對安全群體進行安全資料統計分析。將對ITT群體進行基線及功效資料分析。亦將對PP群體進行功效分析,作為敏感性分析。統計假設 The safety data will be statistically analyzed for the safety groups. The baseline and efficacy data of the ITT population will be analyzed. The efficacy analysis of the PP population will also be conducted as a sensitivity analysis. Statistical assumptions
H01
:在斯戈默測試結果相對於基線的改變中,化合物1半-半乳糖二酸鹽二水合物鼻用噴霧(低劑量、中劑量或高劑量)與安慰劑之間不存在差異。H 01 : There is no difference between the stommer test result and the placebo in the nasal spray of
H11
:在斯戈默測試結果相對於基線的改變中,化合物1半-半乳糖二酸鹽二水合物鼻用噴霧(低劑量、中劑量或高劑量)與安慰劑之間存在差異。H 11 : There is a difference between the
H02
:在EDS自治療前至治療後的改變中,化合物1半-半乳糖二酸鹽二水合物鼻用噴霧(低劑量、中劑量或高劑量)與安慰劑之間不存在差異。H 02 : In the change of EDS from before treatment to after treatment, there was no difference between
H12
:在EDS自治療前至治療後的改變中,化合物1半-半乳糖二酸鹽二水合物鼻用噴霧(低劑量、中劑量或高劑量)與安慰劑之間存在差異。H 12 : In the change of EDS from before treatment to after treatment, there is a difference between
成功結果將為拒絕兩個虛無假設(H01 及H02 )之結果。樣本大小 A successful result will be the result of rejecting the two null hypotheses (H 01 and H 02 ). Sample size
此研究之樣本大小不基於統計能力考慮因素。吾人預期四個治療組中之每一者中將登記大約40位個體,總共大約160個隨機分組個體。假定5%退出率,預期每組大約38位個體完全研究。統計分析 一般考慮因素 The sample size of this study is not based on statistical power considerations. We expect that approximately 40 individuals will be registered in each of the four treatment groups, for a total of approximately 160 randomized individuals. Assuming a 5% withdrawal rate, it is expected that approximately 38 individuals from each group will be fully studied.Statistical Analysis General considerations
定量變數將使用個體數目(n)、平均值、中值、標準差、最小值及最大值概述。定性變數將使用計數及百分比概述。Quantitative variables will be summarized using the number of individuals (n), mean, median, standard deviation, minimum and maximum. Qualitative variables are outlined using counts and percentages.
所有概述將藉由治療組呈現。概述將針對人口統計資料、醫療史、伴隨藥物治療及個體處置提供。All overviews will be presented by the treatment group. The overview will be provided for demographic data, medical history, concomitant medications and individual treatment.
出於概述目的,醫療史、伴隨藥物治療及AE將按需要根據MedDRA及世界衛生組織藥物詞典編碼。For overview purposes, medical history, concomitant medications, and AEs will be coded according to MedDRA and the World Health Organization Drug Dictionary as needed.
基線量測定義為在起始研究治療之前,通常在問診1篩選時之最後一次量測。
分析單位Baseline measurement is defined as the last measurement prior to the initiation of study treatment, usually at the time of Screening for
分析兩隻眼睛之安全終點。對於功效終點,分析單位將為如下所定義之研究用眼睛:Analyze the safety endpoint of both eyes. For the efficacy endpoint, the unit of analysis will be the research eye defined as follows:
研究用眼睛之定義為符合所有納入/淘汰標準之眼睛;若兩隻眼睛均合格,則為在篩選問診時使用棉花棒刺激會增加產生最多淚液之眼睛,或若刺激之淚液產生無差異,則為在篩選時具有較低基礎斯戈默評分之眼睛。若任一量度均無差異,則以右眼用作研究用眼睛。遺漏數據 Research eyes are defined as those that meet all inclusion/elimination criteria; if both eyes are qualified, the use of cotton swabs to stimulate the eyes that produce the most tears during screening interviews, or if there is no difference in the stimulation of tears, then Eyes with a lower basic Sgormer score at the time of screening. If there is no difference in any measurement, the right eye is used as the research eye. Missing data
初步分析將使用觀測數據(不填補遺漏數據)進行。主要功效分析之敏感性分析將使用馬可夫鏈蒙地卡羅(Markov Chain Monte Carlo)多重填補法填補遺漏數據而進行。預期遺漏數據比率較低;然而,若遺漏數據比率超過5%,則額外遺漏數據填補方法(諸如臨界點分析)將用於理解遺漏數據對初步結果之潛在影響。The preliminary analysis will be performed using observation data (without filling in missing data). The sensitivity analysis of the main efficacy analysis will be performed using the Markov Chain Monte Carlo multiple filling method to fill in the missing data. It is expected that the rate of missing data is low; however, if the rate of missing data exceeds 5%, additional missing data filling methods (such as critical point analysis) will be used to understand the potential impact of missing data on preliminary results.
將僅使用觀測數據進行其他功效分析。多重性考慮 Only observed data will be used for other power analysis. Multiple considerations
此早期研究將不實施針對多個測試進行調整。主要功效分析 This early study will not implement adjustments for multiple tests. Main efficacy analysis
將根據以下終點進行主要功效分析:
問診1時之斯戈默測試
在問診2時,在暴露於人工創造之不利環境期間之乾眼評分The main efficacy analysis will be based on the following endpoints:
Stommer test at 1 o'clock
At the time of
斯戈默測試及乾眼評分將藉由問診、時間點(適當時)及處理法,採用定量描述性統計(n、平均值、中值、標準差、最小值及最大值)概述。The Gomer test and dry eye scoring will be summarized using quantitative descriptive statistics (n, mean, median, standard deviation, minimum and maximum) by questioning, time point (where appropriate) and treatment.
採用ANCOVA模型來比較各劑量之化合物1半-半乳糖二酸鹽二水合物鼻用噴霧與安慰劑治療組之間同時處理之斯戈默測試結果。ANCOVA模型將包括基線斯戈默測試(在篩選時擷取),以處理法及研究部位作為共變數。由此ANCOVA模型計算各處理法之最小均方(LS平均值)、對應之95%信賴區間(CI)及各劑量之化合物1半-半乳糖二酸鹽二水合物鼻用噴霧與安慰劑之間的估計處理法差異。另外,在獨立模型中,藉由處理法交互作用來探討研究部位,以評估研究部位之間之處理效果可能的差異。The ANCOVA model was used to compare the results of the Sgormer test for the simultaneous treatment of nasal sprays of
EDS自治療前至治療後之變化將使用ANCOVA模型分析,以治療前EDS作為共變數且以治療及時間點作為固定效應(考慮重複量測)。各治療之LS平均值、對應95%CI及各劑量之化合物1半-半乳糖二酸鹽二水合物鼻用噴霧與安慰劑之間的估計治療差異將計算自此ANCOVA模型。亦將在獨立模型中藉由治療相互作用來探索研究地點以評估治療效果可如何跨研究地點不同。The change of EDS from before treatment to after treatment will be analyzed using the ANCOVA model, with pre-treatment EDS as a covariate and treatment and time point as a fixed effect (considering repeated measurements). The LS mean of each treatment, the corresponding treatment difference between 95% CI and each dose of
將根據觀測數據對ITT群體進行初步分析。雙樣本t-檢驗及非參數威爾科克森(Wilcoxon)秩和檢驗將用於以未經調整的敏感性分析形式比較治療。亦將對藉由多重填補(MI)來填補遺漏數據之ITT群體,以及僅藉由觀測數據之PP群體進行敏感性分析。其他功效分析 Based on the observation data, a preliminary analysis of the ITT population will be conducted. Two-sample t-test and non-parametric Wilcoxon rank sum test will be used to compare treatments in an unadjusted sensitivity analysis format. Sensitivity analysis will also be performed on the ITT population that uses missing data (MI) to fill in missing data, and the PP population that uses observation data only. Other power analysis
亦將以與斯戈默測試之初步分析類似之方式在各個別時間點分析EDS自治療前至治療後之變化。此等ANCOVA模型將包括治療前EDS、治療及研究地點作為共變數。The changes in EDS from before treatment to after treatment will also be analyzed at various time points in a manner similar to the initial analysis of the Sgormer test. These ANCOVA models will include pre-treatment EDS, treatment and study site as covariates.
眼部不適量表結果自治療前至治療後之變化將藉由問診、時間點(適當時)及治療用定量描述性統計概述且將以與EDS類似之方式在各個別時間點分析。The changes in the results of the Ocular Discomfort Scale from before to after treatment will be summarized by questioning, time point (when appropriate) and quantitative quantitative descriptive statistics for treatment and will be analyzed at various time points in a similar manner to EDS.
分析將僅針對ITT及PP群體之觀測數據進行。安全性變數 The analysis will only be performed on the observation data of the ITT and PP populations. Security variable
AE將使用MedDRA詞典編碼。具有治療引發AE (TEAE)、嚴重TEAE及引起過早中止之TEAE之個體的頻率及百分比將由治療組提供。若AE在研究治療之第一劑量之後出現或惡化,則其為治療引發的。此外,將藉由系統器官類別;藉由系統器官類別及較佳術語;藉由系統器官類別、較佳術語及最大嚴重度;藉由系統器官類別、較佳術語及最強關係;及藉由系統器官類別、較佳術語、最大嚴重度及最強關係給出具有TEAE之個體的頻率。將對於眼部特異性及所有AE (包括全身性)進行獨立分析。AE will use MedDRA dictionary encoding. The frequency and percentage of individuals with treatment-induced AE (TEAE), severe TEAE, and TEAE causing premature discontinuation will be provided by the treatment group. If AE appears or worsens after the first dose of study treatment, it is treatment-induced. In addition, by system organ class; by system organ class and preferred term; by system organ class, preferred term and maximum severity; by system organ class, preferred term and strongest relationship; and by system Organ category, preferred terms, maximum severity, and strongest relationship give the frequency of individuals with TEAE. Eye specificity and all AEs (including systemic) will be analyzed independently.
包括視力、裂隙燈活組織檢視法及鼻內內窺鏡檢查之其他安全終點將由治療組及問診使用描述性統計概述。自基線之變化或偏移亦將在適當時概述。對於藉由眼睛進行之評估,將分別概述研究用眼睛及對側眼。另外,將概述自基線偏移至眼部安全評估之最差治療期間值。期中分析 Other safety endpoints including vision, slit lamp biopsy, and endoscopic nasal endoscopy will be used by the treatment group and the descriptive statistical summary of the consultation. Changes or deviations from the baseline will also be summarized as appropriate. For the evaluation by eye, the research eye and the contralateral eye will be summarized separately. In addition, the worst treatment period values from baseline to ocular safety assessment will be summarized. Interim analysis
未針對此研究計劃期中分析。與良好臨床實踐、倫理考量及管理問題之順應性 No mid-term analysis for this research plan. Compliance with good clinical practice, ethical considerations, and management issues
此研究將按照方案良好臨床實踐(Good Clinical Practices),包括國際協調會議(ICH)指南進行,且一般而言,與赫爾辛基宣言(Declaration of Helsinki)一致。另外,將遵守與所涉及國家之研究藥物使用相關之所有適用的地方、州及聯邦要求。人類個體保護 This study will be conducted in accordance with Good Clinical Practices of the protocol, including the International Conference on Harmonization (ICH) guidelines, and is generally consistent with the Declaration of Helsinki. In addition, all applicable local, state, and federal requirements related to the use of research drugs in the countries involved will be complied with. Human individual protection
必須在開始任何研究特異性程序之前進行知情同意(consent/assent)。署名且註有日期之書面知情同意書必須在入選研究之前獲自各個體及/或個體之父母或法定監護人。若個體低於法定同意年齡,則同意書必須由法定監護人或視需要由州及/或地方法律及法規署名。Informed consent (consent/assent) must be done before starting any research-specific procedures. The signed and dated written informed consent must be obtained from the parent or legal guardian of each individual and/or individual before being selected for the study. If the individual is younger than the legal age of consent, the consent must be signed by the legal guardian or, if necessary, by state and/or local laws and regulations.
所有知情同意書必須在其使用之前經批准使用且自IRB接收批准/有利觀點。若同意書需要校正(例如由於方案修正或重大的新安全資訊),則調查員有職責確保修正的知情同意書在呈遞至監管IRB之前經審查及批准,且其由隨後入選研究之所有受個體以及當前入選研究之個體閱讀、署名及標註日期。All informed consents must be approved for use before their use and receive approval/favorable opinions from the IRB. If the consent form needs to be corrected (for example, due to amendments to the plan or significant new safety information), the investigator is responsible for ensuring that the amended informed consent form is reviewed and approved before being submitted to the regulatory IRB, and that it is selected by all recipients of the subsequent enrolled study As well as the individual reading, signature and date marking of the current selected study.
此研究係根據IRB法規[U.S. 21 Code of Federal regulations (CFR) Part 56.103]進行。調查員必須在開始研究之前獲得適當IRB批准且至少每年獲得重新批准。僅將使用IRB批准版本的知情同意書。This research was conducted in accordance with IRB regulations [U.S. 21 Code of Federal regulations (CFR) Part 56.103]. The investigator must obtain appropriate IRB approval before starting the study and at least annually reapproval. Only IRB approved versions of informed consent will be used.
此研究將根據源於赫爾辛基宣言之倫理原則進行。個體保密性 This research will be based on the ethical principles derived from the Declaration of Helsinki. Individual confidentiality
出於此研究之目的收集及處理之所有個人研究個體資料應由調查員及其工作人員以足夠防護措施維持,以根據地方、州及聯邦法律及法規確保資料之保密性。標記、包裝 All personal research individual data collected and processed for the purpose of this research should be maintained by investigators and their staff with adequate protective measures to ensure the confidentiality of the data in accordance with local, state, and federal laws and regulations. Marking, packaging
研究性藥物將在單次用小瓶中提供且在問診1及問診2時在各治療之前分配。在源文件及電子病例報告表上記錄資料 The investigational drug will be provided in a single-use vial and will be dispensed before each treatment at
所有個體資料將在個體源文件中擷取,將轉錄於eCRF中。調查員有責任確保研究資料完整且精確地記錄於各個體之eCRF、源文件及所有研究相關材料上。所有研究資料亦應為可歸屬的、易讀的、同時期的及原始的。記錄之資料僅應以不消除、破壞先前輸入或使其難辨認的方式校正(例如藉由貫穿不正確輸入畫單線且緊鄰經校正資料寫下校正)。已校正資料輸入之個體應藉由向校正添加其姓名縮寫以及校正日期來闡明何人及何時作出校正。All individual data will be extracted from individual source files and will be transcribed in eCRF. The investigator is responsible for ensuring that the research materials are completely and accurately recorded on the eCRF, source files, and all research-related materials of each entity. All research materials should also be attributable, easy to read, contemporaneous and original. The recorded data should only be corrected in a way that does not eliminate, destroy, or make it illegible (eg, by drawing a single line through the incorrect input and writing the correction next to the corrected data). Individuals with input of corrected data should clarify who and when the correction was made by adding their initials and the date of correction to the correction.
