TW200838525A - Methods for treating nasal congestion - Google Patents
Methods for treating nasal congestion Download PDFInfo
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- TW200838525A TW200838525A TW096149093A TW96149093A TW200838525A TW 200838525 A TW200838525 A TW 200838525A TW 096149093 A TW096149093 A TW 096149093A TW 96149093 A TW96149093 A TW 96149093A TW 200838525 A TW200838525 A TW 200838525A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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Abstract
Description
200838525 九、發明說明： 【先前技術】 ^ =地的人們經常遭受與過敏症相關之鼻充血之痛 、一 /、導致氣道部分或完全阻塞。鼻充血及相關症狀通常 對夂折磨者具有不期望之影響，例如，破壞睡眠、工作損 失及學校出勤率損失。 已.、、、員不抗組胺劑對預防及緩解噴嚏、搔癢、鼻漏及 k =症•狀有⑪但並未發現其對緩解與過敏反應相關 t p基極有效。因此，通常同時投與擬交感神經興奮性 胺解充血藥，例如可用作腎上腺素受體激動劑之苯丙 醇胺或偽麻黃驗。妙;&，# > 卜 、 …、而亚非所有過敏症患者皆應使用該 等解充血藥’因為經常觀察到該等解充血藥對中樞神經系 統及：血管有副作帛，包括焦慮、失眠、心動過速、心絞 痛及高血壓。苯丙醇胺已自美國市場撤出。 人們需要針對與過敏病況相關之鼻充血之治療，且其不 表現與擬交感神經興奮性胺相關的對神經系統或心血管有 害之效應。 【發明内容】 在某些態樣中’本發明提供—種治療或減輕有需要的高 血壓病人與過敏性鼻炎相關之鼻充企之方法，其包括向該 高血壓病人投與治療有效量之包含氯雷他定（1。她dine)及 孟魯司特（montelukast)或其醫藥上可接受之鹽之醫藥組合 物。 在某些實施例中，醫藥上可接受之孟魯司特鹽為孟魯司 127803.doc 200838525 特鈉。 在某些實施例中，與擬交感神經藥劑相關之副作用對該 病人係不期望的。實例性擬交感神經藥劑包括（例如）偽廚 黃驗、麻黃鹼、***醇或去氧腎上腺素。 在某些貝％例中，病人血壓為至少140/90、至+ 刪95、或至少2_3()。該病人可患有未受控制之高血麼 及/或嚴重高血壓。該病人可能服用藥物來降低或控制血 壓。200838525 IX. Description of the invention: [Prior Art] ^ = People in the ground often suffer from allergic nasal congestion, a /, leading to partial or complete obstruction of the airway. Nasal congestion and related symptoms often have undesired effects on the tormented person, for example, disruption of sleep, loss of work, and loss of school attendance. The anti-histamine has been used to prevent and relieve sneezing, itching, rhinorrhea and k = symptoms. However, it has not been found to be effective in relieving allergic reactions. Therefore, sympathomimetic excitatory amine decongestants are usually administered at the same time, for example, phenylpropanolamine or pseudoephedrine as an adrenergic receptor agonist. Miao; &,# > Bu, ..., and all allergic patients in Asia and Africa should use these decongestants' because it is often observed that such decongestants have a side effect on the central nervous system and: blood vessels, including Anxiety, insomnia, tachycardia, angina and high blood pressure. Phenylpropanolamine has been withdrawn from the US market. There is a need for treatment of nasal congestion associated with allergic conditions, and it does not exhibit neurological or cardiovascular effects associated with sympathomimetic excitatory amines. SUMMARY OF THE INVENTION In some aspects, the present invention provides a method of treating or alleviating a nasal supplement associated with allergic rhinitis in a hypertensive patient in need thereof, comprising administering to the hypertensive patient a therapeutically effective amount A pharmaceutical composition comprising loratadine (1. her dine) and montelukast or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutically acceptable montelukast salt is Monteluster 127803.doc 200838525 sodium. In certain embodiments, the side effects associated with the sympathomimetic agent are undesirable for the patient. Exemplary sympathomimetic agents include, for example, pseudo-cooker, ephedrine, amphetamine or phenylephrine. In some cases, the patient's blood pressure is at least 140/90, to +95, or at least 2_3(). The patient may have uncontrolled high blood and/or severe hypertension. The patient may take medication to reduce or control blood pressure.
在某些實施例中，該醫藥組合物以約1:1毫克/毫克之比 例包含氯雷他定及孟魯司特或其s藥上可接受之鹽。 在某些實施例中，該醫藥組合物包含約10毫克氯雷他定 及10¾克孟魯司鸦：七榮4^ * Ί特或4效®之其醫藥上可接受之鹽；約10 ，乳田他疋及5毫克孟魯司特或等效量之其醫藥上可接 =鹽…毫克氯雷他定及約5毫克孟魯司特或等效^ 其醫藥上可拯她 目』W4寻双里之 司特或等效量：复：；或約5毫克氯雷他定及約4毫克孟魯 之其W藥上可接受之鹽。 在某些實施合,1 Φ 年性過敏性鼻炎。’以性鼻炎為季節性過敏性鼻炎或常 該病人可患有嚴重鼻充血。 該醫藥組合物進一步包含至少 種額 在某些實施例中 在某些實施例中 外治療藥劑。 在某些實施例中 物。該醫藥紐人坐口、經鼻或經眼投與該醫藥組合 劑、粒劑:、懸二物可調配為液體、丸劑、錠劑、膠囊、栓 手液或膜劑。適宜錠劑包括（例如）可口服、 127803.doc 200838525 可咀嚼或速溶錠劑形式。 在某些悲樣中，本發明提供一種治療或減輕有需要的高 血壓病人與過敏性鼻炎相關之鼻充血之方法，#包括向該 高血壓病人投與治療有效量之包含氯雷他定及孟魯司特或 其w藥上可接％之鹽之醫藥組合物中投與該醫藥組合In certain embodiments, the pharmaceutical composition comprises loratadine and montelukast or a pharmaceutically acceptable salt thereof in a ratio of about 1:1 mg/mg. In certain embodiments, the pharmaceutical composition comprises about 10 mg of loratadine and 103⁄4 g of the medicinal salt of the sirloin or the medicinal salt of the sulphate; Hetian and his 5 mg of montelukast or equivalent amount of its medicine can be connected = salt ... mg of loratadine and about 5 mg of montelukast or equivalent ^ its medicine can save her eyes" W4 Look for the double or the equivalent: complex:; or about 5 mg of loratadine and about 4 mg of Monroe's W pharmaceutically acceptable salt. In some implementations, 1 Φ annual allergic rhinitis. 'Sexual rhinitis is seasonal allergic rhinitis or often the patient can have severe nasal congestion. The pharmaceutical composition further comprises at least an amount of the therapeutic agent in certain embodiments in certain embodiments. In certain embodiments. The pharmaceutical additive is administered by the mouth, nasally or by eye, and the pharmaceutical composition, the granule: the suspension can be formulated into a liquid, a pill, a tablet, a capsule, a hand lotion or a film. Suitable lozenges include, for example, orally, 127803.doc 200838525 in the form of a chewable or instant tablet. In some grievances, the present invention provides a method of treating or alleviating nasal congestion associated with allergic rhinitis in a hypertensive patient in need thereof, #including administering to the hypertensive patient a therapeutically effective amount of loratadine and The pharmaceutical composition of montelukast or its w-drug can be administered to the pharmaceutical composition
物所產生的解除鼻充血效應與由偽麻黃驗所產生的解除鼻 充血效應大體相同。 TThe effect of releasing the nasal congestion caused by the object is substantially the same as the effect of relieving the nasal congestion caused by the pseudoephedrine test. T
”丨！ 土 W醉隊异死血效 係與每日-次投與240毫克偽麻黃鹼相關。 在某些態樣中，本發明接徂絲、y 士 &月徒供一種治療或減輕有需要的 血壓病人與過敏性鼻炎相關 畠 ^广 人相關之鼻充血之方法，其包括向 南血壓病人投與治療有效詈 ^ ^ 文里之包含氯雷他定及孟魯司牿 其醫藥上可接受之鹽之醫率 、 札π女 合物，其中投與該醫藥組 物所產生的解除鼻充血效應 μ、 畠亡人夕為由偽麻黃鹼所產生解 鼻充血效應之9〇%，且不以 鮮 用mm 不引發偽麻黃鹼之一或多種副"丨! The W-drug team is associated with a daily-time dose of 240 mg of pseudoephedrine. In some aspects, the present invention is used for a treatment or alleviation of need for sputum, y, & The method of nasal congestion associated with allergic rhinitis associated with allergic rhinitis, including the administration of treatment to the south blood pressure patient 詈 ^ ^ containing loratadine and montelukast medicinally acceptable The salt rate of the salt, the π π female compound, which is caused by the application of the medical group to relieve the nasal congestion effect μ, 畠 人 夕 为 为 夕 夕 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪 伪Do not induce one or more of pseudoephedrine with mm