所有入選及隨機分組個體之資料輸入將使用符合21 CFR Part 11要求之軟體,且將僅由已關於系統經過訓練且可訪問系統之人員進行。將不輸入篩選不合格個體之資料。將在電子系統內維持審計追蹤以獲取eCRF資料庫內作出之所有改變。在研究結束且資料庫鎖定之後,含有所有適用個體之eCRF之複本的光碟(CD)將提供至各調查員場地以由調查員存檔維護。參考文獻
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31: 1436.問診及量測之排程
以下檢查程序、測試、設備及技術列出如下:視力程序 The following inspection procedures, tests, equipment and techniques are listed below: Vision procedures
LogMAR視力必須使用ETDRS表評估。使用之程序將與關於使用ETDRS視力表提供之建議一致。視力應在研究中之各問診開始時(亦即,在裂隙燈檢查之前)評估。參與者應使用最近校正來獲得其校正遠視力(CDVA);若其忘記眼鏡,則此方案可置於試鏡架中。設備 LogMAR vision must be evaluated using the ETDRS form. The procedures used will be consistent with the recommendations provided for the use of ETDRS vision charts. Vision should be assessed at the beginning of each consultation in the study (ie, before the slit lamp examination). Participants should use the most recent correction to obtain their corrected distance vision (CDVA); if they forget their glasses, this solution can be placed in the trial frame. equipment
待使用之視力表為ETDRS表。若使用較小重現(18"×18",例如來自防盲協會(Prevent Blindness))掛圖,則參與者視距應恰好為10呎(或如由製造商指定)。在所有情況下,出於標準化研究期間之測試條件的目的,所有地點必須僅使用ETDRS Series 2000 Chart 1及2,且應首先測試右眼。對於反射(掛)圖,圖表應置放於前方且經充分照明。量測技術 The vision chart to be used is the ETDRS form. If a smaller reproduction (18" x 18", for example from the Prevent Blindness) wall chart is used, the participant's viewing distance should be exactly 10 feet (or as specified by the manufacturer). In all cases, for the purpose of standardizing the test conditions during the study, all locations must use only
圖表應處於舒適的視角。應首先測試右眼。參與者應嘗試逐行從左到右讀取各字母,在圖表頂部處之第1行開始。應告知參與者圖表僅具有字母,不具有數字。若參與者讀取數字,則應提醒其該圖表不含數字,且審查員接著應要求代替數字的字母。應要求參與者緩慢讀取,以實現最佳鑑別各字母。其直至給出確定回答才前進至下一字母。The chart should be in a comfortable perspective. The right eye should be tested first. Participants should try to read the letters from left to right line by line, starting at
若參與者在其大聲讀出下一字母之前改變回答(例如『其為「C」而非「O」』),則該改變必須為可接受的。若參與者在已讀出下一字母後改變回答,則該改變不可接受。審查員絕不應在測試期間指向圖表或圖表上之特定字母。If the participant changes the answer before he reads the next letter aloud (for example, "It is "C" instead of "O""), the change must be acceptable. If the participant changes the answer after having read the next letter, the change is not acceptable. The examiner should never point to the chart or specific letters on the chart during the test.
應盡最大努力來鑑別圖表上之各字母。當參與者說其無法讀取字母時,應鼓勵其進行猜測。若參與者將一字母鑑別為兩個字母中之一者,則應要求其選擇一個字母,且必要時進行猜測。當顯而易見的是不再可進行有意義的讀取(不管鼓勵讀取或猜測)時,審查員應停止對該眼睛之測試。然而,應嘗試最後一行上的所有字母,因為字母難度變化且最後一行可為經正確讀取之唯一一行。應標註遺漏或錯誤讀取之字母的數目。LogMAR 視力計算 Every effort should be made to identify the letters on the chart. When participants say that they cannot read the letters, they should be encouraged to make guesses. If the participant identifies a letter as one of two letters, they should be asked to choose a letter and make guesses if necessary. When it is obvious that meaningful reading is no longer possible (regardless of encouraging reading or guessing), the examiner should stop testing the eye. However, all letters on the last line should be tried, as the difficulty of the letters varies and the last line can be the only line correctly read. The number of missing or incorrectly read letters should be marked. LogMAR vision calculation
字母經正確讀取之最後一行將視為基礎logMAR讀取。將向此值添加數字「N×0.02」,其中『N』表示直至(且包括)最後一行讀數錯過之字母的總數目。此總和表示該眼睛之logMAR視力。The last line of the letter after correct reading will be regarded as the basic logMAR reading. The number “N×0.02” will be added to this value, where “N” represents the total number of letters missed (and included) in the last line of reading. This sum represents the logMAR vision of the eye.
實例:參與者正確讀取0.2行上之5個字母中之4個,及0.1行上之5個字母中之2個。
對於左眼重複該程序。Repeat the procedure for the left eye.
為了在研究期間提供視力之標準化及控制良好的評估,單一地點之所有視力評估必須在整個研究期間使用相同照明條件及相同校正(若可能)持續地進行。若無法使用相同校正(亦即,參與者打碎其眼鏡),則應記錄校正變化之原因。In order to provide standardized and well-controlled assessments of vision during the study period, all vision assessments at a single location must be conducted continuously using the same lighting conditions and the same corrections (if possible) throughout the study period. If the same correction cannot be used (ie, the participant broke their glasses), the reason for the change in correction should be recorded.
附註:自篩選問診(問診1)之臨床上顯著的視力降低(定義為logMAR評分之0.22或更大增加)應由調查員評估為潛在AE。Note: The clinically significant visual acuity reduction (defined as a 0.22 or greater increase in logMAR score) from the screening interview (interview 1) should be evaluated by the investigator as a potential AE.
裂隙燈活組織檢視法:將在研究期間進行裂隙燈活組織檢視法。觀測結果將分級為正常或異常。將描述臨床上顯著之異常發現。將在各問診時檢查以下各者: 角膜 結膜 前房 眼瞼角膜螢光素染色 Slit-lamp biopsy: Slit-lamp biopsy will be performed during the study. The observation result will be classified as normal or abnormal. Clinically significant abnormal findings will be described. The following will be examined at each consultation: Ÿ cornea Ÿ conjunctiva Ÿ anterior chamber Ÿ eyelid cornea fluorescein staining
審查員應將5 μL之2%無防腐劑之螢光素鈉溶液滴注至各眼睛之下結膜盲管中。或者,角膜染色可使用1.0 mg螢光素鈉條評估。在用無菌緩衝鹽水潤濕條尖端之後,藉由急劇輕彈將過量甩出至垃圾桶中。接著向下牽拉下瞼且尖端的平端應平緩地施加至下瞼板結膜,意圖為不誘發反射流淚,且滴注極小體積之染料。The examiner should inject 5 μL of 2% sodium luciferin solution without preservatives into the conjunctival blind tube under each eye. Alternatively, corneal staining can be evaluated using 1.0 mg luciferin sodium strips. After wetting the tip of the strip with sterile buffered saline, the excess is thrown out into the trash bin by a flick. The lower eyelid is then pulled down and the flat end of the tip should be gently applied to the conjunctiva of the lower tarsal plate, with the intention of not inducing reflective tearing and instilling a very small volume of dye.
將指示參與者自然地眨眼若干次而不強制閉合眼瞼以分配螢光素。為達成最大螢光,審查員應在滴注之後在評估角膜螢光素染色之前等待至少兩分鐘。Wratten #12黃色濾紙將用於增強對螢光素染色分級之能力。染色將用NEI量表分級。上眼瞼略微提昇以對整個角膜表面分級。Participants will be instructed to blink naturally several times without forcibly closing the eyelids to distribute luciferin. To achieve maximum fluorescence, the examiner should wait at least two minutes after infusion before evaluating corneal fluorescein staining.
向測試管理員提供NEI/Industry Workshop量表圖以對各眼睛之角膜上之五個區域中之每一者分級及評分。圖9描繪用於在螢光素染色之後對角膜表面分級之圖式。圖式顯示劃分角膜表面以量測螢光素吸收。0-3之標準化分級系統用於各角膜上之五個區域中之每一者。當不存在染色時,將指定為0級。最大評分為15。對各眼睛之角膜上之五個區域中之每一者評分。鼻內檢查 Provide the test administrator with a NEI/Industry Workshop scale chart to grade and score each of the five areas on the cornea of each eye. Figure 9 depicts a pattern used to grade the corneal surface after luciferin staining. The diagram shows the division of the corneal surface to measure luciferin absorption. A standardized grading system of 0-3 is used for each of the five areas on each cornea. When there is no staining, it will be designated as
合格的研究參與者必須進行鼻內窺鏡檢查以作出最終合格性測定(例如嚴重鼻氣道阻塞,諸如嚴重鼻中隔偏曲或下鼻甲肥大,或血管化息肉(檢查時可見)為排除原因)。為了出於參與者安全而在研究期間監測鼻黏膜完整性,將在篩選問診時(在已完成所有其他篩選程序之後)經由內窺相機進行鼻腔檢查。此檢查將由耳鼻喉(ENT)專家、耳鼻喉科醫師或其他適當合格的開業醫師(亦即,對於進行鼻內窺鏡檢查已經過訓練之醫師)進行。仍可採集影像或視頻。應指示參與者在將進行鼻內窺鏡檢查的當天不進行鼻部刺激。在局部麻醉下之斯戈默測試 Eligible study participants must undergo nasal endoscopy to make a final eligibility determination (eg, severe nasal airway obstruction, such as severe nasal septal deviation or inferior turbinate hypertrophy, or vascularized polyps (visible during examination) as the cause of exclusion). In order to monitor the integrity of the nasal mucosa during the study for the safety of the participants, a nasal cavity examination will be performed via an endoscope at the screening interview (after all other screening procedures have been completed). This examination will be performed by an ENT specialist, an otolaryngologist, or other suitably qualified medical practitioner (ie, a physician who has been trained to perform nasal endoscopy). Can still capture images or videos. Participants should be instructed not to perform nasal irritation on the day the nasal endoscopy will be performed. Sgormer test under local anesthesia
在篩選問診時,將進行一次基礎斯戈默測試,接著進行在棉花棒鼻部刺激下之斯戈默測試。在局部麻醉下之斯戈默測試將用於使用以下步驟評估淚液產生:During the screening interview, a basic Sgormer test will be performed, followed by a Sgormer test under the nasal stimulation of the cotton swab. The Sgormer test under local anesthesia will be used to assess tear production using the following steps:
局部麻醉劑滴劑,諸如0.5%鹽酸丙美卡因或等效物應滴注於參與者之兩隻眼睛中。Drops of local anesthetic, such as 0.5% promethaine hydrochloride or equivalent, should be instilled into both eyes of the participant.
將指示參與者保持眼睛輕閉一分鐘。Participants will be instructed to keep their eyes closed for one minute.
在睜開眼睛且允許眼睛再恢復大致一分鐘之後,用矛平緩地移除下穹中之過量水分。After opening your eyes and allowing them to recover for another minute, use a spear to gently remove excess water from the lower dome.
斯戈默條(35 mm×5 mm尺寸濾紙條)將置於各眼睛中之下眼瞼之中部與側向三分之一的接合處。The gomer strip (35 mm×5 mm size filter paper strip) will be placed at the junction of the middle of the lower eyelid and the lateral third of each eye.
在環境光下,將指示參與者在測試過程向前看且正常地眨眼。測試應在參與者的臉上無直流空氣之房間中進行。Under ambient light, the participant will be instructed to look forward and blink normally during the test. The test should be conducted in a room without direct air on the participant's face.
斯戈默條應保持在適當位置直至五分鐘已過去或兩個條均達到最大評分。The gomer bar should remain in place until five minutes have passed or both bars have reached their maximum score.
在五分鐘之後,將自兩隻眼睛移除條且將記錄潤濕量。條應黏帖至CRF。使用棉花棒鼻部刺激之斯戈默測試 After five minutes, the strip will be removed from both eyes and the amount of wetting will be recorded. Articles should be pasted to CRF. Sgormer test for nasal irritation using cotton swabs
在篩選問診時,應使用棉花棒鼻部刺激進行斯戈默測試。應遵循上文步驟#1至3中指定之相同程序滴注新麻醉劑滴劑。During the screening interview, a cotton swab nasal stimulus should be used for the Gomer test. New anesthetic drops should be infused following the same procedure as specified in
隨著新條就位,審查員應在參與者之兩個鼻孔中同時***棉花棒且平緩地探測兩個中鼻甲大致30秒。此後,審查員可簡單地將棉花棒保持在適當位置、施加平緩壓力且視需要間歇地重複探測。With the new strip in place, the examiner should simultaneously insert cotton swabs in both nostrils of the participant and gently probe the two middle turbinates for approximately 30 seconds. Thereafter, the inspector can simply hold the cotton swab in place, apply gentle pressure, and repeat the probe intermittently as needed.
或者,可指示參與者保持棉花棒且同時平緩地探測兩個中鼻甲,在再次探測之前間歇地休息。審查員應持續地指導參與者如何恰當地進行此測試。Alternatively, the participant may be instructed to hold the cotton swab while simultaneously probing the two middle turbinates gently, resting intermittently before re-probing. The examiner should continually instruct participants on how to perform this test appropriately.
斯戈默條應保持在適當位置直至五分鐘已過去或兩個條均達到最大評分。The gomer bar should remain in place until five minutes have passed or both bars have reached their maximum score.
將記錄兩個斯戈默評分且驗證其滿足納入標準。眼表面疾病 指數 © Two Sgomer scores will be recorded and verified to meet the inclusion criteria. Ocular Surface Disease Index ©
為了最小化偏差,在已由現場人員提供指示之後,將要求參與者獨立地且私密地完成OSDI調查表。To minimize deviations, after instructions have been provided by field personnel, participants will be required to complete the OSDI questionnaire independently and privately.
OSDI為由愛力根結果研究組(Outcomes Research Group at Allergan)(Irvine, CA),(Walt JG 1997)產生之12項調查表,其要求參與者描述其刺激症狀之嚴重度及性質。參與者將藉由圈出最佳表示各回答之數字來回答12個問題:4 (所有時間)、3 (大部分時間)、2 (一半時間)、1 (一些時間)或0 (無任何時間)。調查表之最終評分計算如下: 來自部分I、II及III之部分和相加=A 測定來自部分I、II及III之所回答問題之總數(不包括N/A)=B 最終OSDI評分=A×25除以BOSDI is a 12-item questionnaire produced by Outcomes Research Group at Allergan (Irvine, CA), (Walt JG 1997), which requires participants to describe the severity and nature of their irritation symptoms. Participants will answer 12 questions by circled the number that best represents each answer: 4 (all time), 3 (most time), 2 (half time), 1 (some time) or 0 (no time) ). The final score of the questionnaire is calculated as follows: Ÿ Sum of parts from parts I, II and III = A Ÿ Determine the total number of questions answered from parts I, II and III (excluding N/A) = B Ÿ Final OSDI score = A × 25 divided by B
調查表之實例顯示於圖10中。使用視覺類比量表 ( VAS ) 之乾眼評分 ( EDS ) An example of the questionnaire is shown in Figure 10. Using visual analogue scale (VAS) score of dry eye (EDS)
在人工創造之不利環境暴露期間,將每隔5分鐘向參與者詢問關於乾眼之以下問題。During exposure to artificially created adverse environments, participants will be asked the following questions about dry eyes every 5 minutes.
將要求參與者評定其由乾眼所致之眼部症狀(兩隻眼睛同時),藉由將豎直標記置於水平線上以指示不適水準;0對應於「無不適」且100對應於「最大不適」。量表之評估線長度將為100 mm。視覺類比量表之實例顯示於圖11中。Participants will be asked to assess their eye symptoms caused by dry eyes (both eyes at the same time), by placing a vertical marker on a horizontal line to indicate the level of discomfort; 0 corresponds to "no discomfort" and 100 corresponds to "maximum Discomfort". The length of the evaluation line of the scale will be 100 mm. An example of a visual analog scale is shown in Figure 11.
EDS為已供眼部症狀相關研究中的其他人使用之儀器。眼部不適量表 EDS is an instrument that has been used by others in studies related to ocular symptoms. Eye Discomfort Scale
眼部不適評分將由參與者根據以下量表主觀地分級,分別對各眼睛評級。
0 = 無不適
1 = 間歇性意識
2 = 持續性意識
3 = 間歇性不適
4 = 持續性不適The eye discomfort score will be subjectively graded by participants according to the following scale, and each eye will be rated separately.
0 = no
化合物1半-半乳糖二酸鹽二水合物鼻用噴霧係在多中心、隨機化、受控、雙盲臨床試驗中研究以評估化合物1半-半乳糖二酸鹽二水合物鼻用噴霧對上文所述之乾眼病之病徵及症狀的功效(「PEARL」研究) PEARL研究係設計為劑量範圍研究以在評估乾眼病之病徵(斯戈默測試)及症狀(乾眼評分[EDS])時比較0.11%化合物1游離鹼(0.2%化合物1半-半乳糖二酸鹽二水合物)[低劑量]、0.55%化合物1游離鹼(1.0%化合物1半-半乳糖二酸鹽二水合物)[中劑量,及1.1%化合物1游離鹼(2.0%化合物1半-半乳糖二酸鹽二水合物)[高劑量]相較於安慰劑(化合物1半-半乳糖二酸鹽二水合物媒劑鼻用噴霧)之安全性及有效性。研究係在美國(US)之3個中心進行。
基線人口統計資料指示劑量組為良好平衡的。整體人口主要由比男性更多的女性構成,與乾眼病流行病學一致(表1)。
此研究中之主要病徵功效量度為評估問診1時斯戈默測試之平均變化。一般而言,較高斯戈默評分指示相較於較低斯戈默評分之較大流淚量。如圖1中所概述,接受0.20%濃度之個體的斯戈默評分平均增加為8.6 mm (p=0.0018,n=41),1.00%濃度為17.1 mm (p<0.001,n=41),且2.00%濃度為19.3 mm (p<0.001,n=42)。相比之下,觀測到安慰劑組(n=41)之斯戈默評分僅具有2.6 mm平均增加。藥物治療組之斯戈默評分相較於安慰劑增加且該增加係以劑量依賴型方式。另外,評分變化為統計上顯著,因為p值遠低於0.05。斯戈默評分之統計上顯著上升及淚液產生之對應增加指示診斷患有乾眼病之個體用化合物1半-半乳糖二酸鹽二水合物之治療為有效及立即的。此證明化合物1半-半乳糖二酸鹽二水合物可用於立即增加流淚、治療乾眼病及減少眼部不適。圖1概述在用0.20%、1.00%及2.00%化合物1半-半乳糖二酸鹽二水合物治療後的斯戈默測試結果。在用 0.20% 、 1.00% 及 2.00% 化合物 1 半 - 半乳糖二酸鹽二水合物治療後的乾眼測試結果 The main symptom efficacy measure in this study is the average change in the Sgormer test at the time of evaluation of
此研究中之主要症狀功效量度為在問診2時,在人工創造之不利環境腔室中評估乾眼評分之平均變化。一般而言,較低之乾眼評分係指示其相較於較高乾眼評分(其指示較高不適感),降低由乾眼症狀所致之不適感。因此,乾眼評分下降即為個體症狀之改善。The main symptom efficacy measure in this study was the average change in dry eye scores evaluated in an artificially created adverse environmental chamber at the time of
如圖2中所概述,1.0%及2.0%劑量組之個體的乾眼評分在5分鐘標記處出現統計上顯著下降。1.0%劑量組中之乾眼評分下降16.5 mm (p=0.0067,n=41,乾眼評分為-16.5 mm)且2.0%組中之乾眼評分下降19 mm (p=0.0006,n=37,乾眼評分為-19 mm)。相比之下,觀測到安慰劑組(n=41)之乾眼評分僅平均降低6.8 mm(乾眼評分為-6.8)。藥物治療組之乾眼評分比安慰劑組下降且該降幅係隨劑量變化方式。另外,1.00%及2.00%組之評分變化為統計上顯著性,因為p值遠低於0.05。乾眼評分之統計上顯著下降及眼部不適之對應減少指示在診斷患有乾眼病之個體中使用化合物1半-半乳糖二酸鹽二水合物之治療為有效及立即的。此數據證明化合物1半-半乳糖二酸鹽二水合物可用於立即減少眼部不適及改善乾眼病相關症狀。在用 0.20% 、 1.00% 及 2.00% 化合物 1 半 - 半乳糖二酸鹽二水合物治療後 60 分鐘內的乾眼評分 As outlined in Figure 2, the dry eye score of individuals in the 1.0% and 2.0% dose groups showed a statistically significant decrease at the 5-minute mark. The dry eye score in the 1.0% dose group decreased by 16.5 mm (p=0.0067, n=41, dry eye score was -16.5 mm) and the dry eye score in the 2.0% group decreased by 19 mm (p=0.0006, n=37, The dry eye score is -19 mm). In contrast, the dry eye score of the placebo group (n=41) was only reduced by an average of 6.8 mm (dry eye score of -6.8). The dry eye score of the drug-treated group was lower than that of the placebo group, and the rate of decrease was a function of dose. In addition, the changes in the scores of the 1.00% and 2.00% groups were statistically significant because the p-value was much lower than 0.05. A statistically significant decrease in dry eye score and a corresponding decrease in eye discomfort indicate that the treatment with
圖3概述在60分鐘時間期每5分鐘取得之乾眼評分。此實例證明5分鐘標記處之乾眼評分的立即改善(其為統計上顯著改善)在診斷患有乾眼病之個體中,在1.0%及2.0%劑量濃度之化合物1半-半乳糖二酸鹽二水合物下,維持60分鐘時間期。舉例而言,在投與1.0%劑量後60分鐘處,乾眼評分之改善係在5分鐘標記處所測得改善的10%內(5分鐘,-16.5 mm;60分鐘,-15.3 mm)。在投與2.0%劑量後30分鐘處,乾眼評分之改善相較於在5分鐘標記處測得之改善降幅小於10%(5分鐘,-19.0 mm;60分鐘,-16.1 mm)。在投與2.0%劑量後60分鐘處,乾眼評分之改善相較於在5分鐘標記處測得之改善降幅小於10%(5分鐘,-19.0 mm;60分鐘,-16.1 mm)。此等結果顯示,在用藥物治療後立即下降之眼部不適可維持至少60分鐘,其取決於劑量而定。此數據證明診斷患有乾眼病且用化合物1半-半乳糖二酸鹽二水合物治療之個體之眼部不適的統計上顯著下降可維持超過60分鐘。
在用0.20%、1.00%及2.00%化合物1半-半乳糖二酸鹽二水合物治療後斯戈默評分在較高劑量水準處之上限效應Figure 3 summarizes the dry eye scores obtained every 5 minutes during the 60-minute period. This example demonstrates the immediate improvement of the dry eye score at the 5 minute mark (which is a statistically significant improvement) in individuals diagnosed with dry eye disease, at the 1.0% and 2.0% dose concentrations of
圖4概述在用0.2%、1.0%或2.0%濃度之化合物1半-半乳糖二酸鹽二水合物治療後,具有35 mm斯戈默評分之個體的%。35 mm評分為藉由斯戈默測試量測之最大淚液水準。研究所選之個體在治療之前在篩選時具有小於10 mm之斯戈默評分。在此等個體中,0.2%劑量組中4.9%之個體、1.0%劑量組中29.3%之個體及2.0%劑量組中41.5%之個體經量測具有35 mm斯戈默評分。此為斯戈默測試之最大評分。安慰劑組中0%之個體具有大於35 mm之斯戈默評分增加。此數據另外支持化合物1半-半乳糖二酸鹽二水合物在增加診斷患有乾眼病之個體之淚液產生中的劑量依賴性反應。此資訊可用於確定達成增加之流淚,但避免過度產生淚液之適當給藥量。在用 0.20% 、 1.00% 及 2.00% 化合物 1 半 - 半乳糖二酸鹽二水合物治療後斯戈默評分之中值增加 Figure 4 summarizes the% of individuals with a 35 mm Sgormer score after treatment with
圖5概述在用0.2%、1.0%或2.0%濃度之化合物1半-半乳糖二酸鹽二水合物治療後斯戈默評分之中值變化。測定0.2%劑量組中5.0 mm (n=41)、1.0%劑量組中16.0 mm (n=41)及2.0%劑量組中24.0 mm (n=42)之增加。在安慰劑組(n=41)之個體中僅觀測到2.0 mm中值增加。此數據另外支持化合物1半-半乳糖二酸鹽二水合物在增加診斷患有乾眼病之個體之淚液產生中的劑量依賴性反應。斯戈默評分 >10 mm 之類別變化 Figure 5 summarizes the change in the median value of the Sgormer score after treatment with
圖6概述在用0.2%、1.0%或2.0%濃度之化合物1半-半乳糖二酸鹽二水合物治療後,具有大於10 mm之斯戈默評分變化之個體的%。研究所選之個體在治療之前在篩選時具有小於10 mm之斯戈默評分。在此等個體中,0.2%劑量組(n=41,p=0.0107)中29.3%之個體、1.0%劑量組(n=41,p<0.0001)中29.3%之個體及2.0%劑量組(n=42,p<0.0001)中41.5%之個體經歷大於10 mm之斯戈默評分增加。安慰劑組(n=41)中僅7.1%之個體具有大於10 mm之斯戈默評分增加。此數據支持用化合物1半-半乳糖二酸鹽二水合物治療導致診斷患有乾眼病之個體之斯戈默評分之統計顯著類別變化(>10 mm)。斯戈默評分 >20 mm 之類別變化 Figure 6 summarizes the% of individuals with a change in the Sgormer score greater than 10 mm after treatment with
圖7概述在用0.2%、1.0%或2.0%濃度之化合物1半-半乳糖二酸鹽二水合物治療後,具有大於20 mm之斯戈默評分變化之個體的%。研究所選之個體在治療之前在篩選時具有小於10 mm之斯戈默評分。在此等個體中,0.2%劑量組(n=41,p=0.0119)中14.6%之個體、1.0%劑量組(n=41,p<0.001)中43.9%之個體及2.0%劑量組(n=42,p<0.001)中56.1%之個體經歷大於20 mm之斯戈默評分增加。安慰劑組(n=41)中0%之個體具有大於20 mm之斯戈默評分增加。此數據支持用化合物1半-半乳糖二酸鹽二水合物治療導致診斷患有乾眼病之個體之斯戈默評分之統計顯著類別變化(>20 mm)。此資訊可用於確定達成增加之流淚,但避免過度產生淚液之適當給藥量。不良事件 Figure 7 summarizes the% of individuals with a change in the Sgormer score greater than 20 mm after treatment with
圖8概述最常見不良事件,在臨床研究中觀測之任何治療組中>5%。總體而言,40.6%之個體呈現有一或多種不良事件。在0.2%劑量組中存在單一嚴重不良事件發育不良,其係視為與研究性療法不相關。圖8亦描繪100微升遞送裝置及50微升鼻用噴霧裝置之非限制性實例,其中遞送量為醫藥調配物之每次投與(「噴霧」)。Figure 8 summarizes the most common adverse events, >5% in any treatment group observed in clinical studies. Overall, 40.6% of individuals showed one or more adverse events. There was a single serious adverse event in dysplasia in the 0.2% dose group, which was deemed not related to research therapy. Figure 8 also depicts a non-limiting example of a 100 microliter delivery device and a 50 microliter nasal spray device, where the delivery amount is each administration of a pharmaceutical formulation ("spray").
相較於0.2%及安慰劑劑量組,1.0%及2.0%劑量組中存在較高百分比具有喉部/軟齶之藥物相關刺激(咳嗽、喉部刺激)的個體。許多此上喉/軟齶刺激可與遞送體積(各鼻孔100 μL)以及使用MAD Nasal™鼻內黏膜霧化裝置(MAD)增加研究性藥物之鼻後滴注可能性相關。另外,相較於0.2%及安慰劑劑量組,鼻刺激(滴注位點刺激及打噴嚏)以較高百分比存在於1.0%及2.0%劑量組個體中。大約88.5%之喉部刺激的嚴重度係視為輕度,且11.5%之嚴重度係指示為中等。滴注部位刺激之嚴重度係在100%個體中視為輕度。所有藥物相關事件均為短暫性及自限制的。Compared with the 0.2% and placebo dose groups, there was a higher percentage of individuals with drug-related stimuli (cough, throat irritation) of the larynx/soft palate in the 1.0% and 2.0% dose groups. Many of this upper larynx/soft palate stimulation can be related to the delivery volume (100 μL of each nostril) and the use of the MAD Nasal™ intranasal mucosal nebulizer device (MAD) to increase the likelihood of post-nasal instillation of research drugs. In addition, compared with the 0.2% and placebo dose groups, nasal irritation (drip site stimulation and sneezing) was present in a higher percentage in individuals in the 1.0% and 2.0% dose groups. About 88.5% of the severity of throat irritation is considered mild, and 11.5% is indicated as moderate. The severity of irritation at the instillation site is considered mild in 100% of individuals. All drug-related events are transient and self-limiting.