用。在某些實施例中， 裡田J ^ 由偽麻頁鹼所產生的解除S右i 應係與每日一次投與240 ，、V充血 例中，副作用可為（例如k 驗相關。在某些實 施例中，在晚上或就寢時間二或頭軍。在某些 在某些態樣中，本發明提供一 尿病病人與過敏性鼻炎相關之’ "療或減輕有需要的 糖尿病病人投與治療有 :A之方法，其包括向 其醫藥上可接受之踏…〜氯雷他定及孟魯司特 又<鹽之醫藥組合物。 【實施方式】 127803.doc 200838525use. In some embodiments, Rita J ^ is caused by pseudo-prostaglandin, and S is immediately administered to 240, and in V-filled cases, the side effects may be (eg, k-test related. In some embodiments, at night or at bedtime, or in the first place, in some aspects, the present invention provides a "" treatment for a urinary tract patient associated with allergic rhinitis; And the treatment includes: A method comprising a medicinally acceptable step ... ~ loratadine and montelukast and < salt pharmaceutical composition. [Embodiment] 127803.doc 200838525
在某些實施例中，本文所述方法包括治療、預防或減輕 病人與過敏性鼻炎相關之鼻充血，對該等病人而言，投與 擬交感神經藥劑可能會導致不期望副作用、加重已存在病 況、受到禁忌、或在使用前需要咨詢醫師。舉例而言，該 等病人可能患有疾病或病症，例如高血壓、糖尿病、缺血 性心臟病、眼内壓增加、甲狀腺機能亢進、腎損傷、或前 列腺肥大。其他該等病人包括（例如）月艮用單胺氧化酶抑制 劑（MAOI)之病人。在某些實施例中，本文所述方法包括 治療、預防或減輕病人與過敏性鼻炎相關之鼻充血，該等 病人已經診斷患有疾病或病症，例如高血壓、糖尿病、缺 血性心臟病、眼内壓增加、甲狀腺機能亢進、腎損傷、或 ***肥大。 本文所提供方法包括治療、預防或減輕與過敏性鼻炎相 關之鼻充血之方法，其係藉由向病人投與治療有效量之抗 組胺劑及白三烯D4受體拮抗劑來達成。適宜抗組胺劑之實 例包括（例如）馬來酸氯苯拉敏（chlorpheniramine maleate) (Chlor-trimeton®)、馬來酸右撲爾敏（dexchlorpheniramine maleate)、鹽酸苯海拉明（diphenhydramine hydrochloride) (Benadryl®)、號 ί白酸多西拉敏（doxylamine succinate)、鹽 酸異丙嗓及鹽酸曲普立定（triprolidine hydrochloride)。亦 可結合本文所述各種方法使用低鎮靜型或非鎮靜型抗組胺 劑。適宜低鎮靜型或非鎮靜型抗組胺劑之實例包括（例如） 氯雷他定（Claritin®)、鹽酸非索那定（fexofenadine hydrochloride) (Allegra⑧）、鹽酸西替立嗪（cetirizine 127803.doc 200838525 hydrochloride) (Zyrtec⑧）、左西替立唤（16乂〇0€山121116) (Xyzal⑧)及特非那定（terfenadine) (Teldane®)。適宜白三 烯D4受體拮抗劑之實例包括（例如）孟魯司特 (Singulair®)、紮魯司特（Zafirlukast) (Accolate®)、齊留通 (Zileuton) (Zyflo®)及普侖司特（praniukast)。 在某些實施例中，本文所述方法包括治療、預防或減輕 高血壓病人與過敏性鼻炎相關之鼻充血且涉及向高血壓病 人投與治療有效量之氣雷他定及孟魯司特或醫藥上可接受 之孟魯司特鹽。 高金壓病人係血壓反覆升高至正常值之上的病人，例如 血壓為至少140/90之病人。高血壓病人包括輕度高血壓病 人，例如血壓為約140/90至159/94之病人；中度高血壓病 人，例如血壓為160/95至179/99之病人；及重度高血壓病 人例如血壓為至少180/100之病人。在某些實施例中， 血壓為至少200/130之病人亦可根據本文所述各種方法加 以治療。 夕種因素可引發高血壓，包括遺傳組成、疾病、飲食、 或藥物投與（例如藥物誘發型高血壓）。熟習此項技術之臨 床酉師可使用臨床檢驗、體格檢查及病史/家族史即可判 別高血壓病人。在某些實施例中，本文所述方法可用於治 療、預防或減輕高血壓病人鼻充血，其中該高血壓未經藥 物療法控制或經藥物療法控制。在某些實施例中，可結合 針對高血壓之藥物療法治療高血壓病人與過敏性鼻炎相關 ^充血。舉例而$，病人可接受使用/3 -阻斷劑、血管 127803.doc 200838525 緊張素轉化酶(ACE)抑制劑、血管緊張素„受體阻斷劑 (細)、利尿劑、或鈣通道阻斷劑，同時投與氯雷他定及 孟魯司特或其醫藥上可接受之鹽之治療。In certain embodiments, the methods described herein comprise treating, preventing, or ameliorating nasal congestion associated with allergic rhinitis in a patient, for which administration of a sympathomimetic agent may result in undesirable side effects, exacerbation of existing Conditions, be contraindicated, or consult a physician before use. For example, such patients may have a disease or condition such as hypertension, diabetes, ischemic heart disease, increased intraocular pressure, hyperthyroidism, kidney damage, or prostatic hypertrophy. Other such patients include, for example, patients with monthly monoamine oxidase inhibitor (MAOI). In certain embodiments, the methods described herein comprise treating, preventing, or ameliorating nasal congestion associated with allergic rhinitis in a patient who has been diagnosed with a disease or condition, such as hypertension, diabetes, ischemic heart disease, Increased intraocular pressure, hyperthyroidism, kidney damage, or enlarged prostate. The methods provided herein include methods of treating, preventing or ameliorating nasal congestion associated with allergic rhinitis by administering to a patient a therapeutically effective amount of an antihistamine and a leukotriene D4 receptor antagonist. Examples of suitable antihistamines include, for example, chlorpheniramine maleate (Chlor-trimeton®), dexchlorpheniramine maleate, and diphenhydramine hydrochloride. (Benadryl®), doxylamine succinate, isopropyl hydrazine and triprolidine hydrochloride. Low sedative or non-sedating antihistamines can also be used in conjunction with the various methods described herein. Examples of suitable low-sedating or non-sedating antihistamines include, for example, loratadine (Claritin®), fexofenadine hydrochloride (Allegra8), cetirizine hydrochloride (cetirizine 127803.doc) 200838525 hydrochloride) (Zyrtec8), Levocetine (16乂〇0€山121116) (Xyzal8) and terfenadine (Teldane®). Examples of suitable leukotriene D4 receptor antagonists include, for example, Singulair®, Zafirlukast (Accolate®), Zileuton (Zyflo®), and Prolenz Special (praniukast). In certain embodiments, the methods described herein comprise treating, preventing, or ameliorating nasal congestion associated with allergic rhinitis in a hypertensive patient and involving administering to the hypertensive patient a therapeutically effective amount of ralostatin and montelukast or A pharmaceutically acceptable montelukast salt. Patients with high blood pressure are patients whose blood pressure rises above normal, such as patients with a blood pressure of at least 140/90. Hypertensive patients include patients with mild hypertension, such as patients with blood pressures of approximately 140/90 to 159/94; patients with moderate hypertension, such as patients with blood pressures of 160/95 to 179/99; and patients with severe hypertension such as blood pressure For patients of at least 180/100. In certain embodiments, a patient having a blood pressure of at least 200/130 can also be treated according to various methods described herein. Eve factors can trigger high blood pressure, including genetic makeup, disease, diet, or drug administration (eg, drug-induced hypertension). Clinically, physical examinations, and medical history/family history can be used to identify hypertensive patients. In certain embodiments, the methods described herein can be used to treat, prevent, or alleviate nasal congestion in a hypertensive patient, wherein the hypertension is not controlled by medication or controlled by medication. In certain embodiments, hypertensive patients may be associated with hypersensitivity rhinitis in combination with drug therapy for hypertension. For example, the patient can receive /3 - blocker, blood vessel 127803.doc 200838525 angiotensin converting enzyme (ACE) inhibitor, angiotensin „receptor blocker (fine), diuretic, or calcium channel block Broken agents are administered simultaneously with loratadine and montelukast or a pharmaceutically acceptable salt thereof.
在某些實施例中’本文所述方法包括治療、預防或減輕 糖尿1病人與過敏性鼻炎相關之鼻充血，且涉及向糖尿病 病人投與治療有效量之氯雷他定及孟魯司特或醫藥上可接 受之孟魯司特鹽。可使用空腹血糖檢驗（FpG)及/或口服葡 萄糖耐量檢驗（OGTT)來診斷糖尿病。使訂pG檢驗時，空 腹血糖濃度為126毫克/分升或更高者患有糖尿病。使: 〇GTT檢驗時，在禁食後及飲人富㈣糖飲料後兩小時量 測個人A糖濃度。兩小時血糖濃度為細毫克 者患有糖尿病。 V及更阿 文所述各種方法可用於治療、預p方、減輕或緩解與 敏(·生T火相關之嚴重、中度或輕度鼻充血。在某些實施 中’提供嚴重鼻充血之治療、預防或減輕。 可治療、預防或減輕之鼻充血„包括日間鼻充血及 間鼻充血。若病人患有通常在日間或夜間特定時間發作 =血可改蜒投藥時間以最有效地治療該病人。在某些 例中—可在晚上或在就寢時間投與氯雷他定與孟魯司 s'、W藥上可接文之鹽之組合以治療、預肖或減輕夜間 充t。在某些實施例中’可在早上、醒來後或在早餐時In certain embodiments, the methods described herein comprise treating, preventing or ameliorating nasal congestion associated with allergic rhinitis in a diabetic patient, and in administering to a diabetic patient a therapeutically effective amount of loratadine and montelukast or A pharmaceutically acceptable montelukast salt. Diabetes can be diagnosed using the Fasting Glucose Test (FpG) and/or the Oral Glucose Tolerance Test (OGTT). When the pG test was performed, those with a fasting blood glucose concentration of 126 mg/dl or higher had diabetes. To: 〇GTT test, measure the concentration of personal A sugar two hours after fasting and after drinking rich (four) sugar drinks. A two-hour blood glucose concentration of fine milligrams has diabetes. Various methods described in V and more can be used to treat, pre-prely, reduce or alleviate severe, moderate or mild nasal congestion associated with sensitization (in some implementations) to provide severe nasal congestion. Treatment, prevention or alleviation. Nasal congestion that can be treated, prevented or alleviated „including daytime nasal congestion and nasal congestion. If the patient has a specific time during the day or at night, the blood can be changed to the most effective treatment. Patient. In some cases - in the evening or at bedtime, a combination of loratadine and montelukine s', W can be used in combination with the salt of the medicine to treat, pre-short or reduce nighttime filling. In some embodiments, 'in the morning, after waking up, or at breakfast
與氣雷他定盘孟，备q 土士丄、U #司特或其醫藥上可接受之鹽之組合以 療、預防或減輕曰間鼻充血。在某些實施例中，可在 來後或在早餐時投與氣雷他定與孟魯司特或其醫 127803.doc -10- 200838525 上可接受之鹽之組合以治療、預防或減輕夜間鼻充血。在 某些實施例中，可在晚上或在就寢時間投與氯雷他定與孟 魯司特或其醫藥上可接受之鹽之組合以治療、預防或減輕 曰間鼻充血。 在某些實施例中，本文所述方法可用於治療、預防或減 I與過敏性鼻炎相關之鼻充血，包括季節性過敏性鼻炎 (SAR)及常年性過敏性鼻炎（pAR)。各種方法亦涵蓋對同時 μ有SAR及PAR:者之病人之治療。季節性過敏性鼻炎包 括在秋季、春季或冬季或在其組合發生之過敏症。在某些 實施例中，方法包括可用於治療、預防或減輕與戶内過敏 原、戶外過敏原或二者相關之過敏性鼻炎之彼等。戶内過 敏原之貝例包括（例如）粉塵、黴菌及寵物皮屑。戶外過敏 原之實例包括(例如)樹木花粉、雜草、草及花。常年性過 敏性鼻炎通常與戶内過敏原相關，且季節性過敏性鼻炎通 常與戶外過敏原相關。 在某些實施例中，可向病人預防性地投與氯雷他定與孟 魯司特或其醫藥上可接受之鹽之組合。預防性投與可能有 利於多種病Λ，例如有肖鼻充血相關之過敏症歷史之病 人、對季節性過敏性鼻炎易感之病人、及對由特異性過敏 原(例如寵物皮屑、草、花等)引發之過敏症易感之病人。 在某些實施例中’患有與過敏性鼻炎相關之鼻充血之病 人亦可患有其他病症，例如哮喘。 _^文所述各種方法可緩解鼻充血，同時避免與擬交感神 、二藥^ (例如偽麻黃驗、麻黃驗、苯丙醇胺或去氧腎上腺 127803.doc 200838525 素）相關之一或多種不期望副作用，或顯著降低副作用之 發生率及/或嚴重度。與投與擬交感神經興奮性胺相關之 釗作用可包括（例如）失眠、神經質、神經過敏、煩亂不 女焦慮、口乾燥、高金壓、心動過速、頭痛、及頭暈。 在某些實施例中，投與氯雷他定及孟魯司特之組合導致與 投與安慰劑相當之副作用狀況。In combination with the sputum, it is a combination of the sputum, the squid, the U, or its pharmaceutically acceptable salt to treat, prevent or reduce the congestion of the nose. In certain embodiments, a combination of raltrexine and montelukast or its acceptable salt on 127803.doc -10- 200838525 may be administered after treatment or at breakfast to treat, prevent or reduce nighttime Nasal congestion. In certain embodiments, a combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof can be administered at night or at bedtime to treat, prevent, or reduce intercondylar nasal congestion. In certain embodiments, the methods described herein can be used to treat, prevent, or reduce nasal congestion associated with allergic rhinitis, including seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (pAR). Various methods also cover the treatment of patients with both SAR and PAR:. Seasonal allergic rhinitis includes allergies that occur in the fall, spring, or winter, or in combination. In certain embodiments, the methods include those useful for treating, preventing, or ameliorating allergic rhinitis associated with indoor allergens, outdoor allergens, or both. Examples of indoor allergens include, for example, dust, mold, and pet dander. Examples of outdoor allergens include, for example, tree pollen, weeds, grasses, and flowers. Perennial allergic rhinitis is often associated with indoor allergens, and seasonal allergic rhinitis is often associated with outdoor allergens. In certain embodiments, a combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof can be administered prophylactically to a patient. Preventive administration may be beneficial to a variety of conditions, such as patients with a history of allergies associated with rhinoplasty, patients susceptible to seasonal allergic rhinitis, and specific allergens (eg pet dander, grass, Flowers, etc.) Patients who are susceptible to allergies. In certain embodiments, a patient suffering from nasal congestion associated with allergic rhinitis may also have other conditions, such as asthma. _^ The various methods described in the article can alleviate nasal congestion, and avoid one of the related problems with the sympathetic, two drugs ^ (such as pseudo-aesthetic test, ephedra test, phenylpropanolamine or phenylephrine 127803.doc 200838525) Or multiple undesirable side effects, or significantly reduce the incidence and/or severity of side effects. The sputum effects associated with administration of sympathomimetic excitatory amines can include, for example, insomnia, nervousness, nervousness, anxiety, dry mouth, high golden pressure, tachycardia, headache, and dizziness. In certain embodiments, administration of a combination of loratadine and montelukast results in a side effect condition comparable to the administration of a placebo.
在某些實施例中，可避免擬交感神經藥劑之一或多種不 期望副作用，同時產生與藉由治療有效量的擬交感神經藥 劑所獲得解除鼻充血效應大體相同之效應。與擬交感神經 藥劑^體相同之解除鼻充血效應意指所產生效應為由治療 有效量之擬交感神經藥劑所產生解除鼻充血效應±30%、士 = /〇、± 10%或±5% ’如使用量測鼻充血之標準程序所測 定。在某些實施例中，與擬交感神經藥劑大體相同之解除 f充血效應意指所產生效應為由治療有效量的擬交感神經 藥剤所產生解除鼻充血效應之至少7〇%、8〇%、㈣、㈣ 或更回纟某些員施例中’本文所述方法在Μ小時給藥期 間、在投與後最初12小時内、或在投與後12·24小時期間 產生與擬交感神經藥劑大體相同之解除鼻充*效應。在某 ^施例中’擬交感神經藥劑之治療有效量係指在24小時 療鼻充血之偽麻黃驗之量。舉例而言，偽麻 : 療有效量可為(例如)存於每曰-次投與的延長釋 放調配物中之240毫克偽麻黃 丨。偽麻黃鹼之該等調配 八⑽I項技術者加以製備或可自J〇h_…-議 a 司（New Brunswick，m)購得。 127803.doc 200838525 氯雷他定，即4-(8-氯-5,6-二氫]1H_苯并[5,6]環庚d，2_ b] 口比啶-11-亞基）小六氫。比$ f酸乙酯，係非鎮靜型組胺 -受體拮抗劑。用於治療過敏症之氯雷他定係由 schering-Pl0Ugh Health Care Pr〇ducts 公司以商品名 aadtin®出售，且可（例如）如美國專利第七加如號中所 述加以製備。 孟魯司特’即H[[(1R)-W3_[(1E)_2_(7_氯·2_喧啉基）乙 烯基]苯基]-3-[2-(ι-經基小甲基乙基）苯基]丙基]硫]甲基] 環丙基乙酸’係選擇性白三軌受體拮抗劑。用於治療過 敏症之孟魯司特鈉係由Merck & c〇公司以商品名 singulair®出售，且可（例如）如美國專利第5,27〇,324號中所 述加以製備。 醫藥上有效之孟魯司特鹽包括（例如）自醫藥上可接受之 無毒鹼（包括無機鹼及有機鹼）製備之鹽。源自無機鹼之鹽 包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂 鹽、猛鹽、二價猛鹽、鉀鹽、納鹽、鋅鹽及諸如此類。在 某些實施例中’ 1藥上可接受之孟魯司特鹽為孟魯司特 鈉。源自醫藥上可接受之有機無毒鹼的鹽包括一級、二級 以及二級胺、經取代胺（包括天然經取代胺卜環胺以及鹼 I*生離子父換樹脂的鹽，例如精胺酸、甜菜鹼、咖啡因、膽 鹼、N，N，-二苄基乙二胺、二乙胺、2_二乙胺基乙醇、2_二 甲胺基乙醇、乙醇胺、乙二胺' N•乙基嗎啉、N•乙基六氫 比疋還原葡糖胺、葡萄糖胺、組胺酸、哈胺 (hydrabamine)、異丙胺、離胺酸、甲基還原葡糖胺、嗎 127803.doc -13- 200838525 啉、六氫吡嗪、六氫吡啶、聚胺樹脂、普魯卡因 (pr〇caine)“票吟、可可驗、三乙胺、三甲胺、三丙胺、 胺丁三醇等類似鹼的鹽。 本文所用等效量之醫藥上可接受之孟魯司特鹽係指 定毫克量孟魯司特（游離酸）包含基本相同陰離子莫耳量^ 毫克量的孟魯司特鹽形式。因此’為測定特定鹽形式：等 效量’使孟魯司特(游離酸)之指定量乘以孟魯司特陰離子 分子量除以孟魯司特分子量之比(例如，孟魯司特二孟魯 司特為⑽.細6.20)。舉例而言’ 1〇 4毫克孟魯司特鈉相 當於1 〇宅克孟魯司特（游離酸）。 在某些實施例中，本文所提供方法包括共投與氣雷他定 :孟魯司特或其醫藥上可接受之鹽。可藉由分別調配個體 藥物然後將其一起投與（同時或依次）來實施共投與。在某 些實施例中’氣雷他定及孟魯司特或其醫藥上可接受之鹽 係作為包含兩種活性藥劑之共調配物來投與。可以包人、△ 療有效Ϊ之氯雷他定及孟魯司特或其醫藥上可接受之踏之 每日-次的單一劑型形式共調配該等活性藥劑。可在：或 數天内每曰一次投與單一日劑型，例如， 5 你 天、兩天、 -周、兩周、-個月或更長時間内每天投與一:欠。 每曰投與單-曰劑型以治療與持續性過敏症相關之菖充 血，或可根據需要散發性投與以治療鼻充灰，例如急^及/ 或慢性治療。 可有效治療、預防或減輕與過敏性鼻炎相關之鼻充企之 氯雷他定及孟魯司特或其醫藥上可接受之鹽之量可隨年 127803.doc -14· 200838525 齡、性別、體重、一般健康、鼻充血嚴重度、投與途徑、 所投與製劑之生物利用度、所選擇劑量方案、及伴隨藥物 之使用而變化。可調節投與劑量及/或頻率以滿足個體病 人之需要。彼等熟習此項技術者使用習用技術可容易地確 定適宜總曰劑量範圍。曰劑量可以單一劑量或分開劑量來 投與。 可以以約1··5毫克/毫克至約5:1毫克/毫克、約1:3毫克/毫 克至約3··1毫克/毫克、約1:2毫克/毫克至約2:1毫克/毫克、 或約1:1毫克/毫克之比例包含氯雷他定及孟魯司特或其醫 藥上可接受之鹽之調配物投與氣雷他定及孟魯司特或其醫 藥上可接受之鹽之組合。 在單-劑量或分開劑量中，可有效治療、預防或減輕與 過敏性鼻炎相關之鼻充血之氯雷他定及孟魯司特或其醫藥 上可接受之鹽之量通常為約10至約20毫克氯雷他定及約 至約20毫克孟魯司特或等效量之其醫藥上可接受之鹽、約 • 10至約15毫克氣雷他定及約10至約15毫克孟魯司特或等效 量之其醫藥上可接受之鹽、約8至約12毫克氯雷他定及約8 至約12毫克孟魯司特或等效量之其醫藥上可接受之鹽。