未來在臨床上遞送化合物1半-半乳糖二酸鹽二水合物將在各鼻孔中使用50 μL體積及應藉由減少滴注後鼻後滴注而減少上喉/軟齶刺激之發生率的鼻用噴霧泵。實例 3 :經四週之化合物 1 半 - 半乳糖二酸鹽二水合物 2.0% 之 2 期 臨床研究 In the future, the clinical delivery of
2期研究之概要呈現於下。
概要
當以鼻內噴霧形式遞送時,化合物1半-半乳糖二酸鹽二水合物可促進三叉副交感路徑活化且因此表示改善乾眼病之病徵及症狀的新穎候選物。When delivered in the form of an intranasal spray,
此研究將利用人工創造之不利環境模型來評估乾眼症狀。人工創造之不利環境由藉由調節濕度、溫度、氣流、照明條件及視覺任務分配而使環境條件標準化之房間組成。乾眼患者暴露於人工創造之不利環境至多兩小時,在此期間可在暴露之前、期間及之後評估主觀及客觀參數。人工創造之不利環境表示乾眼患者遇到的每日情況,諸如強制熱風供暖系統、飛機旅行及電腦使用且允許此等變數之標準化。 1 先前臨床經歷This study will use artificially created adverse environmental models to assess dry eye symptoms. The artificially created unfavorable environment consists of rooms that standardize environmental conditions by regulating humidity, temperature, airflow, lighting conditions, and visual task assignment. Dry eye patients are exposed to an artificially created adverse environment for up to two hours, during which subjective and objective parameters can be evaluated before, during, and after exposure. The artificially created unfavorable environment represents the daily conditions encountered by patients with dry eyes, such as forced hot air heating systems, aircraft travel and computer use and allows the standardization of these variables. 1 Previous clinical experience
先前臨床經歷可見於實例2中。 2 研究目標Previous clinical experience can be found in Example 2. 2 Research objectives
此研究之目標為評估相較於安慰劑,化合物1半-半乳糖二酸鹽二水合物鼻用噴霧經4週時段對乾眼病之病徵及症狀之安全性及有效性。
3 臨床假設The goal of this study was to evaluate the safety and effectiveness of
此研究測試化合物1半-半乳糖二酸鹽二水合物鼻用噴霧在治療乾眼病之病徵及症狀中優於安慰劑之假設。
4 總體研究設計This study tested the hypothesis that
方案OPP-003為2期、多中心、隨機化、雙盲、安慰劑對照研究,其經設計以評估化合物1半-半乳糖二酸鹽二水合物鼻用噴霧對患有乾眼病之成年參與者的安全性及功效。大致45個由醫師診斷患有乾眼病且符合所有其他研究合格性標準的至少22歲之個體將隨機分組以接受每日兩次(BID)施用之化合物1半-半乳糖二酸鹽二水合物或安慰劑,持續4週。Protocol OPP-003 is a
將要求在施用時段期間提早終止之參與者在研究出口之前完成安全性評估(若參與者同意)。將不替換自研究提早終止之參與者。 5 研究群體 5.1 個體數目Participants who terminate early during the administration period will be required to complete a safety assessment (if the participant agrees) before the study exit. Participants who have terminated the study early will not be replaced. 5 Research groups 5.1 Number of individuals
大約45個參與者(大約30個分至2.0%化合物1半-半乳糖二酸鹽二水合物且15個分至化合物1半-半乳糖二酸鹽二水合物媒劑鼻用噴霧)將在美國的大約兩個地點登記。個體將2:1隨機分組以接受以下劑量分配中之一者。
安慰劑(化合物1半-半乳糖二酸鹽二水合物媒劑鼻用噴霧)
2.0%化合物1半-半乳糖二酸鹽二水合物鼻用噴霧Approximately 45 participants (approximately 30 points to 2.0
所有劑量將在各鼻孔中以50微升(µL)鼻內噴霧形式BID遞送,持續總共4週。 5.2 研究群體特徵All doses will be delivered in each nostril as a 50 microliter (µL) intranasal spray BID for a total of 4 weeks. 5.2 Studying group characteristics
所有個體必須為至少22歲,為任何性別,且為任何人種,且必須滿足所有納入標準及不滿足任何排除標準。 5.3 納入標準All individuals must be at least 22 years old, of any gender, and of any ethnic origin, and must meet all inclusion criteria and do not meet any exclusion criteria. 5.3 Inclusion criteria
個體必須
:
1. 在篩選問診時為至少22歲
2. 在問診1之前的60天內已使用及/或期望使用針對乾眼症狀之人工淚液替代物
3. 在篩選問診時具有≥23之OSDI©
評分與≤3次「N/A」反應
4. 在篩選問診時在研究用眼睛中具有所有以下各者:
至少一個角膜區中≥2之角膜螢光素染色評分或所有角膜區具有≥4之總和
每5分鐘≤10 mm之基線斯戈默測試(在局部麻醉下)評分,相同眼睛中之棉花棒鼻部刺激斯戈默測試評分大至少7 mm
研究用眼睛斯戈默測試及對側眼斯戈默測試之差異<20 mm
醫師之乾眼病診斷
研究用眼睛將定義為符合所有納入標準之眼睛;若兩隻眼睛均合格,則為在篩選問診時藉由用棉花棒刺激而具有淚液產生最大增加之眼睛,或若刺激之淚液產生無差異,則為在篩選時具有較低基礎斯戈默評分之眼睛。若任一量度均無差異,則右眼將用作研究用眼睛。
5. 在篩選問診時各眼睛中之0.7最小解析角對數(logMAR)或更好(logMAR<0.7;20/100或更好的Snellen等效評分)的BCVA
6. 具有正常眼瞼/睫毛解剖結構、眨眼功能及閉合,如由調查員所測定
7. 識字、能說英語且能夠獨立完成調查表
8. 能夠在問診4時參與研究大約連續四小時
9. 能夠且願意使用研究藥物且參與所有研究評估及問診
10. 已提供口頭及書面知情同意書
11. 若為未使用可接受之節育方法(可接受之避孕方法包括:激素-經口、可植入、可注射或經皮避孕藥,機械-殺***劑與諸如子宮帽或保險套之障壁結合、IUD或對伴侶手術絕育)的具有生育潛能之女性,則在1第天具有陰性尿妊娠測試
5.4 排除標準The individual must : 1. be at least 22 years of age at the time of
個體必須不
:
1. 在進行斯戈默測試之前的研究第1天具有臨床上顯著的角膜上皮缺陷
2. 具有慢性或復發性流鼻血、凝血障礙或其他在調查員看來將導致臨床上顯著的出血增加風險之病況
3. 此等區域已進行鼻部或鼻竇手術(包括施用鼻燒灼術之病史)或具有顯著創傷
4. 具有血管化息肉、嚴重偏曲之鼻中隔、慢性反覆性流鼻血或嚴重鼻氣道阻塞,如藉由在第1天之前進行之鼻內檢查確認
5. 當前用經鼻持續呼吸道正壓通氣(CPAP)治療
6. 已在問診1之三個月內在任一隻眼睛中進行任何眼內手術(諸如白內障手術)、眼外手術(諸如瞼成形術)或在十二個月內進行屈光手術(例如雷射上皮角膜磨削術、雷射輔助原位角膜磨削術、屈光性角膜切除術或角膜植入)
7. 已在任一隻眼睛中進行角膜移植
8. 在過去60天內使用或Restasis®
或Xiidra®
。
9. 已在問診1之前的7天內使用隱形眼鏡或預期在研究時段期間使用隱形眼鏡
10. 具有任何形式之淚點或小管內阻塞
11. 在任一隻眼睛中具有任何眼部病症或病況之病史或存在,其在調查員看來將可能干擾解釋研究結果或參與者安全性,諸如顯著角膜或結膜疤痕;翼狀胬肉或結節性結膜黃斑;當前眼部感染、結膜炎或與乾眼不相關之發炎;前(上皮)基底膜角膜營養不良或其他臨床上顯著之角膜營養不良或變性;眼部疱疹感染;圓錐形角膜之證據;等。允許不需要治療之瞼炎及通常與乾眼病相關之輕度瞼板腺疾病。
12. 具有癲癇或其他降低個體之癲癇發作臨限值之因素的病史。
13. 具有不穩定或由調查員判定為與參與研究或研究所需之冗長評估不相容的全身病況或疾病(例如當前全身感染、不受控自體免疫疾病、不受控免疫缺陷疾病、心肌梗塞或心臟病史等)
14. 對程序藥劑或研究藥物組分中之任一者具有已知過敏性
15. 在研究期間或先前30天內當前伴隨使用鼻菸、嚼菸或香菸/雪茄
16. 當前伴隨使用菸鹼乙醯膽鹼受體促效劑[Nicoderm®
、Nicorette®
、Nicotrol NS®
(菸鹼)、Tabex®
、Desmoxan®
(金雀花鹼)及Chantix®
(伐侖克林)]或在先前30天內
17. 具有活躍或不受控的嚴重:
a. 全身過敏
b. 在研究期間處於活躍風險下之慢性季節性過敏
c. 在篩選問診時需要諸如抗組織胺、解充血劑、口服或氣霧劑類固醇之治療的鼻炎或鼻竇炎
d. 在問診1時之未治療鼻感染
18. 具有在調查員看來可干擾研究順應性、結果量測、安全性參數及/或個體之一般醫學狀況的任何病況或病史
19. 為在問診1時懷孕、哺乳嬰兒或計劃懷孕之女性。未使用可接受之節育方法的具有生育潛能之女性;可接受之避孕方法包括:激素-經口、可植入、可注射或經皮避孕藥,機械-殺***劑與諸如子宮帽或保險套之障壁結合;IUD;或對伴侶手術絕育
20. 當前入選研究性藥物或裝置研究或在問診1之前的30天內已使用研究性藥物或裝置
5.5 退出標準The individual must not : 1. Have a clinically significant corneal epithelial defect on
若在研究期間之任何時候,調查員判定個體安全已受損,則個體可退出治療,但將在研究持續時間內關於安全性進行隨訪,除非其拒絕參加隨訪。If at any time during the study, the investigator determines that the individual's safety has been compromised, the individual may withdraw from treatment, but will be followed up on safety for the duration of the study unless they refuse to participate in the follow-up.
個體可在任何時候自研究撤回同意書。Individuals may withdraw consent from the study at any time.
調查員可在研究過程中出於非順應性或任何有效的醫療原因而中止任何個體之研究治療(參見第9.6.2章節)。 6 研究參數 6.1 功效量度 6.1.1主要功效量度 The investigator may suspend research treatment for any individual during the research process due to non-compliance or any effective medical reason (see Section 9.6.2). 6 Research parameters 6.1 Efficacy measures 6.1.1 Main efficacy measures
將測試以下主要終點:
問診5 (第28天)時之斯戈默測試
6.1.2次要功效量度
問診4 (第21天)時之EDS
6.2 其他功效量度 患者報告結果:眼部不適量表
角膜染色
6.3 安全性量度 不良事件
6.4 其他量度 尿妊娠測試(問診1及問診4/ET)
7 研究材料 7.1 研究藥物 7.1.1方案 The following primary endpoints will be tested: Ÿ Gomer's test at the time of consultation 5 (day 28) 6.1.2 Secondary efficacy measure Ÿ EDS 6.2 at the time of consultation 4 (day 21) 6.2 Other efficacy measures Appropriate scale Ÿ Corneal staining 6.3 Safety measures Ÿ Adverse events 6.4 Other measures Ÿ Urine pregnancy test (
研究藥物將在各鼻孔中以50微升(µL)鼻內噴霧形式BID遞送:
■ 2.0%化合物1半-半乳糖二酸鹽二水合物鼻用噴霧
■ 安慰劑鼻用噴霧(化合物1半-半乳糖二酸鹽二水合物媒劑鼻用噴霧)
7.1.2分配排程
在問診1時,合格個體將隨機分組且研究藥物之第一劑量將在辦公室中投與。第二次每日投與將在家發生。
在問診4時,個體將接受其在人工創造之不利環境暴露期間之研究藥物的第一日劑量。第二次每日投與將在家發生。
在問診2、問診3及問診5時,研究藥物之第一日劑量將與斯戈默測試同時在辦公室投與。第二次每日投與將在家發生。
在臨床問診之間,個體將在各鼻孔中BID自投與呈50 µL鼻內噴霧形式之化合物1半-半乳糖二酸鹽二水合物/安慰劑。
7.1.3使用說明書 一般狀況
化合物1半-半乳糖二酸鹽二水合物/安慰劑將以無菌水溶液形式在磷酸鹽緩衝鹽水中之所需濃度(取決於劑量組分配)下調配,且在多次用無防腐劑鼻泵中呈現。
產品不含防腐劑且僅預期供鼻內使用。若產品混濁或若存在粒子,則不應使用。
化合物1半-半乳糖二酸鹽二水合物溶液必須在不稀釋的情況下投與。
7.2 其他研究供應品 尿妊娠測試套組
螢光素鈉溶液或螢光素條
斯戈默測試條
丙美卡因(Proparacaine)
8 研究方法及程序 8.1 參與者進入程序 8.1.1概述 The study drug will be delivered in each nostril as a 50 microliter (µL) intranasal spray BID: ■ 2.0
如由第6.2、6.3及6.4章節中之標準所定義之參與者將視為進入此研究。 8.1.2知情同意書 Participants as defined by the criteria in Sections 6.2, 6.3 and 6.4 will be deemed to have entered this study. 8.1.2 Informed consent
在參與者入選試驗之前(亦即,在任何研究相關程序之前),將與各潛在參與者討論該研究且希望參與之參與者必須經管制且使用機構審查委員會(IRB)批准之知情同意書(ICF)提供書面知情同意書。ICF必須為已由結構合理的IRB批准之最新版本。 8.1.3清除間隔 Before participants are enrolled in the trial (that is, before any research-related procedures), the study will be discussed with each potential participant and participants who wish to participate must be regulated and use the Informed Consent Form approved by the Institutional Review Board (IRB) ( ICF) Provide written informed consent. The ICF must be the latest version approved by the well-structured IRB. 8.1.3 Clear interval
禁止之藥物、治療及活動概述於排除標準(章節6.4)中。 8.1.4最終研究進入之程序 Prohibited drugs, treatments and activities are outlined in the exclusion criteria (Section 6.4). 8.1.4 Procedures for final research entry
個體必須滿足所有納入標準且不滿足任何排除標準。 8.1.5分配至治療組之方法 The individual must meet all inclusion criteria and not meet any exclusion criteria. 8.1.5 Method of allocation to treatment group
進入研究篩選時段(定義為個體簽署知情同意書(ICF)之時間點之各個體在進行任何研究相關活動/程序之前接受獨特個體標識號。此編號用於在整個臨床研究中鑑別個體且必須使用於與該個體相關之所有研究文件。Entering the research screening period (defined as the time point when an individual signs an informed consent (ICF)) Individuals receive a unique individual identification number before conducting any research-related activities/procedures. This number is used to identify individuals throughout the clinical study and must be used For all research documents related to the individual.
個體標識號必須在整個臨床研究中保持恆定。此編號將未必與隨機分組編號相同。The individual identification number must remain constant throughout the clinical study. This number will not necessarily be the same as the random group number.
滿足合格性要求之個體將隨機分至2個治療組中之1個。 8.2 並行療法Individuals who meet the eligibility requirements will be randomly assigned to one of the two treatment groups. 8.2 Concurrent therapy
使用任何並行藥物、處方或非處方將連同服用藥物之原因一起記錄於個體之源文件及對應eCRF上。The use of any concurrent medication, prescription or over-the-counter will be recorded on the individual's source file and corresponding eCRF along with the reason for taking the medication.