在 $些實施例中’氯雷他定及孟魯司特或其醫藥上可接受之 鹽之量為約10毫克氯雷他定及約10毫克孟魯司特或等效量 之/、西某上可接文之鹽；約10毫克氣雷他定及約5毫克孟 ”特或等效量之其醫藥上可接受之鹽；約5毫克氯雷他 疋及約5¾克孟魯司特或等效量之其醫藥上可接受之鹽； 或約5毫克氣雷他定及約4毫克孟魯司特或等效量之其醫藥 127803.doc •15- 200838525 上可接受之鹽。 在某些實施例中，本文所述方法包括每日一次向患有與 過敏性鼻炎相關之鼻充血之病人投與單一日劑型，其包含 約10毫克氯雷他定及約10.4毫克孟魯司特鈉。 在某些實施例中，本文所述方法涉及以與可向具有正常 肝機能、正常腎機能及/或正常血壓之年齡及體重類似的 ' 病人投與之日劑量水平等效之日劑量水平，向病人投與氯 雷他定及孟魯司特或其醫藥上可接受之鹽之組合。 • 本文所述治療、預防或減輕與過敏性鼻炎相關之鼻充血 之各種方法可包括投與氯雷他定及孟魯司特或其醫藥上可 接受之鹽與至少一種其他治療藥劑。該等治療藥劑可包括 (例如）非麻醉性鎮痛藥（例如對乙醯胺基酚（Tylenol®)或環 氧化酶-2抑制劑（例如塞來考昔（celecoxib) (Celebrex®)、伐 地考昔（valdecoxib) (Bextra⑧）、魯米考昔（lumiracoxib) (Prexige®)，依託考昔（etoricoxib) (Arcoxia®)等））；非類固 ^ 醇抗炎藥（例如阿斯匹靈（aspirin)、σ引味美辛 (indomethacin) (Indocin®)、布洛芬（ibuprofen) (Motrin®)、 萘普生（naproxen) (Naprosyn®)、啦羅昔康（piroxicam) (Feldene®)、及萘普酮（nabumetone) (Relafen®)等）；長效 /3 2-腎上腺素能激動劑（LABA)(例如沙美特羅（salmeterol)、 福莫特羅（formoterol)、班布特羅（bambuterol)等）；皮質類 固醇（例如潑尼松（prednisone)、潑尼松龍（prednisolone)、 甲基潑尼松龍、糠酸莫米松（mometasone furoate monohydrate)、倍氯米松（beclomethasone)、氣尼縮松 127803.doc •16- 200838525 (flunisolide)、丙酮縮去炎松（triamcinolone acetonide)、丙 酸氟替卡松（fluticasone propionate)、***磷酸鈉 (dexamethasone sodium phosphate)、布***（budesonide) 等）；或鎮咳藥（例如右美沙芬（dextromethorphan)、可待因 (codeine)、氫可酮（hydrocodone)等）。可將該等額外治療 藥劑單獨調配且單獨投與病人或可與氯雷他定及孟魯司特 或其醫藥上可接受之鹽一起共調配。 可以習用方式使用一或多種生理學上可接受之載劑或賦 形劑來調配氣雷他定及孟魯司特或其醫藥上可接受之鹽之 共調配物。通常技術及調配物可參見Α· Gennar〇 (ed.)， Remington、Pharmaceutical Sciences,第 18 版，（199〇) Mack Publishing公司，Easton，PA 〇 根據本文所述各種方法’可採用任一適宜投與途徑來向 病人提供有效劑量之氯雷他定及孟魯司特或其醫藥上可接 受之鹽。舉例而言，可採用經口、口内、經直腸、非經 腸、級表皮、經皮、皮下、肌内、鼻内、舌下、硬膜内、 眼内、呼吸器官内、經口或經鼻吸入及類似投與形式。 可使用各種適宜劑型來投與氯雷他定及孟魯司特或其醫 藥上可接受之鹽，该專劑型包括（例如）鍵劑、可吸，錢 劑、速融調配物、片劑、分散液、粒劑、懸浮液、溶液、 膠囊、貼劑、液體、糖漿劑、酏劑、凝膠、粉劑、乳漿 劑、菱形錠劑、軟貧劑、乳劑、糊劑、硬膏劑、洗劑、圓 盤形劑、栓劑、膜劑、鼻用或口用噴霧劑、氣溶膠及諸如 此類。因其易於投用，故錠劑及膠囊代表最佳的口服劑量 127803.doc •17- 200838525 早7G形式’在該情況下，可採用固體醫藥載劑。在某些實 %例中，可藉由標準水性或非水性技術來包被錠劑。 在某 > 實知例中，可以持續釋放形式調配組合物來控制 釋放氣田他疋及/或孟魯司特或其醫藥上可接受之鹽之速 率，以使治療效果最優化。適用於持續釋放之劑型包括分 =叙劑’纟包含若干具有不同崩解速率或具有經活性組份 浸潰且定形為錠劑形式之控制釋放聚合物基質的層；或包 含該等經浸潰或經包埋之多孔聚合物基質的膠囊。 固體形式製劑包括粉劑、旋劑、菱形旋劑、可分散粒 劑、膠囊、扁囊劑及栓劑。該等固體劑型可藉由習用月方法 以醫藥上可接受之賦形劑加以製備，例如黏合劑(例如預 膠凝玉米殿粉、聚乙、说其 t乙烯基吡咯啶酮或羥丙基甲基纖維 常），填充劑（例如乳糖、料s她Μ主 循诞日日纖維素或磷酸氫鈣）；潤滑劑 (例如硬脂酸鎮、滑石粉或二氧切）；崩解劑（例如馬铃箸 殿粉或澱㈣乙酸納）；或潤濕劑（例如十二㈣硫酸納）。 活性成份可構成固體劑型總重量之約5%至約95%n 知劑、愛形錠劑、扁囊劑及膠囊可用作適用於經Π投盥之 固體劑型。可藉由業内熟知之方法包被錠劑。 ' 可使用標準方法製備鍵劑，例如藉由（視需要声一或多 ==份：起壓製或模製來製備。壓製錠劑可藉由在適 且機斋中壓縮呈自由流動形式（諸 β、、、 （渚如杨劑或粒劑）之活性成 ^ /、黏5劑、潤滑劑、惰性 稀釋诏、表面活性劑或分散劑混 宜機器中模製用惰性液體稀釋劑潤劑可藉由在適 y /閑濕的粉末化合物之混合 127803.doc -18- 200838525 物來製備。 快速崩解或溶解劑型（例如速融調配物）可用於醫藥活性 藥劑之快速吸收，尤其可用於頰内及舌下吸收。可使用標 準技術製備諸如錠劑等速融調配物。舉例而言，可使藉由 噴務乾燥或預壓緊製程製備之速融錠劑之顆粒與賦形劑混 合且使用習用錠劑製備機器將其壓縮成錠劑。該等顆粒可 與各種載劑（包括低密度高模壓加工性醣類、低模壓加工In certain embodiments, one or more undesirable side effects of the sympathomimetic agent can be avoided while producing substantially the same effect as the nasal congestion-enhancing effect obtained by a therapeutically effective amount of the sympathomimetic agent. The same effect of relieving nasal congestion as the sympathomimetic agent means that the effect produced by the therapeutically effective amount of the sympathomimetic agent is ±30%, ±=〇, ±10% or ±5%. 'As determined by the standard procedure for measuring nasal congestion. In certain embodiments, the de-frozen effect substantially the same as the sympathomimetic agent means that the effect produced is at least 7%, 8%, of the effect of relieving nasal congestion by a therapeutically effective amount of the sympathomimetic drug. , (d), (iv) or more in the case of certain members. 'The method described herein produces sympathomimetic during the hourly dosing, during the first 12 hours after administration, or during the 12-24 hours after administration. The drug is generally the same as the nasal discharge* effect. In a certain embodiment, the therapeutically effective amount of the sympathomimetic agent refers to the amount of pseudoephedrine test for nasal congestion at 24 hours. For example, pseudoephedrine: The therapeutically effective amount can be, for example, 240 mg of pseudoephedrine in an extended release formulation per administration. Such blending of pseudoephedrine is prepared by the eight (10) I technicians or may be purchased from J〇h_...-New Brunswick, m. 127803.doc 200838525 Loratadine, ie 4-(8-chloro-5,6-dihydro]1H_benzo[5,6]cycloheptide d,2_b]pyridin-11-subunit) Hexahydrogen. A non-sedating histamine-receptor antagonist than the $f acid ethyl ester. Loratadine for the treatment of allergies is sold under the trade name aadtin® by the company schering-Pl0 Ugh Health Care Pr〇ducts and can be prepared, for example, as described in U.S. Patent No. 7, PCT. Montelukast's H[[(1R)-W3_[(1E)_2_(7_Chloro-2-pyridinyl)vinyl]phenyl]-3-[2-(ι-carbyl) Ethyl)phenyl]propyl]thio]methyl]cyclopropylacetic acid' is a selective white triazole receptor antagonist. The montelukast sodium for the treatment of allergies is sold by the company Merck & c. under the trade name singulair® and can be prepared, for example, as described in U.S. Patent No. 5,27,324. Pharmaceutically effective montelukast salts include, for example, those prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, eucalyptus salts, divalent salts, potassium salts, sodium salts, zinc salts, and the like. . In certain embodiments, the pharmaceutically acceptable montelukast salt is montelukast sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and secondary amines, substituted amines (including naturally substituted amine amphoteric amines and base I*ionic ion-replaced resins, such as arginine) , betaine, caffeine, choline, N, N,-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine' N• Ethylmorpholine, N•ethylhexahydropyrene reduction glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl-reducing glucosamine, 127803.doc - 13- 200838525 porphyrin, hexahydropyrazine, hexahydropyridine, polyamine resin, procaine (pr〇caine) "ticket, cocoa test, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. Alkaloid salt. An equivalent amount of a pharmaceutically acceptable montelukast salt as used herein specifies a milligram amount of montelukast (free acid) comprising a substantially identical anionic molar amount of the amount of montelukast salt. Therefore 'to determine the specific salt form: equivalent amount' to multiply the specified amount of montelukast (free acid) by the montelukast anion The ratio is divided by the molecular weight ratio of montelukast (for example, montelukast sedation of montelukast (10). 6.20). For example, '1〇4 mg of montelukast sodium is equivalent to 1 〇家克孟鲁Sterling (free acid). In certain embodiments, the methods provided herein comprise co-administered gas, thunderidine, montelukast, or a pharmaceutically acceptable salt thereof, by separately formulating the individual drug and then disposing it Co-administered (simultaneously or sequentially) to perform co-administration. In certain embodiments, 'alradazidine and montelukast or a pharmaceutically acceptable salt thereof are used as a co-formulation comprising two active agents. The active agent may be formulated in a single dosage form of loratadine and montelukast or its pharmaceutically acceptable tread. Each day, once a day, a single daily dosage form is administered, for example, 5 days, two days, - weeks, two weeks, - months, or longer, one daily: one owed. Each dose is administered with a single-sputum dosage form for treatment. Congestion associated with persistent allergies, or sporadic administration as needed to treat nasal ash, such as urgency ^ and / or chronic treatment. It can effectively treat, prevent or alleviate the amount of loratadine and montelukast or its pharmaceutically acceptable salt in nasal supplements related to allergic rhinitis, which can be 127803.doc - 14· 200838525 Age, sex, weight, general health, severity of nasal congestion, route of administration, bioavailability of the formulation administered, choice of dosage regimen, and use of concomitant medication. Adjustable dosing dose and / Or frequency to meet the needs of individual patients. Those skilled in the art can easily determine the appropriate total dose range using conventional techniques. The dose can be administered in a single dose or in separate doses. It can be about 1··5 mg/ From milligrams to about 5:1 mg/mg, from about 1:3 mg/mg to about 3··1 mg/mg, from about 1:2 mg/mg to about 2:1 mg/mg, or about 1:1 mg/ A ratio of milligrams comprising a combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof is administered in combination with a solution of rivastigmine and montelukast or a pharmaceutically acceptable salt thereof. In a single-dose or divided dose, the amount of loratadine and montelukast or a pharmaceutically acceptable salt thereof which is effective for treating, preventing or ameliorating nasal congestion associated with allergic rhinitis is usually from about 10 to about 20 mg of loratadine and about 20 mg of montelukast or an equivalent amount of its pharmaceutically acceptable salt, from about 10 to about 15 mg of raldadine and from about 10 to about 15 mg of montelukast A particularly or equivalent amount of a pharmaceutically acceptable salt thereof, from about 8 to about 12 mg of loratadine and from about 8 to about 12 mg of montelukast or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the amount of 'loratadine and montelukast or its pharmaceutically acceptable salt is about 10 mg of loratadine and about 10 mg of montelukast or equivalent amount of /, west An acceptable salt; about 10 mg of rivastigmine and about 5 mg of mannose or equivalent of its pharmaceutically acceptable salt; about 5 mg of lorata and about 53⁄4 g of montelukast Or an equivalent amount of a pharmaceutically acceptable salt thereof; or about 5 mg of gas rituximab and about 4 mg of montelukast or an equivalent amount of its 127,803.doc •15-200838525 acceptable salt. In certain embodiments, the methods described herein comprise administering to a patient having nasal congestion associated with allergic rhinitis once a day a single daily dosage form comprising about 10 mg of loratadine and about 10.4 mg of montelukast. Sodium. In certain embodiments, the methods described herein relate to a daily dose equivalent to a daily dose level that can be administered to a patient having a normal liver function, normal renal function, and/or normal blood pressure. At the level, the patient is administered a combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof. Various methods of treating, preventing or ameliorating nasal congestion associated with allergic rhinitis can include administering loratadine and montelukast or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. The agent may include, for example, a non-narcotic analgesic (eg, for acetaminophen (Tylenol®) or a cyclooxygenase-2 inhibitor (eg, celecoxib (Celebrex®), valdecoxib (valdecoxib) ( Bextra8), lumiracoxib (Prexige®), etoricoxib (Arcoxia®), etc.); non-steroidal anti-inflammatory drugs (eg aspirin, σ scented beauty) Indomethacin (Indocin®), ibuprofen (Motrin®), naproxen (Naprosyn®), piroxicam (Feldene®), and naproxen (nabumetone) (Relafen®), etc.; long-acting/3 2-adrenergic agonist (LABA) (eg salmeterol, formoterol, bambuterol, etc.); corticosteroids (eg prednisone, prednisolone, Mometasone furoate monohydrate, beclomethasone, benzisone 127803.doc •16- 200838525 (flunisolide), triamcinolone acetonide, propionic acid Fluticasone propionate, dexamethasone sodium phosphate, budesonide, etc.; or antitussives (eg dextromethorphan, codeine, hydrocodone) )Wait). The additional therapeutic agents may be formulated separately and administered separately to the patient or may be co-formulated with loratadine and montelukast or a pharmaceutically acceptable salt thereof. One or more physiologically acceptable carriers or excipients may be used in a conventional manner to formulate co-modulations of raltreline and montelukast or a pharmaceutically acceptable salt thereof. For general techniques and formulations, see Α Gennar〇 (ed.), Remington, Pharmaceutical Sciences, 18th Edition, (199〇) Mack Publishing Company, Easton, PA. 各种 Any of the various methods described herein can be used. And means to provide an effective dose of loratadine and montelukast or a pharmaceutically acceptable salt thereof to a patient. For example, oral, intraoral, transrectal, parenteral, grade epidermis, transdermal, subcutaneous, intramuscular, intranasal, sublingual, intradural, intraocular, intravesical, oral or oral Nasal inhalation and similar forms of administration. Various suitable dosage forms can be used to administer loratadine and montelukast or a pharmaceutically acceptable salt thereof, including, for example, a key, a smokable, a money, a quick-melting formulation, a tablet, Dispersions, granules, suspensions, solutions, capsules, patches, liquids, syrups, elixirs, gels, powders, granules, lozenges, softeners, emulsions, pastes, plasters, washes Agents, discs, suppositories, films, nasal or oral sprays, aerosols and the like. Lozenges and capsules represent the best oral dosage because of their ease of administration. 127803.doc • 17- 200838525 Early 7G form 'In this case, a solid pharmaceutical carrier can be used. In some examples, the tablet may be coated by standard aqueous or non-aqueous techniques. In a > embodiment, the composition can be formulated in a sustained release form to control the rate at which the gas field and/or montelukast or its pharmaceutically acceptable salt is released to optimize the therapeutic effect. Dosage forms suitable for sustained release include those comprising a plurality of layers having different disintegration rates or having a controlled release polymer matrix impregnated with the active ingredient and shaped into a tablet form; or comprising such impregnation Or a capsule of an embedded porous polymer matrix. Solid form preparations include powders, squeezing agents, rhomboids, dispersible granules, capsules, cachets, and suppositories. The solid dosage forms can be prepared by conventional monthly methods using pharmaceutically acceptable excipients, such as binders (eg, pregelatinized corn powder, polyethylene, t-vinylpyrrolidone or hydroxypropyl-methyl) Base fiber often), filler (such as lactose, material s she is the main day of cellulose or calcium hydrogen phosphate); lubricant (such as stearic acid town, talc or dioxo); disintegrant (such as Ma Ling Yu Dian powder or lake (tetra) sodium acetate; or wetting agent (such as twelfth (tetra) sodium sulphate). The active ingredient may comprise from about 5% to about 95% by weight of the total weight of the solid dosage form. The formulation, love lozenge, cachet and capsule may be used as a solid dosage form suitable for transdermal administration. The tablets can be coated by methods well known in the art. 'The key can be prepared using standard methods, for example by (as needed, one or more == parts: pressed or molded). The compressed tablets can be compressed in a free-flowing form by suitable means. β,,, (such as yang or granules) active into / /, 5 agents, lubricants, inert diluents, surfactants or dispersants in the machine for the molding of inert liquid thinner It is prepared by mixing 127803.doc -18-200838525 of powder compound which is suitable for y/idle. Rapid disintegration or dissolved dosage form (such as quick-melt formula) can be used for rapid absorption of medicinal active agents, especially for buccal Internal and sublingual absorption. Rapid-melt formulations such as tablets can be prepared using standard techniques. For example, the particles of the fast-melt lozenge prepared by spray drying or pre-compacting process can be mixed with excipients and It is compressed into tablets using a conventional tablet preparation machine. The particles can be mixed with various carriers (including low density and high mold processing sugars, low molding processing).