不允許同時入選另一研究性藥物或裝置研究。 8.2.1禁止之藥物 / 治療 It is not allowed to be enrolled in another study drug or device study at the same time. 8.2.1 Prohibited drugs / treatment
在研究期間不允許之藥物/治療概述於排除標準(章節6.4)中 8.2.2逃避藥物 Drugs/treatments that were not allowed during the study are outlined in the exclusion criteria (Section 6.4) 8.2.2 Escaping drugs
此研究不需要逃避藥物。 8.2.3特殊飲食或活動 This study does not require drug evasion. 8.2.3 Special diet or activities
此研究不需要特殊飲食或活動。 8.3 檢查程序 8.3.1關於研究目標在各研究問診時待執行之程序 No special diet or activities are required for this study. 8.3 Inspection procedures 8.3.1 Procedures for research objectives to be executed at the time of consultation in each study
將執行以下程序(關於描述,參見下文標題為檢查程序、測試、設備及技術之章節)。 篩選/問診1 (第1天):篩選及斯戈默測試評估 知情同意書/健康資訊便攜性及責任法案(HIPAA)同意書 人口統計資料、醫療史、先前藥物治療及眼部病史 合格性標準 尿妊娠測試(若可行) OSDI© 調查表 EDS (視覺類比量表) 眼部不適量表 BCVA (治療前及治療後程序) 裂隙燈活組織檢視法(治療前及治療後程序) 角膜螢光素染色 斯戈默測試(治療前及治療後程序;程序將在角膜螢光素染色之後進行) 在鼻刺激下之斯戈默測試(棉花棒;在鼻刺激下之斯戈默測試將在第一斯戈默測試之後至少10分鐘進行) 鼻內檢查 隨機分組 分配新研究藥物/安慰劑鼻內泵 與斯戈默測試同時投與研究藥物/安慰劑 伴隨藥物治療 AE詢問 問診2 (第7±2天):斯戈默測試評估 BCVA (治療前及治療後) 裂隙燈活組織檢視法(治療前及治療後) 投與研究藥物/安慰劑 斯戈默測試(治療後) 伴隨藥物治療 AE詢問 問診3 (第14±2天):斯戈默測試評估 BCVA (治療前及治療後) 裂隙燈活組織檢視法(治療前及治療後) 投與研究藥物/安慰劑 斯戈默測試(與治療同時) 分配新研究藥物/安慰劑鼻內泵 伴隨藥物治療 AE詢問 問診4 (第21±2天):暴露於人工創造之不利環境評估 人工創造之不利環境之前的程序: 尿妊娠測試(若可行) EDS (視覺類比量表) 眼部不適量表 伴隨藥物治療 AE詢問 治療前暴露於人工創造之不利環境評估 EDS (視覺類比量表)直至符合臨限值 眼部不適量表直至符合臨限值 投與研究性藥物/安慰劑The following procedures will be performed (for the description, see the section below titled Inspection Procedures, Tests, Equipment and Technology). Screening/Interview 1 (Day 1): Screening and Sgormer Test Evaluation Ÿ Informed Consent/Health Information Portability and Accountability Act (HIPAA) Consent Ÿ Demographic data, medical history, previous drug treatment and eye history Ÿ Eligibility criteria Ÿ Urine pregnancy test (if feasible) Ÿ OSDI © questionnaire Ÿ EDS (visual analogue scale) Ÿ Eye discomfort scale BCVA (pre-treatment and post-treatment procedures) Ÿ Slit lamp biopsy (pre-treatment) And post-treatment procedures) Ÿ corneal fluorescein staining Ÿ Gomer test (pre- and post-treatment procedures; the procedure will be performed after corneal luciferin staining) Stommer test under nasal irritation (cotton stick; in the nose The Sgormer test under stimulation will be performed at least 10 minutes after the first Sgormer test) Ÿ Intranasal examination Ÿ Random group Ÿ Assign new study drug/placebo intranasal pump / Placebo Ÿ Concomitant medication Ÿ AE questioning 2 (Day 7±2): Sgormer test assessment BCVA (before and after treatment) Ÿ Slit lamp biopsy (before and after treatment) Ÿ cast With study drug/placebo Ÿ Sgormer test (after treatment) Ÿ Concomitant medical treatment Ÿ AE interrogation 3 (Day 14±2): Sgormer test evaluation BCVA (before and after treatment) Ÿ Slit lamp activity Tissue Examination (Before and After Treatment) Ÿ Administration of study drug/placebo Ÿ Sgormer test (simultaneous with treatment) Ÿ Allocation of new study drug/placebo intranasal pump Ÿ Concomitant drug therapy Ÿ AE Interview 4 (No. 21±2 days): Exposure to artificially created adverse environment. Procedure before assessing artificially created adverse environment: Ÿ urine pregnancy test (if feasible) Ÿ EDS (visual analogue scale) Ÿ eye discomfort scale Ÿ concomitant medication Ÿ AE inquires about the assessment of the unfavorable environment exposed to artificial creation before treatment Ÿ EDS (Visual Analogue Scale) until the threshold is met Ÿ Eye discomfort scale until the threshold is met Administer study drug/placebo
在使用眼部不適量表,參與者在人工創造之不利環境暴露期間的兩個或更多個連續時間點於至少一隻眼睛中報告≥3之眼部不適評分後,將投與研究性藥物/安慰劑治療(在時間=0時一隻眼睛之眼部不適評級為3之參與者必須在兩次連續量測中針對該眼睛報告眼部不適評級4)。參與者將每隔5分鐘重新繼續症狀評估,在施用結束之後1分鐘起始。 治療後人工創造之不利環境評估 EDS (視覺類比量表) 眼部不適量表 BCVA (由調查員判斷為需要) 裂隙燈活組織檢視法(由調查員判斷為需要) AE詢問 問診5 (第28±2天):斯戈默測試評估 BCVA (治療前及治療後) 裂隙燈活組織檢視法(治療前及治療後) 鼻內檢查 投與研究藥物/安慰劑 角膜螢光素染色(治療後) 斯戈默測試(與治療同時) EDS (視覺類比量表;治療後) 伴隨藥物治療 AE詢問 提早終止(若可行) BCVA 裂隙燈活組織檢視法 鼻內檢查 尿妊娠測試(若可行) 伴隨藥物治療 AE詢問 8.4 問診、量測及給藥排程 8.4.1預定問診 After using the Eye Discomfort Scale, participants report an eye discomfort score of ≥3 in at least one eye at two or more consecutive time points during the artificially created adverse environmental exposure, and will be administered the investigational drug /Placebo treatment (participants with an eye discomfort rating of 3 at time=0 must report an eye discomfort rating of 4 for that eye in two consecutive measurements). Participants will resume symptom assessment every 5 minutes, starting 1 minute after the end of administration. Assessment of the adverse environment artificially created after treatment Ÿ EDS (Visual Analogue Scale) Ÿ Eye Discomfort Scale BCVA (decided by investigator as necessary) Ÿ Slit lamp biopsy (decided by investigator as necessary) Ÿ AE inquiry Interview 5 (Day 28±2): Sgormer test assessment BCVA (before and after treatment) Ÿ slit lamp biopsy (before and after treatment) Ÿ intranasal examination Ÿ study drug/placebo Ÿ Corneal fluorescein staining (after treatment) Ÿ Gomer test (simultaneous with treatment) Ÿ EDS (Visual Analogue Scale; after treatment) Ÿ Concomitant medication Ÿ AE inquiry for early termination (if feasible) Ÿ BCVA Ÿ Slit lamp activity Tissue Examination Ÿ Intranasal Examination Ÿ Urine Pregnancy Test (if applicable) Ÿ Accompanying medication Ÿ AE Interview 8.4 Interview, Measurement and Dosing Schedule 8.4.1 Scheduled Interview
參看下文標題為問診及量測排程之章節。 8.4.2非預定問診 See the section below titled Interview and Measurement Schedule. 8.4.2 Unscheduled consultation
可進行此等問診以確保個體安全性。在非預定問診時進行之所有程序將記錄於源文件中及非預定問診eCRF頁上。eCRF中指示之任何未進行之程序應表示為「未進行(Not done)」。These consultations can be conducted to ensure individual safety. All procedures performed during an unscheduled consultation will be recorded in the source file and on the unscheduled consultation eCRF page. Any unprocessed procedures indicated in the eCRF should be indicated as "Not done".
可在非預定問診時進行之評估包括: 裂隙燈活組織檢視法; 視力; 鼻內檢查; 尿妊娠測試(若可行); 評估AE; 評估並行藥物及/或治療;及 由調查員判斷必需之任何其他評估。 8.5 方案順應性Assessments that can be performed during unscheduled consultations include: Ÿ Slit lamp biopsy; Ÿ Vision; Ÿ intranasal examination; Ÿ urine pregnancy test (if feasible); Ÿ Evaluate AE; Ÿ Assess concurrent medication and/or treatment; and Ÿ Any other assessment as judged by the investigator is necessary. 8.5 Compliance with the plan
將在問診1、2、3及4時指示個體恰當使用及儲存研究藥物,且在問診1及問診3時在分配其研究藥物後提供書面說明書。
8.6 個體處置 8.6.1完成個體 Individuals will be instructed to properly use and store study medication at
完成個體為已完成4週研究問診之個體。 8.6.2中止個體 Completed individuals are those who have completed 4 weeks of study interviews. 8.6.2 Discontinued individuals
個體可歸因於以下各者而在其完成研究之前的任何時候中止治療,或中止參與研究: AE; 當醫療上需要時解遮蔽; 方案違反; 管理原因(例如不能繼續、失訪); 研究終止; 個體選擇(例如撤回同意書);及 其他The individual can suspend treatment at any time before completing the study due to the following: Ÿ AE; Ÿ Unmask when medically necessary; Ÿ program violation; Ÿ Management reasons (for example, unable to continue, lost to follow-up); Ÿ Research termination; Ÿ Individual choice (eg withdrawal of consent); and Ÿ Other
附註:另外,任何個體可出於由調查員決定之任何合理醫療原因而中止治療或中止研究參與。Note: In addition, any individual may suspend treatment or suspend research participation for any reasonable medical reason determined by the investigator.
個體中止通知及中止原因將清楚地記錄於eCRF上。The notice of individual suspension and the reason for suspension will be clearly recorded on eCRF.
將不替換中止個體。 8.7 研究終止Suspended individuals will not be replaced. 8.7 Termination of research
研究可有調查員在任何時候停止。 8.8 研究持續時間Research can be stopped by an investigator at any time. 8.8 Research duration
個別個體之參與將涉及大約4週(28天)內之5次問診 8.9 監測及品質保證Individual participation will involve 5 visits within approximately 4 weeks (28 days) 8.9 Monitoring and quality assurance
在研究過程期間,監測者或指定人員將進行常規現場視察以檢查方案順應性、評估研究藥物可追究性、個體安全性及確保研究係根據相關的監管要求進行。個體醫療記錄之審查將以充分維持個體保密性的方式進行。監測計劃將概述研究監測之其他細節。During the research process, monitors or designated personnel will conduct routine on-site inspections to check protocol compliance, assess study drug traceability, individual safety, and ensure that research is conducted in accordance with relevant regulatory requirements. The review of individual medical records will be conducted in a way that maintains the confidentiality of the individual. The monitoring plan will outline other details of the research monitoring.
國內及國外機構之監管當局可進行現場檢驗及/或審計,其可包括原始源資料檢查。因此,檢驗及/或審計將需要直接存取原始源資料。所有檢驗及審計將在地方、州及聯邦法律適用之程度上考慮資料保護以及個體保密性而進行。 9 安全定義、安全監測及報告 9.1 不良事件Supervisory authorities of domestic and foreign institutions may conduct on-site inspections and/or audits, which may include original source data inspections. Therefore, inspection and/or auditing will require direct access to the original source material. All inspections and audits will be conducted taking into account data protection and individual confidentiality to the extent applicable by local, state, and federal laws. 9 Safety definition, safety monitoring and reporting 9.1 9.1 Adverse events
不良事件(AE)係定義為與在人體中使用藥物相關之任何不良醫療事件,無論該事件是否視為藥物相關。AE因此可為在開始向個體投配研究藥物之後出現之任何不利及非預期病徵(例如異常實驗室發現)、症狀或疾病,而不對因果關係進行任何判斷。在投與研究藥物之後惡化之任何預先存在之醫學病況亦將視為新AE。An adverse event (AE) is defined as any adverse medical event related to the use of drugs in the human body, regardless of whether the event is considered to be drug-related. AE can therefore be any adverse and unexpected symptoms (eg, abnormal laboratory findings), symptoms, or disease that occur after starting to administer the study drug to the individual without any judgment of causality. Any pre-existing medical conditions that deteriorate after administration of the study drug will also be considered a new AE.
研究藥物包括正進行評估之研究性藥物及安慰劑。Study drugs include research drugs and placebos that are being evaluated.
關於AE之文件製作應關於性質、起始日期、結束日期、嚴重度、與研究藥物之關係、採取之行動、嚴重性及由調查員觀測或在間接詢問後由個體報告之任何病徵或症狀之結果來進行。 9.1.1嚴重度 The documentation about AE should be about the nature, start date, end date, severity, relationship with study drug, action taken, severity, and any signs or symptoms observed by the investigator or reported by the individual after indirect inquiry The results are carried out. 9.1.1 Severity
AE之嚴重度係定義為如由調查員所測定或由患者/個體向其報告之AE強度程度的定性評估。嚴重度評估無關於與研究藥物之關係或事件嚴重性而進行且應根據以下標度評估: 輕度 :事件對個體而言為明顯的,但易於容忍且不干擾個體之每日活動。 中度 :事件為麻煩的,可能需要額外療法,且可干擾個體之每日活動。 重度 :事件為不能忍受的,需要額外療法或更改療法,且干擾個體之每日活動。 9.1.2與研究藥物之關係 The severity of AE is defined as the qualitative assessment of the degree of AE intensity as determined by the investigator or reported to it by the patient/individual. Severity assessments are conducted without regard to the relationship with the study drug or the severity of the event and should be evaluated on the following scale: Ÿ Mild : The event is obvious to the individual, but is easily tolerated and does not interfere with the individual's daily activities. Ÿ Moderate : The event is troublesome, may require additional therapy, and may interfere with the individual's daily activities. Ÿ Severe : The event is intolerable, requires additional therapy or changes in therapy, and interferes with the individual's daily activities. 9.1.2 Relationship with research drugs
各AE與研究產品之關係應由調查員(以盲法方式)使用此等解釋來確定: 確定: 當存在良好原因及足夠文件以展現研究產品與AE之間的直接因果關係時 很可能: 當存在良好原因及足夠文件以在似乎合理、可設想、可能但未必高度可能之意義上假定因果關係時 有可能: 當存在足夠資訊以在並非不可能及並非不太可能之意義上接受因果關係之可能性,儘管關聯歸因於例如遺漏資料或證據不足而不確定或有疑問時 無: 當存在足夠資訊以接受無因果關係(在不可能及不大可能之意義上)時 未分類: 當因果關係出於歸因於證據不足、資料衝突或文件不佳之任何原因而不可評定時 9.1.3預期性 The relationship between each AE and the research product should be determined by the investigator (in a blinded manner) using these interpretations: y determined: when there is a good cause and sufficient documentation to demonstrate the direct causal relationship between the research product and the AE, it is likely : When there are good reasons and sufficient documentation to assume causality in the sense that it seems reasonable, conceivable, possible, but not necessarily highly likely, it is possible: when there is enough information to accept in the sense that it is not impossible and not unlikely Possibility of causality, although the association is due to, for example, missing data or insufficient evidence and is uncertain or questionable. None: When there is enough information to accept a non-causal relationship (in the unlikely and unlikely sense). Unclassified: When the cause and effect relationship cannot be assessed for any reason attributed to insufficient evidence, conflicting data, or poor documentation 9.1.3 Expectancy
AE之預期性應基於關於研究藥物之現有安全性資訊使用此等解釋來確定: 未預期 : 未列於調查員手冊(IB)中或未列於已觀測之特異性或嚴重度下之AE。 預期: 列於IB中已觀測之特異性及嚴重度下之AE。 不適用: 與研究藥物無關之任何AE。The predictability of AEs should be determined using these interpretations based on the existing safety information about the study drug: Unexpected : AEs that are not listed in the Investigator's Handbook (IB) or are not listed in the observed specificity or severity . ŸExpectation : AE listed in IB under the observed specificity and severity. Ÿ Not applicable: Any AE not related to the study drug.
在IB中提及為在一類藥物之情況下出現或由藥物之藥理學特性而預料,但未特定提及為在調查中之特定藥物之情況下出現之AE係視為未預期的。Mentioned in IB as occurring in the case of a class of drugs or expected from the pharmacological properties of the drug, but not specifically mentioned as appearing in the case of the specific drug under investigation is considered unexpected.
調查員應起初對AE之預期性進行分類,但最終分類以醫學監察員之判定為準。 9.2 嚴重不良事件The investigator should initially classify the AE's expectations, but the final classification is subject to the medical inspector's judgment. 9.2 Serious adverse events
若在調查員看來,AE導致以下結果中之任一者,則將其視為「嚴重的」(SAE): 死亡 危及生命之AE 附註:若在調查員看來,AE之出現將患者或個體置於死亡之即時風險下,則將其視為「危及生命的」。其不包括若以更嚴重形式出現,則有可能引起死亡之AE。 住院或延長現有住院 附註:術語「住院」係指任何入院(即使小於24小時)。對於慢性或長期住院病人,入院包括在醫院內轉移至急症/重症護理住院病人病房。住院不包括:急診;門診/當日/非臥床手術;觀察/短暫停留病房;康復設施;臨終關懷設施;療養院;或臨床研究/1期單位。 附註:術語「延長現有住院」係指任何延長住院而超出由於調查員或治療醫師所確定之初始入院所預期或所需之停留。 持續性或顯著無能力或執行正常生活功能之能力的重大破壞 附註:尤其與視覺威脅相關之SAE將解釋為對個體眼睛之任何潛在減損或損害(例如出血、視網膜剝離、中央角膜潰瘍或視神經損傷)。 研究個體之後代的先天性異常/天生缺陷。If, in the eyes of the investigator, AE causes any of the following results, it is considered "serious" (SAE): Ÿ death Ÿ Life-threatening AE Note: If it appears to the investigator that the occurrence of AE places the patient or individual at immediate risk of death, it is considered "life-threatening". It does not include AEs that may cause death if they occur in a more serious form. Ÿ Hospitalization or extension of existing hospitalization Note: The term "hospitalization" refers to any admission (even if less than 24 hours). For chronic or long-term inpatients, admission includes transfer to emergency/intensive care inpatient wards within the hospital. Hospitalization does not include: emergency department; outpatient/same day/ambulatory surgery; observation/short stay in ward; rehabilitation facility; hospice facility; nursing home; or clinical research/1 phase unit. Note: The term "extension of existing hospitalization" refers to any extended hospitalization that exceeds the expected or required stay for the initial admission determined by the investigator or treating physician. Ÿ Sustained or significant incapacity or significant disruption of normal life functions Note: SAE, especially related to visual threats, will be interpreted as any potential loss or damage to the individual's eyes (such as bleeding, retinal detachment, central corneal ulcer, or optic nerve damage). Ÿ Study congenital anomalies/inherent defects of individual offspring.