性醣類、多元醇組合）組合，然後將其直接壓製為表現改 良之溶解性及崩解性狀況之錠劑。速融錠劑通常具有約2 至約6 Strong-Cobb單位（scu)之硬度。在咀嚼時此硬度範圍 内之錠劑可迅速崩解或溶解。此外，該等錠劑在水中快速 崩解。平均而言’在不擾拌情況下，通常1.1至1.5克錠劑 在1-3分鐘内崩解。此快速崩解有利於活性材料之遞送。 參見例如美國專利第5，112,616號及第5，G73,374號；美國專 利第4,616,047號中進一步闡述速融調配物。 用於經口投與之液體製劑可採用（例如）溶液、糖漿劑、 乳液或懸浮液之形式，或其可以無水產物形式存在以在使 用前再經水或其他適宜媒劑組成。該等液體製劑可藉由習 用方法以醫藥上可接受之添加劑來製備，例如懸浮劑(例 如山梨醇糖襞、纖維素衍生物或氫化食用脂肪）；乳化劑 (例如印磷脂或***膠）；非水媒劑（例如油、油醋、乙醇 或精製植物油”及防腐劑(例如對，基苯甲酸甲輯或丙酯 或山梨酸）。視情況，製劑亦可含有緩衝鹽、矯味劑、色 素及甜味齊卜可適當調配料經口投與之製劑，以便控制 127803.doc -19· 200838525 ，放活陡化合物。可經靜脈内、肌内或經皮下輸注之非經 腸幵7式通G無菌溶液形式且可包含滲透調節劑（鹽或葡 萄糖）及緩衝劑。液體形式製劑亦可包括鼻内投與之溶 液。 對於吸入式投與（例如肺部遞送），藉由使用諸如惰性壓 縮氣體⑼如二氟m氣三氯甲烧、^^ 烷、虱乳、二氧化碳或其他適宜氣體）等適宜推進劑，可 ^氣心膠喷霧劑投送之形式自加壓封裝或噴霧器遞送活性 藥劑。若係加壓氣轉，則可藉由_投祕計量之數量 來確疋劑里單位。用於吸人器或吹人器中的諸如明膠等膠 囊及卡官可調配為包含該化合物與適宜粉末基質（例如乳 糖或澱粉）之粉劑混合物。 氯雷他定及孟魯司特或其醫藥上可接受之鹽之組合亦可 為可經皮遞送。經皮組合物可採用乳劑、洗劑、氣溶膠及/ 或乳液形式，且可包含於用於該目的之業内習用基質或儲 存型經皮貼劑中。 在某些實施例中，醫藥製劑可呈單位劑型形式。呈此形 式時’該製劑可細分成含有適量(例如，可達成預期目的 之有效量）活性組份之適宜規格的單位劑量。 範例 現在概述本發明，藉由參照下述實例可更容易地理解本 發明，引入該等實例僅係出於闡釋本發明某些態樣及實施 例之目的，而非欲以任何方式限制本發明。 實例1 :與偽麻黃鹼相比之氣雷他定/孟魯司特組合（LMC> 127803.doc -20- 200838525 之#政The combination of a saccharide and a polyol is then directly compressed into a tablet which exhibits improved solubility and disintegration conditions. Fast melt tablets typically have a hardness of from about 2 to about 6 Strong-Cobb units (scu). The tablet in this hardness range can rapidly disintegrate or dissolve upon chewing. In addition, the tablets rapidly disintegrate in water. On average, 1.1 to 1.5 grams of tablet usually disintegrates in 1-3 minutes without disturbing. This rapid disintegration facilitates the delivery of the active material. See, for example, U.S. Patent Nos. 5,112,616 and 5, G73,374; U.S. Patent No. 4,616,047, which is incorporated herein by reference. The liquid preparation for oral administration can be in the form of, for example, a solution, syrup, emulsion or suspension, or it can be present as an anhydrous product to be reconstituted with water or other suitable vehicle before use. The liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (for example, sorbitol glycoside, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example, phospholipids or gum arabic); Non-aqueous agents (such as oil, oil vinegar, ethanol or refined vegetable oils) and preservatives (for example, benzoic acid or propyl or sorbic acid). Depending on the case, the preparation may also contain buffer salts, flavors, pigments. And the sweetness and taste can be adjusted by appropriate oral administration of the preparation, in order to control 127803.doc -19· 200838525, to release the steep compound. The enteral sputum can be intravenously, intramuscularly or subcutaneously infused. G can be in the form of a sterile solution and may contain a osmo-regulator (salt or glucose) and a buffer. The liquid form preparation may also include a solution for intranasal administration. For inhaled administration (eg, pulmonary delivery), by using, for example, inert compression A suitable propellant such as a gas (9) such as difluorom gas, trichloromethane, hexane, hydrazine, carbon dioxide or other suitable gas may be delivered from a pressurized package or sprayer in the form of a gas-sprayed spray. The active agent. If the pressurized gas is rotated, the unit can be determined by the amount of the metered dose. The capsules such as gelatin used in the inhaler or the blower can be adjusted to include the capsule. A powder mixture of a compound and a suitable powder base such as lactose or starch. The combination of loratadine and montelukast or a pharmaceutically acceptable salt thereof may also be transdermally deliverable. The transdermal composition may be an emulsion, In the form of a lotion, aerosol and/or lotion, and may be included in a conventional or transdermal patch for use in the art. In certain embodiments, the pharmaceutical preparation may be in unit dosage form. In the form of a 'the formulation can be subdivided into unit dosages containing suitable quantities (for example, an effective amount to achieve the desired purpose) of the active ingredient. Examples The present invention will now be summarized, and the invention will be more readily understood by reference to the following examples The examples are given for the purpose of illustrating certain aspects and embodiments of the invention, and are not intended to limit the invention in any way. Example 1: Combination of talostatin/Montelukast compared to pseudoephedrine LMC > 127803.doc -20- 200838525 # affairs of
評估採用孟魯司特及氯雷他定之組合療法之多種研究已 經公佈。舉例而言，以雙盲、使安慰劑為對照組之試驗評 估孟魯司特、氯雷他定及採用孟魯司特及氯雷他定之組合 療法對治療患有秋季季節性過敏性鼻炎之病人之有效性及 耐受性（參見 Nayak，A.S·等人，五〇/ montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter} randomized, double-blind，placebo-controlled trial performed in the fall， Annals of Allergy，Asthma & Immunology 88: 592-600 (2002))。該研究之結論為單獨使用孟魯司特或與氯雷他定 組合使用時，使患有季節性過敏性鼻炎之病人具有良好耐 受性且可提供臨床及生活品質益處。另一研究評估氯雷他 定及孟魯司特組合對患有嚴重鼻充血之季節性過敏性鼻炎 受試者之療效（參見Prenner，B·等人，〇/ efficacy of loratadine (L)-Montelukast (M) combination (LMC) in seasonal allergic rhinitis (SAR) subjects with severe nasal congestion (NC) without a history of perennial allergic rhinitis (PAR)y Annals of Allergy, Asthma & Immunology 90: 122(摘要第 30 頁）（2003) ·，及 Rachelefsky， G. ^k，Assessmentoftheefficacyofloratadine(L)-Montelukast (M) combination (LMC) in seasonal allergic rhinitis (SAR) subjects with severe nasal congestion (NC)， Annals of Allergy，Asthma & Immunology 90: 123(摘要第 127803.doc -21 - 200838525 31頁）（2003))。該研究之結論為組合之效果與單獨使用氯 雷他定之效果相當。另一隨機雙盲研究在季節性過敏性鼻 炎治療中比較非索那定-偽麻黃鹼組合與氯雷他定-孟魯司 特組合（參見 Moinuddin，K.專尺，Comparison of the combinations of fexofenadine-pseudoephedrine and loratadine-mnonielukast in the treatment of seasonal allergic rhinitis, Annals of Allergy, Asthma Sc Immunology 92: 73-79 (2004))。該研究之結論為在季節性過敏性鼻炎 ® 中，非索那定-偽麻黃鹼與氣雷他定·孟魯司特在改善症 狀、鼻結膜炎生命品質調查（RQLQ)評分及鼻塞方面療效 相當。 該研究之一目的係評估在患有季節性過敏性鼻炎（SAR) 且經1 5天治療以緩解鼻充血之受試者中，固定劑量之氣雷 他定/孟魯司特組合（LMC)(包含10毫克氯雷他定及10毫克 孟魯司特之每日一次錠劑）之療效與安慰劑療效之比較。 | 該研究之其他目的為：（i)使用健康相關生活品質 (HrQoL)、鼻腔最大吸氣流量（？见[)、8八11之整體病況、 及整體治療反應來評估LMC對安慰劑之療效；及（ii)使用 受試者報告之不良事件（AE)及生命體徵評價來評價LMC相 對於安慰劑及偽麻黃鹼之安全性。 ~ 此係根據優良臨床試驗規範實施之第3階段、多中心、 平行組、雙盲、雙模擬、隨機研究。將受試者分配至三治 療組之一：組1-LMC(10毫克/10毫克）；組2-偽麻黃鹼（240 毫克）；組3-安慰劑。受試者參與4次就診··第1次就診-篩 127803.doc -22- 200838525 :;第2次就診_基線；第3次及第4次就診_治療期。符合研 九條件之文试者在第2次就診時於診所接受其第一劑量。 將總共1095名受試者隨機分配至該研究中·· [Me，363 試者中，1057名（96.5%)完成研究。 該等治療組一般而言對於人口統計及基線特徵可良好匹 名受試者；偽麻黃鹼，369名受試者；及安慰劑，363名受 試者。所有受試者皆接受至少一次劑量之研究藥物。所有 組的平均治療期程為15天’且在15天之方案指H療期間 各組中至少91%之受試者接受研究藥物。在隨機受A variety of studies evaluating the combination therapy with montelukast and loratadine have been published. For example, a double-blind, placebo-controlled trial evaluated montelukast, loratadine, and combination therapy with montelukast and loratadine for the treatment of seasonal allergic rhinitis in the fall. Patient effectiveness and tolerability (see Nayak, AS et al., 〇 〇 / montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter} randomized, double-blind, placebo-controlled trial performed in the fall, Annals of Allergy, Asthma & Immunology 88: 592-600 (2002)). The study concluded that when montelukast alone or in combination with loratadine, patients with seasonal allergic rhinitis are well tolerated and provide clinical and quality of life benefits. Another study evaluated the efficacy of loratadine and montelukast combination in subjects with seasonal allergic rhinitis with severe nasal congestion (see Prenner, B. et al., 〇/ efficacy of loratadine (L)-Montelukast (M) combination (LMC) in seasonal allergic rhinitis (SAR) subjects with severe nasal congestion (NC) without a history of perennial allergic rhinitis (PAR) y