當基於適當醫學判斷,可危及患者或個體且可需要醫療或手術干預以預防此定義中所列之結果之一時,可能不導致死亡、危及生命且需要住院之重大醫療事件可視為嚴重。 9.3 報告不良事件之程序When, based on appropriate medical judgment, a patient or individual may be endangered and medical or surgical intervention may be required to prevent one of the results listed in this definition, a major medical event that may not result in death, life-threatening and requires hospitalization may be considered serious. 9.3 Procedures for reporting adverse events
所有AE及其結果必須向IRB/IEC報告,如由IRB/IEC、聯邦、州或地方法規及健康管理當局所要求,且記錄於適當eCRF上。 9.3.1報告疑似的未預期不良反應 All AEs and their results must be reported to the IRB/IEC, as required by the IRB/IEC, federal, state or local regulations, and health management authorities, and recorded on the appropriate eCRF. 9.3.1 Report suspected unanticipated adverse reactions
所有『疑似』及『未預期』之AE應向IRB/IEC報告,如由IRB/IEC、聯邦、州或地方法規及健康管理當局所要求。 9.3.2報告嚴重不良事件 All "suspicious" and "unexpected" AEs should be reported to the IRB/IEC, as required by the IRB/IEC, federal, state or local regulations and health management authorities. 9.3.2 Report serious adverse events
為了確保個體安全,不管與研究藥物之關係,所有SAE必須立即報告。與SAE相關之所有資訊必須記錄於適當CRF上。調查員有義務追求及獲得CRF上報告之資訊。經歷SAE之所有個體必須隨訪且報告結果。To ensure individual safety, all SAEs must report immediately regardless of the relationship with the study drug. All information related to SAE must be recorded on the appropriate CRF. Investigators are obliged to pursue and obtain the information reported on the CRF. All individuals undergoing SAE must be followed up and report the results.
若發生SAE,調查員必須立即通知調查員;在其檔案中獲得及維持來自協助個體治療及隨訪之同事的所有相關的醫療記錄、資訊及醫學判斷;提供完全病歷,其包括關於事件是否疑似與研究藥物使用相關之陳述;且告知SAE之IRB在其指南內報告SAE。 9.4 對研究藥物解遮蔽之程序If an SAE occurs, the investigator must notify the investigator immediately; obtain and maintain all relevant medical records, information, and medical judgments from colleagues who assist the individual in treatment and follow-up in their files; provide a complete medical record, including information about whether the event is suspected and Statements related to study drug use; and inform SAE's IRB to report SAE within its guidelines. 9.4 Procedures for unmasking research drugs
涉及進行研究之所有個體、調查員及研究人員將關於治療分配經遮蔽。當醫療上需要時,調查員可能需要確定已向個體分配何治療方案。若由與醫學監察員磋商之調查員保證,則解遮蔽個體將繼續研究。 9.5 個體在不良事件之後的隨訪之類型及持續時間All individuals, investigators, and researchers involved in conducting the study will be covered regarding treatment allocation. When medically necessary, the investigator may need to determine what treatment plan has been assigned to the individual. If guaranteed by an investigator in consultation with the medical inspector, the unmasked individual will continue to study. 9.5 Type and duration of individual follow-up after adverse events
調查員將追蹤未解決的AE至解決,直至個體失訪或直至AE以其他方式分類。解決意謂個體已返回至基線健康狀態或調查員不預期AE之任何進一步的改善或惡化。若患者失訪,則調查員應進行3次合理的嘗試以經由電話、郵件或保證郵件來聯繫患者。所有隨訪將記錄於個體之源文件中。在最後一次預定聯繫時鑑別之非嚴重AE必須伴以注意到的狀態記錄於AE eCRF上。The investigator will track unresolved AEs until resolution, until the individual is lost to follow-up or until AEs are classified in other ways. Resolution means that the individual has returned to baseline health or the investigator does not expect any further improvement or deterioration of AE. If the patient is lost to follow-up, the investigator should make 3 reasonable attempts to contact the patient by phone, mail or guarantee mail. All follow-up visits will be recorded in the source file of the individual. The non-serious AE identified at the last scheduled contact must be recorded on the AE eCRF with the status noted.
若調查員意識到關於現有SAE之任何新資訊(亦即,解決、狀況變化或新治療),則必須在意識到新資訊之24小時內完成新SAE/非預期報告表且發傳真。原始SAE表不改變。報告應描述事件已解決或繼續且如何處理該事件。 10 統計分析If the investigator is aware of any new information about the existing SAE (ie, resolution, status change, or new treatment), then the new SAE/unexpected report form must be completed and faxed within 24 hours of being aware of the new information. The original SAE table is unchanged. The report should describe how the incident has been resolved or continued and how to handle the incident. 10 Statistical analysis
此研究之分析之統計考慮因素及方法提供於下;伴隨的統計分析計劃(SAP)含有所計劃之分析的完整細節。 10.1 樣本大小及能力考慮The statistical considerations and methods for the analysis of this study are provided below; the accompanying Statistical Analysis Plan (SAP) contains complete details of the planned analysis. 10.1 Sample size and ability considerations
研究將大致45位個體以2:1比率隨機分為兩個治療組。預期2.0%化合物1半-半乳糖二酸鹽二水合物治療組之30位個體中之大約28個及安慰劑(化合物1半-半乳糖二酸鹽二水合物媒劑)鼻用噴霧治療組之15位個體中之13個完成其分配治療且在問診5時具有終點評估。The study randomly divided approximately 45 individuals into two treatment groups at a 2:1 ratio. Approximately 28 out of 30 individuals in the 2.0
主要功效終點為斯戈默測試評分(STS)自基線至問診5之變化。將使用杜奈特(Dunnett)校正5%顯著性下之雙側t-檢驗。The primary efficacy endpoint was the change in the Sgormer Test Score (STS) from baseline to visit 5. Dunnett will be used to correct for a two-sided t-test at 5% significance.
先前2b期研究(OPP-001)顯示STS變化之大致10個單位的標準差(SD)。假設高劑量與安慰劑之間10個單位之標準差及16.7個單位之平均差,比較將顯著之概率(亦即,能力)為大致99%。 10.2 分析群體 10.2.1意向治療群體 A previous phase 2b study (OPP-001) showed a standard deviation (SD) of approximately 10 units of STS change. Assuming a standard deviation of 10 units and an average difference of 16.7 units between the high dose and placebo, the comparison will have a significant probability (ie, ability) of approximately 99%. 10.2 Analysis group 10.2.1 Intention-to-treat group
意向治療(ITT)群體將包括所有隨機分組個體。使用ITT群體之分析將根據個體所隨機分入之治療而對其分組。 10.2.2安全群體 The intention-to-treat (ITT) population will include all randomly grouped individuals. Analysis using the ITT population will group individuals according to the treatment they are randomly assigned to. 10.2.2 Security groups
安全群體將包括接受至少一個劑量之研究藥物的所有隨機分組個體。安全群體分析將根據實際接受之治療而對個體分組。 10.3 統計假設The safe population will include all randomized individuals who receive at least one dose of study drug. Safety group analysis will group individuals according to the actual treatment received. 10.3 Statistical assumptions
STS自基線至問診5之平均變化對於安慰劑及2.0%化合物1半-半乳糖二酸鹽二水合物分別表示為µp 及µh 。 H01 :µp = µh H11 :µp ≠ µp ≠ µh STS mean change from baseline to the inquiry of 5 and 2.0% for placebo semi Compound 1 - mucate dihydrate are represented by μ p and μ h. H 01 : µ p = µ h H 11 : µ p ≠ µ p ≠ µ h
成功結果將為拒絕給定劑量之虛無假設的結果。 10.4 統計分析A successful result will be the result of rejecting the null hypothesis of a given dose. 10.4 Statistical analysis
此章節簡要概述計劃之功效分析。SAP詳細描述待使用之方法。若SAP與方案不一致,則將以SAP之細節及方法為準。 10.4.1一般考慮因素 This chapter briefly outlines the efficacy analysis of the plan. SAP details the method to be used. If SAP is inconsistent with the plan, the details and methods of SAP will prevail. 10.4.1 General considerations
定量變數將使用個體數目(n)、平均值、SD、中值、第25及第75百分位數以及最小值及最大值概述。定性變數將使用計數及百分比概述。Quantitative variables will be summarized using the number of individuals (n), mean, SD, median, 25th and 75th percentiles, and minimum and maximum values. Qualitative variables are outlined using counts and percentages.
所有概述將藉由治療組呈現。概述將針對人口統計資料、醫療史、伴隨藥物治療及個體處置提供。All overviews will be presented by the treatment group. The overview will be provided for demographic data, medical history, concomitant medications and individual treatment.
為進行概述,醫療史、伴隨藥物治療及AE將按需要根據MedDRA及世界衛生組織藥物詞典編碼。For an overview, medical history, concomitant medication, and AE will be coded according to MedDRA and the World Health Organization Drug Dictionary as needed.
基線量測定義為在起始研究治療之前,通常在問診1篩選時之最後一次量測。
10.4.2分析單位 Baseline measurement is defined as the last measurement prior to the initiation of study treatment, usually at the time of Screening for
對於功效終點,分析單位將為定義為符合所有納入及排除標準之眼睛的研究用眼睛。若兩隻眼睛均合格,則研究用眼睛將為在篩選問診時藉由用棉花棒刺激而具有淚液產生最大增加之眼睛。若刺激之淚液產生無差異,則為在篩選時具有較低基礎斯戈默評分之眼睛。若任一量度均無差異,則右眼將用作研究用眼睛。For the end point of efficacy, the unit of analysis will be the research eye defined as the eye that meets all inclusion and exclusion criteria. If both eyes are qualified, the research eye will be the one with the largest increase in tears by stimulation with a cotton swab during screening interviews. If there is no difference in the irritated tears, it is an eye with a lower basic Sgormer score at the time of screening. If there is no difference in any measurement, the right eye will be used as the research eye.
對於安全終點,將分析兩隻眼睛。 10.4.3個體人口統計資料及基線特 徵 For the safety endpoint, two eyes will be analyzed. 10.4.3 individual demographics and baseline characteristics
將對於以年計之年齡(根據治療組)及所有個體產生連續概述統計量。將對於以下定性人口統計變數產生離散概述統計量:年齡層、性別、種族、人種及其他基線鼻內檢查結果,根據治療組且對於所有個體列表。個別個體資料清單將支持彙總表。 10.4.4主要功效分析 A continuous summary statistic will be generated for age in years (based on treatment group) and all individuals. Discrete summary statistics will be generated for the following qualitative demographic variables: age group, gender, race, ethnicity, and other baseline intranasal examination results, according to the treatment group and for all individual lists. Individual individual data lists will support summary tables. 10.4.4 Main efficacy analysis
主要功效終點為STS在問診5時相對於基線之改變。主要終點將藉由問診及藉由治療用定量描述性統計(n、平均值、中值、標準差、第25四分位數、第75四分位數、最小值及最大值)來概述。The primary efficacy endpoint was the change of STS from baseline at the 5th visit. The primary endpoint will be summarized by questioning and by quantitative descriptive statistics for treatment (n, mean, median, standard deviation, 25th quartile, 75th quartile, minimum and maximum).
STS相對於基線之改變的主要功效分析將使用對共變量分析(ANCOVA)之分析來比較治療組差異(2.0%化合物1半-半乳糖二酸鹽二水合物相對於安慰劑)。ANCOVA模型將包括治療組及基線STS作為共變數。將計算比較之平均差的差異且連同其95%信賴區間一起報告。The main efficacy analysis of STS change from baseline will use analysis of the covariate analysis (ANCOVA) to compare treatment group differences (2.0
將對ITT群體進行初步分析。截尾均值將用於處理未完成問診5 STS之個體。杜奈特檢驗(Dunnett's Test)將用於成對多重比較。A preliminary analysis will be conducted on the ITT community. The censored mean will be used to treat individuals who have not completed the 5 STS visit. Dunnett's Test will be used for pairwise multiple comparisons.
SAP提供描述功效分析模型及處理遺漏資料之方法的細節。 10.4.5二次功效分析 SAP provides details describing the power analysis model and the method of dealing with missing data. 10.4.5 Secondary power analysis
EDS將使用連續概述統計量概述。將計算2.0%化合物1半-半乳糖二酸鹽二水合物組與安慰劑組之間的平均差以及相關95% CI。EDS will use a continuous summary statistics summary. The average difference between the 2.0
SAP將提供描述計劃用於結果之統計方法、多重性之校正及處理遺漏資料之方法的細節。 10.4.6其他功效分析 SAP will provide details describing the statistical methods planned for the results, the correction of multiplicity, and the methods for processing missing data. 10.4.6 Other power analysis
將對角膜染色評估及眼部不適量表進行其他功效分析。描述性統計將由問診及治療概述。SAP將提供描述計劃用於此等結果之統計方法、多重性之校正及處理遺漏資料之方法的細節。 10.4.7安全分析 Corneal staining assessment and eye discomfort scale will be analyzed for other efficacy. Descriptive statistics will be summarized by consultation and treatment. SAP will provide details describing the statistical methods planned for these results, the correction of multiplicity, and the methods for processing missing data. 10.4.7 Safety analysis
將對安全群體進行所有安全分析。All safety analyses will be conducted on the safety groups.
化合物1半-半乳糖二酸鹽二水合物之安全性將主要由AE發生率評估。若AE在治療開始時或之後出現或惡化,則將其視為治療引發AE (TEAE)。將根據針對TEAE之治療組以基於嚴重性、與治療之關係及嚴重度之若干類別呈現TEAE之總體概述,包括事件數目及具有事件之個體數目(連同百分比)。The safety of
包括視力、裂隙燈活組織檢視法及鼻內檢查之其他安全終點將由治療組及問診使用描述性統計概述。自基線之變化或偏移將在適當時概述。對於藉由眼睛進行之評估,將分別概述研究用眼睛及對側眼。另外,將概述自基線偏移至眼部安全評估之最差治療期間值。Other safety endpoints including vision, slit lamp biopsy, and intranasal examination will be summarized by the treatment group and the use of descriptive statistics. Changes or offsets from the baseline will be summarized as appropriate. For the evaluation by eye, the research eye and the contralateral eye will be summarized separately. In addition, the worst treatment period values from baseline to ocular safety assessment will be summarized.