Annals of Allergy, Asthma & Immunology 90: 122 (Abstract page 30) (2003) ·, and Rachelefsky, G. ^k, Assessment of theefficacyofloratadine(L)-Montelukast (M) combination (LMC) in seasonal allergic rhinitis (SAR) subjects with severe nasal congestion (NC), Annals of Allergy, Asthma & Immunology 90: 123 (Abstract 127803.doc -21 - 200838525 Page 31) (2003)). The conclusion of the study was that the effect of the combination was comparable to that of loratadine alone. Another randomized, double-blind study compared the combination of fensapride-pseudoephedrine with loratadine- montelukast in the treatment of seasonal allergic rhinitis (see Moinuddin, K., measure of the combinations of fexofenadine-pseudoephedrine) And loratadine-mnonielukast in the treatment of seasonal allergic rhinitis, Annals of Allergy, Asthma Sc Immunology 92: 73-79 (2004)). The study concluded that fonadodine-pseudoephedrine was comparable to ralostazidine montelukast in improving symptoms, rhinitis and conjunctivitis quality of life (RQLQ) scores, and nasal congestion in seasonal allergic rhinitis ® . One of the goals of this study was to evaluate a fixed-dose of thunderidine/Montelukast combination (LMC) in subjects with seasonal allergic rhinitis (SAR) who were treated for 15 days to relieve nasal congestion. (Comparative effect of placebo with 10 mg of loratadine and 10 mg of montelukast daily dose). The other objectives of the study were: (i) to assess the efficacy of LMC on placebo using health-related quality of life (HrQoL), nasal maximum inspiratory flow (see [), overall condition of 8:8, and overall treatment response. And (ii) assessing the safety of LMC relative to placebo and pseudoephedrine using adverse events (AEs) and vital sign assessments reported by the subjects. ~ This is a phase 3, multicenter, parallel group, double-blind, double-simulation, randomized study based on good clinical trial specifications. Subjects were assigned to one of three treatment groups: group 1-LMC (10 mg/10 mg); group 2-pseudoephedrine (240 mg); group 3-placebo. Subjects participated in 4 visits · 1st visit - screening 127803.doc -22- 200838525 :; 2nd visit _ baseline; 3rd and 4th visit _ treatment period. Subjects who meet the conditions of Study 9 receive their first dose at the clinic at the second visit. A total of 1095 subjects were randomly assigned to the study. [Me, 363 subjects, 1057 (96.5%) completed the study. The treatment groups were generally well-recognized for demographic and baseline characteristics; pseudoephedrine, 369 subjects; and placebo, 363 subjects. All subjects received at least one dose of study drug. The mean treatment period for all groups was 15 days' and at least 91% of the subjects in each group received the study drug during the 15-day program. Randomly subject to
配。三個治療組中，受試者群體之6〇%至66%為女性且平 均年齡為35.7至36.6歲。該研究群體主要包括高加索人種 (78%至79%)受試者。 主要納入標準包括：⑴至少2年之有記錄的SAR歷史， 其在研究季節加重，（ii)在第i次就診（篩檢）時對至少兩種 適宜季節性過敏原具有皮膚點刺檢驗陽性反應，（iii)在篩 才双就矽時之臨床症候學（由受試者評估八症狀評分必須滿足 下列祆準·鼻漏>2、鼻充血>2、總鼻症狀、總非鼻症狀 >4、及整體評價>2)，及（iv)在基線就診（第2次就診）時之臨 床症候學（基線就診前3天之7輪日誌内反映（pRI〇R)評分及 基線就診之AM評分必須總計為：鼻充血、總鼻症狀 >42、及總非鼻症狀>28)。 在篩檢、基線、及治療期就診期間，根據下述量表每天 兩次（AM及PM)由受試者評測充血/不通氣嚴重度作為反映 (PRIOR)(即受試者在前12小時内的狀態）。同樣，在篩檢 127803.doc -23 · 200838525 =療期期間受試者每天兩次量測並記錄其鼻腔最大吸氣 /爪里（使用在篩檢就診時所分配之pnif量器）。在所有就診 守（第1 8 15日）’研究者或被指派者及受試者根據該相 同里表_SAR整體病況：〇==無（無明顯症狀）；卜輕度（症 狀明顯存在但可覺察度最低；易於耐受且不干擾日常生活 及/或睡眠）；2=中度（可明確覺察症狀，該等症狀令人焦慮 仁尚可耐文），3一嚴重（症狀難於耐受；可導致干擾日常生 活活動及/或睡眠）。評價包括自先前就診後之整個時期。 對於主要療效變置及治療期中所評估之唯一症狀·鼻充Match. Of the three treatment groups, 6 to 66% of the subject population were female and the average age was 35.7 to 36.6 years. The study population consisted primarily of Caucasian (78% to 79%) subjects. The primary inclusion criteria included: (1) a recorded SAR history of at least 2 years, which was exacerbated during the study season, and (ii) a skin prick test positive for at least two suitable seasonal allergens at the ith visit (screening) Reaction, (iii) Clinical symptomology when the sieve is double-carrying (the evaluation of the eight-symptom score by the subject must meet the following criteria: rhinorrhea > 2, nasal congestion > 2, total nasal symptoms, total non-nasal Symptoms > 4, and overall evaluation > 2), and (iv) clinical symptom at baseline visit (2nd visit) (reported (pRI〇R) scores in 7 rounds of logs 3 days prior to baseline visit and The AM score for baseline visits must total: nasal congestion, total nasal symptoms > 42, and total non-nasal symptoms > 28). During the screening, baseline, and treatment visits, the subject was assessed twice as daily (AM and PM) for the assessment of hyperemia/non-ventilation severity (PRIOR) (ie, subjects in the first 12 hours) State inside). Similarly, during screening 127803.doc -23 · 200838525 = during the treatment period, subjects measured and recorded their nasal maximal inspiratory/paws twice daily (using the pnif gauge dispensed at the screening visit). At all visits (18th 15th) 'researchers or assignees and subjects according to the same table _SAR overall condition: 〇 == no (no obvious symptoms); mild (symptoms are clearly present but The lowest perceived degree; easy to tolerate and does not interfere with daily life and / or sleep); 2 = moderate (can clearly detect symptoms, these symptoms are anxious and can still be good), 3 serious (symptoms are difficult to tolerate Can cause disturbances in daily activities and/or sleep). The evaluation included the entire period since the previous visit. For the main efficacy changes and the only symptoms evaluated during the treatment period · nasal filling
血，三治療組間平均AM pRI〇R、pM pRi〇R& AM/pM PRIOR評估之平均基線評分相當。 AM PRIOR鼻充血評分 主要療效指標係AM PRIOR鼻充血評分自基線之變化， 其表彳政在投藥後12至24小時之過夜症狀緩解。結果歸納於 表1中，其顯示LMC及偽麻黃鹼之效應在整個研究期間彼 此相似。分析顯示，在15天治療期期間，LMC之am PRIOR鼻充血評分自基線之平均降低較安慰劑在統計學上 顯著更有效。在第2至15天（主要時間點）LMC鼻充血評分 之平均降低較安慰劑之降低多012點（p=〇 〇〇9)。由於該評 估係在早上投藥前實施，故LMC在整個投藥間期維持其效 應。 在第2至15天期間，偽麻黃鹼之am PRIOR鼻充血評分自 基線之降低較安慰劑在統計學上亦顯著更有效（評分較安 慰劑多降低〇·13點；Ρ=0·〇〇4)。然而，在第2至15天之主要 127803.doc -24- 200838525 日守間點或所分析任一其他時間點鼻充血評分自基線之變化 方面，LMC與偽麻黃鹼間無顯著差異。LMC之效應（〇·12 點）係偽麻黃驗效應（0· 13點）之92%。The mean baseline scores for the mean AM pRI〇R, pM pRi〇R& AM/pM PRIOR assessments were comparable between the three treatment groups. AM PRIOR nasal congestion score The main efficacy index is the change from the baseline of the AM PRIOR nasal congestion score, which is relieved by overnight symptoms at 12 to 24 hours after administration. The results are summarized in Table 1, which shows that the effects of LMC and pseudoephedrine are similar to each other throughout the study. Analysis showed that the mean decrease in the AM PRIOR nasal congestion score from LMC from baseline during the 15-day treatment period was statistically significantly more effective than placebo. On days 2 to 15 (major time points), the mean reduction in LMC nasal congestion score was 012 points lower than placebo (p = 〇〇 〇〇 9). Since the assessment was performed prior to administration in the morning, the LMC maintained its effect throughout the administration interval. During the second to fifteenth day, the decrease in the pseudo-ephedrine am PRIOR nasal congestion score from baseline was statistically significantly more effective than placebo (the score was lower than the placebo; 〇·13 points; Ρ=0·〇〇4) . However, there was no significant difference between LMC and pseudoephedrine in terms of changes in nasal congestion scores from baseline at the primary 127803.doc -24-200838525 day of the 2nd to 15th day or at any other time point analyzed. The effect of LMC (〇·12 points) is 92% of the pseudo-ephedrine test effect (0·13 points).