SAP將詳細呈現分析此等界定參數之方法。 10.4.8期中分析 SAP will present a detailed analysis of these defined parameters. 10.4.8 Interim analysis
未針對此研究計劃期中分析。 11 與良好臨床實踐、倫理考量及管理問題之順應性No mid-term analysis for this research plan. 11 Compliance with good clinical practice, ethical considerations and management issues
參看實例2中之章節11「與良好臨床實踐、倫理考量及管理問題之順應性」。
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問診及量測之排程
關於檢查程序、測試、設備及技術之描述,參看實例2中標題為檢查程序、測試、設備及技術之章節。 結果 For a description of inspection procedures, tests, equipment, and technology, see the chapter entitled Inspection procedures, tests, equipment, and technology in Example 2. result
基於上文所述之方案,對53個診斷患有乾眼病之個體進行用於評估2.0%化合物1半-半乳糖二酸鹽二水合物(1.1%化合物1游離鹼)鼻用噴霧對乾眼病之病徵及症狀之功效的多中心、隨機化、受控、雙盲臨床試驗。此等個體展現10 mm或更小之斯戈默評分及23或更大之OSDI評分。個體係隨機分至安慰劑組(19)或治療組(34),其中向其投與含有媒劑對照或2.0%化合物1半-半乳糖二酸鹽二水合物溶液之鼻用噴霧。經4週之時段一天兩次地向各鼻孔投與50微升鼻用噴霧(總共100微升)。Based on the protocol described above, 53 individuals diagnosed with dry eye disease were evaluated for 2.0
研究結果支持化合物1半-半乳糖二酸鹽二水合物在4週治療之後有效地改善乾眼病之病徵及症狀。特定言之,個體展現(a)第4週時研究用眼睛及對側眼之斯戈默評分的改善;(b)第3週時在對照不利環境內部以及外部乾眼評分之改善;及(c)第4週時角膜螢光素染色結果之改善。另外,個體不展示由其化合物1半-半乳糖二酸鹽治療所致之任何有意義的全身或眼部不良事件。個體可能經歷副作用,諸如打噴嚏、咳嗽或刺激,其與任何鼻用噴霧治療一致。
在用2.0%化合物1半-半乳糖二酸鹽二水合物治療後經4週時段之斯戈默評分變化The results of the study support that compound 1 hemi-galactonate dihydrate effectively improves the signs and symptoms of dry eye disease after 4 weeks of treatment. In particular, the individual exhibited (a) an improvement in the Stommer score of the study eye and the contralateral eye at
功效之主要量度為研究之第28天的斯戈默測試。一般而言,較高斯戈默評分指示相較於相較於較低評分之較大量。如圖12中所概述,用化合物1半-半乳糖二酸鹽二水合物治療之個體相較於基線評分之斯戈默評分的平均變化在研究之第28天(第4週)為10.3 mm (p=0.08),且安慰劑組自基線斯戈默評分之平均增加為5.9 mm。治療組之斯戈默評分相較於安慰劑的超過4 mm平均增加指示化合物1半-半乳糖二酸鹽二水合物在4週治療之後有效地增加淚液。The main measure of efficacy was the Sgormer test on the 28th day of the study. Generally speaking, a higher Sgormer score indicates a larger amount compared to a lower score. As outlined in Figure 12, the average change in the Sgormer score of subjects treated with
另外,基於在第1天(15.7 mm,p<0.001)、第7天(第1週,9.5 mm,p<0.05)及第14天(第2週,10.4 mm,p=0.001)時平均斯戈默評分相較於基線評分之統計上顯著變化,用化合物1半-半乳糖二酸鹽二水合物治療提供流淚之立即及持續增加。此等結果概述於圖12中。In addition, based on the average time on day 1 (15.7 mm, p<0.001), day 7 (
亦在個體之對側眼中顯示相較於安慰劑,在用化合物1半-半乳糖二酸鹽二水合物治療後,平均斯戈默評分經4週時段之較大變化。(研究用眼睛及對應對側眼之選擇論述於以上方案中)。研究結果顯示在用化合物1半-半乳糖二酸鹽二水合物治療後,在第1天(16.2 mm,p<0.001)、第7天(第1週,9.6 mm,p<0.05)、第14天(第2週,9.6 mm,p<0.05)及第28天(第4週,9.9 mm,p=0.003)自基線評分之統計上顯著變化。此等結果概述於圖13中。Also shown in the individual's contralateral eye compared to placebo, after treatment with
與來自研究用眼睛及對側眼之結果結合以包括所有符合方案條件的眼睛,研究顯示相較於安慰劑,在用化合物1半-半乳糖二酸鹽二水合物治療後,平均斯戈默評分經4週時段自基線之較大變化。研究結果顯示在用化合物1半-半乳糖二酸鹽二水合物治療後,在第1天(16 mm)、第7天(第1週,9.8 mm)、第14天(第2週,10.6 mm)及第28天(第4週,10.9 mm)斯戈默評分相較於基線評分之變化。此等結果概述於圖14中。Combined with the results from the research eye and the contralateral eye to include all eyes that meet the conditions of the regimen, the study showed that after treatment with
相較於安慰劑組,用化合物1半-半乳糖二酸鹽二水合物治療組之研究用眼睛及對側眼中之斯戈默評分自第1天至第28天之較大增加證明化合物1半-半乳糖二酸鹽二水合物可用於立即增加流淚,以及經四週時段維持增加之流淚。此證據支持化合物有效治療乾眼病及減少眼部不適之用途。斯戈默評分之類別變化 Compared with the placebo group, the study with the
研究所選之個體在篩選時及在治療之前具有小於10 mm的斯戈默評分(基線評分)。相較於基線斯戈默評分展現斯戈默評分之10 mm或更大增加(類別變化)之化合物1半-半乳糖二酸鹽二水合物治療個體之百分比大於安慰劑組中個體之百分比。在治療組中,64.7%之個體在第1天,38.2%之個體在第7天,47.1%之個體在第14天,且41.2%之個體在第28天具有10 mm或更大的斯戈默評分。在安慰劑組中,21.1%之個體在第1天,21.1%之個體在第7天,10.5%之個體在第14天,且15.8%之個體在第28天具有超過其基線評分10 mm或更大的斯戈默評分。此等結果概述於圖15中。Individuals selected for the study had a Sgormer score (baseline score) of less than 10 mm at the time of screening and before treatment. The percentage of
此等結果支持用化合物1半-半乳糖二酸鹽二水合物治療導致診斷患有乾眼病之個體之斯戈默評分的類別變化(>
10 mm增加)。在用 2.0% 化合物 1 半 - 半乳糖二酸鹽二水合物治療 21 及 28 天之後的乾眼評分結果 These results support that treatment with
功效之次要量度為研究之第21天(第3週)時之EDS。一般而言,相較於指示較少不適之較低EDS,較大EDS指示由乾眼症狀所致之較大不適。來自研究之結果顯示相較於基線評分,治療組之EDS在第21天平均減小-9.6 mm。相比之下,安慰劑組中之EDS減小-4.3 mm。此等結果概述於圖16(A)中。在治療3週之後,治療組之EDS相較於安慰劑組的較大減小指示乾眼病症狀之較少不適及較大改善。此結果證明化合物1半-半乳糖二酸鹽二水合物有效地減少與乾眼病相關之眼部不適及症狀。The secondary measure of efficacy was EDS at the 21st day (week 3) of the study. In general, larger EDS indicates greater discomfort caused by dry eye symptoms than lower EDS that indicates less discomfort. The results from the study showed that the EDS of the treatment group decreased by -9.6 mm on
圖16(B)概述28天(第4週)時之EDS。條形圖顯示治療組之EDS減小-16.9 mm且安慰劑組減小-19.8 mm。Figure 16(B) summarizes the EDS at 28 days (Week 4). The bar graph shows that the EDS of the treatment group decreased by -16.9 mm and the placebo group decreased by -19.8 mm.
在21天時,個體經受受控的不利環境,接著投與安慰劑或化合物1半-半乳糖二酸鹽二水合物。在給藥後5、10及15分鐘量測個體之EDS。給與化合物1半-半乳糖二酸鹽二水合物之組中之平均EDS減小在5分鐘處為-7.2 mm,在10分鐘處為-11.4 mm且在15分鐘處為-11.4 mm。給與安慰劑之組中之平均EDS減小在5分鐘處為-6.1 mm,在10分鐘處為-7.7 mm且在15分鐘處為-5.9 mm。此等結果概述於圖17中。At 21 days, the subject experienced a controlled adverse environment and was then administered a placebo or
治療組之EDS相較於安慰劑組的較大減小指示在診斷患有乾眼病且用化合物1半-半乳糖二酸鹽二水合物治療之個體中,彼等個體經歷眼部不適的較大減少。此結果證明化合物1半-半乳糖二酸鹽二水合物可用於有效地治療乾眼病症狀。角膜染色之變化 The greater reduction in EDS in the treatment group compared to the placebo group indicates that among individuals diagnosed with dry eye disease and treated with
治療功效之另一量度為角膜螢光素染色測試。一般而言,較高數目指示對角膜表面之較大損害,且較低數目指示對角膜表面之較低損害水準。角膜螢光素染色評分隨時間推移之減小證明對角膜表面之損害減小且眼表面健康改善。來自研究之結果顯示在用化合物1半-半乳糖二酸鹽二水合物治療28天之後,鼻部(-0.12)、角膜表面上區(-0.06)及下區(-0.12)之平均角膜染色評分的減小。相比之下,安慰劑組展現鼻部(0.17)及上(0.22)角膜區之角膜評分增加,且下區之角膜評分減小(-0.06)。此等結果概述於圖18中。Another measure of therapeutic efficacy is the corneal luciferin staining test. In general, a higher number indicates a greater damage to the corneal surface, and a lower number indicates a lower level of damage to the corneal surface. The decrease in corneal fluorescein staining score over time proves that the damage to the corneal surface is reduced and the health of the ocular surface is improved. Results from the study showed that after 28 days of treatment with
用化合物1半-半乳糖二酸鹽二水合物治療組中之鼻部、上區及下區之角膜螢光素染色評分的減小證明角膜健康在28天治療之後改善。此等結果與用化合物1半-半乳糖二酸鹽二水合物有效治療乾眼病、增加淚液產生及改善眼部不適一致。安全概況 The reduction in corneal fluorescein staining scores in the nose, upper and lower areas of the treatment group with
與投與化合物1半-半乳糖二酸鹽二水合物潛在地相關且出現於大於5%之研究組中之事件包括(自較頻繁至較不頻繁):打噴嚏、咳嗽、喉部及滴注部位刺激,以及咽部及投與部位感覺遲鈍。結果概述於圖19中。各事件在本質上為短暫性的且在嚴重度上為輕度的。此等事件與由任何鼻用噴霧投與產生之副作用一致。未自研究觀測到有意義的全身或眼部不良事件。此等結果支持在用化合物1半-半乳糖二酸鹽二水合物鼻內治療28天之後的強力安全性結果。
實例4:量測最大血漿濃度Events that are potentially related to the administration of
此實例描述在投與包含nAChR促效劑或其醫藥學上可接受之鹽的醫藥調配物之後,量測個體中nAChR促效劑或其醫藥學上可接受之鹽之最大血漿濃度(Cmax)的方法。給藥 This example describes the measurement of the maximum plasma concentration (Cmax) of an nAChR agonist or a pharmaceutically acceptable salt in an individual after administration of a pharmaceutical formulation containing the nAChR agonist or a pharmaceutically acceptable salt thereof Methods. Administration
向個體投與一劑nAChR促效劑或其醫藥學上可接受之鹽。劑量及體積範圍之實例描述於本文中。血液收集及樣本處理 A dose of nAChR agonist or a pharmaceutically acceptable salt is administered to the individual. Examples of dose and volume ranges are described herein. Blood collection and sample processing
在投與nAChR促效劑或其醫藥學上可接受之鹽之前自個體收集血液樣本。在向個體投與nAChR促效劑或其醫藥學上可接受之鹽之後,在一段時間內以特定時間間隔收集多個血液樣本。舉例而言,在投與nAChR促效劑或其醫藥學上可接受之鹽之後的10分鐘、20分鐘、30分鐘、1小時、2小時、3小時及4小時處收集血液樣本。Blood samples are collected from the individual before administration of the nAChR agonist or its pharmaceutically acceptable salt. After the individual is administered the nAChR agonist or a pharmaceutically acceptable salt thereof, multiple blood samples are collected at specific intervals over a period of time. For example, blood samples are collected at 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after administration of the nAChR agonist or a pharmaceutically acceptable salt thereof.
將血液樣本(4 mL於K2 EDTA管中)自臂靜脈收集至含有K2 EDTA之真空管(Vacutainer tube)中。血液樣本經平緩混合且維持冷卻直至在收集之2小時內離心。A blood sample (4 mL in a K 2 EDTA tube) was collected from the arm vein into a Vacutainer tube containing K 2 EDTA. Blood samples were gently mixed and kept cold until centrifuged within 2 hours of collection.
將血漿樣本分離成兩個相等的等分試樣且標以個體之鑑定及標稱時間點且冷凍儲存(於<-70℃下)直至分析。藥物動力學樣本之生物分析方法 Plasma samples were separated into two equal aliquots and labeled with individual identification and nominal time points and stored frozen (at <-70°C) until analysis. Pharmacokinetic sample bioanalysis method
來自個體之血液樣本經處理以獲得血漿,且使用液相層析繼之以串聯質譜(LC-MS/MS)生物分析方法(高效液相層析[HPLC]伴以質譜偵測)獲得nAChR促效劑或其醫藥學上可接受之鹽之血漿濃度。藥物動力學分析 Blood samples from individuals are processed to obtain plasma, and liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) biological analysis method (high performance liquid chromatography [HPLC] with mass spectrometry detection) is used to obtain nAChR The plasma concentration of the effective agent or its pharmaceutically acceptable salt. Pharmacokinetic analysis
所有藥物動力學(PK)分析及報告均根據普遍接受的標準操作程序及方案規範進行。藥物動力學參數係藉由使用普遍接受的軟體工具,例如Phoenix® WinNonlin® 8.0計算。All pharmacokinetic (PK) analyses and reports are conducted in accordance with generally accepted standard operating procedures and protocol specifications. Pharmacokinetic parameters are calculated by using commonly accepted software tools, such as Phoenix® WinNonlin® 8.0.
血漿濃度時間曲線圖係藉由繪製nAChR促效劑或其醫藥學上可接受之鹽濃度隨時間之變化而產生。Cmax係藉由檢驗個體之血漿濃度時間曲線圖而計算。另一Cmax相關參數為nAChR促效劑或其醫藥學上可接受之鹽之最大觀測濃度除以毫克劑量,(Cmax/D)。Cmax係針對治療之後的個體計算。若計算超過一位個體之Cmax,則亦可計算該組之算術平均值Cmax及中值Cmax。實例 5 :在用化合物 1 治療後量測之 Cmax Plasma concentration time curve is generated by plotting the change of nAChR agonist or its pharmaceutically acceptable salt concentration with time. Cmax is calculated by examining the plasma concentration time curve of the individual. Another Cmax-related parameter is the maximum observed concentration of the nAChR agonist or its pharmaceutically acceptable salt divided by the milligram dose, (Cmax/D). Cmax is calculated for individuals after treatment. If the Cmax of more than one individual is calculated, the arithmetic mean Cmax and median Cmax of the group can also be calculated. Example 5 : Cmax measured after treatment with
經由鼻用噴霧(200微升總體積;約2216微克化合物1游離鹼)用1.1%化合物1游離鹼(2.0%化合物1半-半乳糖二酸鹽二水合物)治療之30位個體之血漿係使用實例4中所述之方案分析。量測之化合物1之平均Cmax為2.92 ng/mL。實例 6 :表現於爪蟾屬卵母細胞中之人類 nAChR 之 化合物 1 檸檬酸鹽促效活性 Plasma lines of 30 individuals treated with 1.1
此實例描述表徵化合物1檸檬酸鹽對表現於爪蟾屬卵母細胞中之人類神經元菸鹼乙醯膽鹼受體(nAChR) α3β4、α3α5β4、α4β2、α4α6β2及α7之促效活性的實驗。
方法This example describes an experiment characterizing the agonistic activity of
測試化合物:化合物1檸檬酸鹽Test compound:
參考化合物:氯化乙醯膽鹼Reference compound: Acetylcholine chloride
測試系統:參見實例1。Test system: see example 1.
卵母細胞製備:參見實例1。Oocyte preparation: see Example 1.
電生理記錄:參見實例1。Electrophysiological records: see Example 1.
促效劑製備:參見實例1。化合物1檸檬酸鹽之測試濃度為0.1、0.3、1、3、10、30、100及300 (微莫耳)。氯化乙醯膽鹼之測試濃度為1280微莫耳。Accelerator preparation: see Example 1. The tested concentrations of
資料分析及統計:參見實例1。Data analysis and statistics: see example 1.
實驗程序:使用專用自動注射裝置在至少95個卵母細胞中進行注射編碼人類α3β4、α3α5β4、α4β2、α4α6β2及α7之cDNA。在至少兩天後檢查細胞受體表現。卵母細胞戳有兩個電極且其膜電位在整個實驗中維持(除非有所指示)於-80 mV。Experimental procedure: cDNA encoding human α3β4, α3α5β4, α4β2, α4α6β2 and α7 were injected into at least 95 oocytes using a dedicated automatic injection device. Check cell receptor performance after at least two days. The oocyte has two electrodes and its membrane potential is maintained at -80 mV throughout the experiment (unless indicated).
開發測定表現nAChR之卵母細胞中之促效活性的方案。細胞暴露於一系列增加濃度之nAChR促效劑各10秒,間隔為兩分鐘。nAChR促效劑測試濃度為0.1、0.3、1、3、10、30、100、300 (微莫耳)。記錄由暴露於各濃度之促效劑誘發的電流。對於表現α7 nAChR之卵母細胞,將暴露於促效劑減少為5秒。對於針對各類型之nAChR表現細胞測試之各促效劑重複此過程。 結果Develop protocols to measure the agonistic activity in oocytes that exhibit nAChR. Cells were exposed to a series of increasing concentrations of nAChR agonist for 10 seconds each, with an interval of two minutes. The test concentration of nAChR agonist is 0.1, 0.3, 1, 3, 10, 30, 100, 300 (micromolar). The current induced by exposure to various concentrations of agonist was recorded. For oocytes expressing α7 nAChR, reduce exposure to agonists to 5 seconds. This process is repeated for each agonist tested for each type of nAChR expressing cell. result
化合物1檸檬酸鹽在表現於爪蟾屬(Xenopus)卵母細胞中之人類神經元菸鹼乙醯膽鹼受體處之作用係採用兩個電極電壓鉗研究。化合物1檸檬酸鹽在α3β4、α3α5β4、α4β2、α4α6β2及α7受體處之促效作用的測定展現此化合物在10至300微莫耳範圍內充當此等受體處之促效劑。然而,在受體亞型之間的反應中觀測到顯著差異。亦即,化合物1檸檬酸鹽為300微莫耳濃度下之人類α7受體處之弱部分促效劑。300微莫耳化合物1檸檬酸鹽溶液誘發ACh誘發電流之僅25%的反應。相比之下,對於nAChR亞型α3β4、α3α5β4、α4β2及α4α6β2記錄之資料顯示化合物1檸檬酸鹽充當此等受體處之幾乎完全促效劑。The effect of
化合物1檸檬酸鹽幾乎充當nAChR α3β4處之完全促效劑,產生34.87±4.53微莫耳之EC50
。
化合物1檸檬酸鹽幾乎充當nAChR α3α5β4處之完全促效劑,產生83.00±9.05微莫耳之EC50
。
化合物1檸檬酸鹽幾乎充當nAChR α4β2處之完全促效劑,產生13.48±2.06微莫耳之EC50
。由第二Ach暴露誘發之電流的顯著抑制係歸因於由化合物1檸檬酸鹽暴露引起之脫敏。
化合物1檸檬酸鹽幾乎充當nAChR α4α6β2處之完全促效劑,產生13.14±3.68微莫耳之EC50
。
化合物1檸檬酸鹽充當nAChR α7處之不佳促效劑,在300微莫耳下誘發最大ACh誘發電流之僅25%,產生125.63±28.52微莫耳之EC50
。鑒於由化合物1檸檬酸鹽誘發之小部分電流,EC50
僅為評估。實例 7 :在鼻內投與化合物 1 半 - 半乳糖二酸鹽 28 天之後人類個體中之藥物動力學量測
此實例描述用於測定在用1.1%化合物1 (2.0%半-半乳糖二酸鹽)治療四週之後,及在第29天進行單次兩側鼻噴霧之後的血漿全身暴露及藥物動力學之研究。結果表明在投與之後10分鐘在所有個體中偵測到化合物1,指示化合物1之快速鼻吸收。另外,此實例表明化合物1在鼻內投與之後展現低全身暴露且不應在重複投與之後展現全身循環中之任何積聚。This example describes studies to determine plasma systemic exposure and pharmacokinetics after four weeks of treatment with 1.1% Compound 1 (2.0% galactose diacid salt) and after a single bilateral nasal spray on
向七名患者投與1.1%化合物1 (2.0%半-半乳糖二酸鹽),在各鼻孔中以50 μL鼻內噴霧形式遞送,BID持續28天。在第29天,向患者提供1.1%化合物1 (2.0%半-半乳糖二酸鹽)單次鼻內投與。Seven patients were administered 1.1% Compound 1 (2.0% hemi-galactonate) in each nostril as a 50 μL intranasal spray with BID for 28 days. On
在第29天給藥前(時間0)及在單次投與藥物之後的一系列時間點(10分鐘、20分鐘、30分鐘、1小時、2小時、4小時、5小時、6小時、7小時、8小時及24小時)之後收集患者血漿。針對化合物1分析血漿。A series of time points (10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 5 hours, 6 hours, 7) before the administration on day 29 (time 0) and after a single administration of the drug Hours, 8 hours, and 24 hours) after collecting patient plasma. Plasma was analyzed for
計算化合物1之以下藥物動力學參數:
Cmax
:藉由檢驗個別研究參與者血漿濃度時間曲線圖觀測之最大觀測濃度。
Tmax :
直接自觀測之濃度時間資料獲得之最大觀測濃度的時間。
AUClast :
自時間0至最後可量測之非零濃度的血漿濃度時間曲線下面積,藉由線性及對數梯形方法之組合(線性向上/對數向下方法)計算。
AUC0-4h :
自時間0至4 h時間點的血漿濃度時間曲線下面積,藉由線性及對數梯形方法之組合(線性向上/對數向下方法)計算。
AUCinf :
自零時(給藥前)外推至無限時間之面積(AUCinf)將計算如下:
AUC%Extrap:藉由外推法獲得之AUCinf之百分比(AUC%Extrap)將計算如下:
半衰期:
終末消除半衰期。Calculate the following pharmacokinetic parameters of Compound 1: Cmax : the maximum observed concentration observed by examining the plasma concentration time curve of individual study participants. Ÿ Tmax : the time of the maximum observed concentration obtained directly from the observed concentration time data. Ÿ AUClast : The area under the plasma concentration time curve from
血漿濃度資料。在BID投與1.1%化合物1 28天之後,在零時(給藥前)在7位個體中之4個中偵測到化合物1,平均濃度為0.264 ng/mL。在投與之後十分鐘,在所有個體之血漿中偵測到化合物1,表明快速鼻吸收。平均化合物1血漿暴露在鼻內投與之後隨時間增加,在1 h處具有2.07 ng/mL之暴露峰值且接著在24 h取樣時段內下降。下降為雙相的,在2與4 h之間具有平線區。7位個體中之4個在給藥後5 h處具有可定量水準且在隨後的三個時間點,6、7及8 h中之每一者處損失一個具有可定量化合物1之個體。在投與後8 h僅存在一個具有可定量化合物1之個體,且在投與後24 h不存在具有高於0.200 ng/mL之定量下限之可定量化合物1的個體。Plasma concentration data. 28 days after BID administration of 1.1
藥物動力學參數資料。化合物1平均(SD) Cmax為2.26±1.96 ng/mL,其中7位個體中之個別個體最大值為5.49 ng/mL。中值Tmax出現於0.50 h處且平均(SD)半衰期為1.58±0.818 h。7位個體中之4個之AUC%Extrap為>20%,其應排除計算半衰期及AUCinf,然而,此等個別個體值報告及包括於PK參數AUCinf及半衰期之概述統計量中。平均(SD) AUClast在5.22±4.52 h*ng /mL內變化且最大單一個別值在12.1 h*ng /mL處。然而,在3.69%處具有最低AUC%Extrap之一位個體亦為分別在12.1 h*ng /mL及12.5 h*ng /mL處具有最大AUClast及AUCinf之個體。在6.22±4.63 h*ng /mL處,平均(SD) AUCinf大於平均AUClast 21.3%。最大個別個體半衰期為2.83 h,其將表明一般而言,若每12小時投與化合物1,則對於所有個體,>94% (4個半衰期)之化合物1將在下一投與之前自全身循環清除。總體而言,化合物1之全身暴露較低。Pharmacokinetic parameter data. The average (SD) Cmax of
藥物動力學結果概述於下表中。
結論:在BID投與1.1%化合物1 28天之後,化合物1在展現給藥前全身暴露之7位個體中之4個中(57.1%)展現低全身暴露,平均濃度為0.264 ng/mL。在投與之後十分鐘,在所有個體之血漿中偵測到化合物1,表明快速鼻吸收。化合物1之清除率在本質上為雙相的,在2與4 h之間具有平線區,其可表明口服組分可能吸收至全身概況。然而,在投與後8 h僅存在一個具有可定量之量的化合物1之個體且在投與後24 h無個體。此與1.58±0.818 h之觀測之平均(SD)半衰期相關。最大個別個體半衰期為2.83 h,其將表明一般而言,若每12小時投與化合物1,則對於所有個體,>94% (4個半衰期)之化合物1將在下一投與之前自全身循環清除。總體而言,化合物1之全身暴露較低,平均(SD) Cmax為2.26±1.96 ng/mL,其中7位個體之個別個體最大值為5.49 ng/mL。Conclusion: 28 days after BID administration of 1.1
圖1顯示條形圖,其概述臨床研究中隨化合物1半-半乳糖二酸鹽二水合物之三種濃度而變之個體之斯戈默評分的平均變化。Figure 1 shows a bar graph summarizing the average change in the Sgormer score of an individual in a clinical study as a function of three concentrations of
圖2顯示條形圖,其概述臨床研究中在給藥之後5分鐘隨化合物1半-半乳糖二酸鹽二水合物之三種濃度而變之個體之乾眼評分的平均變化。FIG. 2 shows a bar graph summarizing the average change in dry eye scores of individuals with three concentrations of
圖3顯示一圖示,其概述臨床研究中在60分鐘內隨化合物1半-半乳糖二酸鹽二水合物之三種濃度而變之個體之乾眼評分之平均變化。Figure 3 shows a graph summarizing the average change in dry eye scores of individuals in a clinical study that varied with three concentrations of
圖4顯示條形圖,其概述臨床研究中隨化合物1半-半乳糖二酸鹽二水合物之三種不同濃度而變之具有35 mm之斯戈默評分之個體的%。Figure 4 shows a bar graph summarizing the% of individuals in the clinical study that had a 35 mm Sgormer score as a function of three different concentrations of
圖5顯示條形圖,其概述臨床研究中隨化合物1半-半乳糖二酸鹽二水合物之三種不同濃度而變之個體之斯戈默評分的中值變化。Figure 5 shows a bar graph summarizing the median change in the Sgormer score of an individual in a clinical study as a function of three different concentrations of
圖6顯示條形圖,其概述臨床研究中隨化合物1半-半乳糖二酸鹽二水合物之三種不同濃度而變之具有大於10 mm斯戈默評分變化(類別變化)之個體的%。Figure 6 shows a bar graph summarizing the% of individuals in clinical studies that had a change in the Sgormer score (change in category) of more than 10 mm as a function of three different concentrations of
圖7顯示條形圖,其概述臨床研究中隨化合物1半-半乳糖二酸鹽二水合物之三種不同濃度而變之具有大於20 mm斯戈默評分變化(類別變化)之個體的%。Figure 7 shows a bar graph summarizing the% of individuals in the clinical study that had a change in the Sgormer score (change in category) of more than 20 mm as a function of three different concentrations of
圖8顯示圖表,其概述化合物1半-半乳糖二酸鹽二水合物之臨床研究中個體經歷之最常見不良事件。Figure 8 shows a graph summarizing the most common adverse events experienced by individuals in the clinical study of
圖9顯示基於NEI/Industry Workshop量表劃分角膜表面以量測螢光素吸收之圖式。Fig. 9 shows a diagram for dividing the corneal surface based on the NEI/Industry Workshop scale to measure the absorption of luciferin.
圖10顯示用於測定個體之OSDI評分之調查表的實例。Figure 10 shows an example of a questionnaire used to determine an individual's OSDI score.
圖11顯示用於對個體進行乾眼測試以記錄其症狀嚴重度之視覺類比量表(VAS)的實例。Figure 11 shows an example of a Visual Analogue Scale (VAS) used to perform dry eye testing on individuals to record their symptom severity.
圖12顯示條形圖,其概述在4週時段內,用2.0%化合物1半-半乳糖二酸鹽二水合物治療之個體之斯戈默評分及用安慰劑治療之個體之評分相較於基線評分的平均變化。FIG. 12 shows a bar graph summarizing the Sgormer score of individuals treated with 2.0
圖13顯示條形圖,其概述在4週時段內,用2.0%化合物1半-半乳糖二酸鹽二水合物治療之個體之對側眼之斯戈默評分及用安慰劑治療之個體之對側眼之評分相較於基線評分的平均變化。Fig. 13 shows a bar graph summarizing the Stommer score of the contralateral eye of individuals treated with 2.0
圖14顯示條形圖,其概述在4週時段內,用2.0%化合物1半-半乳糖二酸鹽二水合物治療之個體及用安慰劑治療之個體之所有合格眼睛之斯戈默評分相較於基線評分的平均變化。Figure 14 shows a bar graph summarizing the Sgormer scores of all eligible eyes of individuals treated with 2.0
圖15顯示條形圖,其概述在用2.0%化合物1半-半乳糖二酸鹽二水合物或安慰劑治療後,在4週時段內相較於基線評分具有10 mm或更大斯戈默評分變化(類別變化)之個體的%。Figure 15 shows a bar graph summarizing that after treatment with 2.0
圖16A-16B顯示條形圖,其概述2.0%化合物1半-半乳糖二酸鹽二水合物或安慰劑治療方案中之個體在(A)第3週及(B)第4週時相較於基線評分之乾眼評分變化。16A-16B show a bar graph summarizing the comparison of 2.0
圖17顯示條形圖,其概述在投與2.0%化合物1半-半乳糖二酸鹽二水合物或安慰劑之後,處於受控不利環境中之個體相較於基線評分之乾眼評分變化(以5分鐘遞增)。FIG. 17 shows a bar graph summarizing the change in dry eye score of an individual in a controlled unfavorable environment compared to the baseline score after administration of 2.0
圖18顯示條形圖,其概述在用2.0%化合物1半-半乳糖二酸鹽二水合物或安慰劑治療之第4週,角膜螢光素染色相較於基線評分之平均變化。Figure 18 shows a bar graph summarizing the average change in corneal fluorescein staining compared to baseline scores at 4 weeks of treatment with 2.0
圖19顯示一圖表,其概述在用2.0%化合物1半-半乳糖二酸鹽二水合物或安慰劑治療之4週內個體經歷之最常見事件。Figure 19 shows a chart summarizing the most common events experienced by an individual within 4 weeks of treatment with 2.0
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