表鼻充血分析結果：受試者評價的AM PRIOR 12小時（所 有機受試者）DNasal congestion analysis results: subject evaluated AM PRIOR 12 hours (organic subjects) D
N LMC (A) PSE (B) 安慰劑（C) Pstda LS 平均值a (平均 %變化)b N LS 平均值a (平均 %變化)b N LS 平均值a (平均 %變化)b 基線 362 2.66 366 2.67 360 2.69 自基線之變化 第2天 358 -0.30 (-10.3) 363 -0.30 (-10.6) 358 -0.23 (-8.1) 0.672 第3天 361 -0.44 (-15.7) 364 -0.42 (-15.0) 359 -0.30 (-10.4) 0.728 第4天 360 -0.48 (-17.4) 363 -0.41 (-14.4) 359 -0.33 (-11.4) 0.759 第2至8天 361 -0.48 (-17.4) 365 -0.45 (-16.3) 359 -0.37 (-13.2) 0,581 第9至15天 356 -0.65 (-23.6) 357 -0.70 (-25.3) 358 -0.52 (-18.6) 0.690 第2至15天 362 -0.56 (-20.4) 366 -0.57 (-20.6) 360 -0,44 (-15.8) 0.595 成對比較P 值 95%置信區 間 A-B A-C B-C A-B A-C B-C 自基線之變化 第2天 0.915 0.208 0.171 (-0.09, 0.10) (-0.16,0.04) (-0.17,0.03) 第3天 0.764 0.011 0.024 (-0.12,0.09) (-0.25, -0.03) (-0.23,-0.02) 第4天 0.202 0.007 0.150 (-0.18,0.04) (-0.27, -0.04) (-0.19,0.03) 第2至8天 0.587 0.013 0.052 (-0.11,0.06) (-0.19, -0.02) (-0.17,0.00) 第9至15天 0.317 0.016 <.001 (-0.05, 0.15) (-0.23, -0.02) (-0.28,-0.08) 第2至15天 0.790 0.009 0.004 (-0.08,0.10) (-0.20, -0.03) (-0.21,-0.04) LMC = 10毫克氯雷他定/10毫克孟魯司特組合錠劑； PSE=240毫克偽麻黃驗錠劑。 -25- 127803.doc 200838525 a ：自具有治療及位點效應之雙向ANOVA模型獲得LS平 均值及Pstd(總標準偏差）。 b ：平均百分比變化係原始平均數。 AM/PM PRIOR鼻充血評分 AM/PM PRIOR鼻充血評分表徵投藥後24小時期間之症 狀緩解。在第1至15天期間，LMC之AM/PM PRIOR鼻充血 ^ 評分自基線之平均降低較安慰劑在統計學上顯著更有效 (表2)。LMC之鼻充血評分之平均降低為0·61點，而安慰劑 • 為0.49點。LMC與安慰劑間-0.12點之差異在統計學上顯著 (Ρ=0·003)。 在第1至15天期間，偽麻黃鹼之AM/PM PRIOR鼻充血評 分自基線之平均降低較安慰劑在統計學上亦顯著更有效 (評分較安慰劑多降低〇·16點；P<0.001)。然而，在第1至 15天之平均值方面LMC與偽麻黃鹼間無顯著差異。 表2.鼻充血分析結果：受試者評價的AM/PM PRIOR 12小 時（所有隨機受試者）。 LMC (A) PSE (B) 安慰劑（C) Pstda N LS 平均值a (平均 %變化)b N LS 平均值a (平均 %變化)b N LS 平均值a (平均 %變化)b 基線 362 2.65 368 2.65 360 2.67 自基線之變> [匕 第1天 354 -0.36 (-12.8) 355 -0.48 (-17.8) 352 -0.32 (-11.9) 0.650 第2天 361 -0.44 (-16.0) 365 -0.44 (-16.2) 359 -0.31 (-Π.4) 0.621 第3天 361 -0.50 (-18.5) 365 -0.49 (-18.3) 359 -0.37 (-13.5) 0.642 第4天 361 -0.56 (-20.7) 364 -0,53 (-19.6) 359 -0.42 (Ί5.4) 0.671 第1至8天 361 -0.54 (20.1) 367 -0.54 (-20.2) 360 -0.42 (-15.6) 0.554 -26- 127803.doc 200838525N LMC (A) PSE (B) Placebo (C) Pstda LS Mean a (Average % change) b N LS Mean a (Average % change) b N LS Mean a (Average % change) b Baseline 362 2.66 366 2.67 360 2.69 Change from baseline Day 2 358 -0.30 (-10.3) 363 -0.30 (-10.6) 358 -0.23 (-8.1) 0.672 Day 3 361 -0.44 (-15.7) 364 -0.42 (-15.0) 359 -0.30 (-10.4) 0.728 Day 4 360 -0.48 (-17.4) 363 -0.41 (-14.4) 359 -0.33 (-11.4) 0.759 Day 2 to 8 361 -0.48 (-17.4) 365 -0.45 (- 16.3) 359 -0.37 (-13.2) 0,581 Days 9 to 15 356 -0.65 (-23.6) 357 -0.70 (-25.3) 358 -0.52 (-18.6) 0.690 Days 2 to 15 362 -0.56 (-20.4) 366 -0.57 (-20.6) 360 -0,44 (-15.8) 0.595 Pairwise comparison P value 95% confidence interval AB AC BC AB AC BC Change from baseline Day 2 0.915 0.208 0.171 (-0.09, 0.10) (-0.16 , 0.04) (-0.17, 0.03) Day 3 0.764 0.011 0.024 (-0.12, 0.09) (-0.25, -0.03) (-0.23, -0.02) Day 4 0.202 0.007 0.150 (-0.18, 0.04) (-0.27 , -0.04) (-0.19, 0.03) Days 2 to 8 0.587 0.013 0.052 (-0.11, 0.06) (-0.19, -0.02) (-0.17, 0.00) 9 to 15 days 0.317 0.016 <.001 (-0.05, 0.15) (-0.23, -0.02) (-0.28, -0.08) Days 2 to 15 0.790 0.009 0.004 (-0.08, 0.10) (-0.20, -0.03 (-0.21, -0.04) LMC = 10 mg loratadine/10 mg montelukast combination lozenge; PSE = 240 mg pseudoephedrine lozenge. -25- 127803.doc 200838525 a : LS mean and Pstd (total standard deviation) were obtained from a two-way ANOVA model with treatment and site effects. b: The average percentage change is the original average. AM/PM PRIOR nasal congestion score The AM/PM PRIOR nasal congestion score characterizes the symptom relief during the 24 hour period after administration. During the first to fifteenth days, the mean reduction in the AM/PM PRIOR nasal congestion score for LMC from baseline was statistically significantly more effective than placebo (Table 2). The mean reduction in nasal congestion score for LMC was 0.66 points, compared with 0.49 for placebo. The difference between the LMC and placebo - 0.12 points was statistically significant (Ρ = 0.003). During the first to fifteenth days, the mean reduction in the AM/PM PRIOR nasal congestion score for pseudoephedrine from baseline was statistically significantly more effective than placebo (the score was reduced by 16 points more than placebo; P < 0.001). However, there was no significant difference between LMC and pseudoephedrine in the mean of days 1 to 15. Table 2. Results of nasal congestion analysis: Subjects evaluated AM/PM PRIOR 12 hours (all random subjects). LMC (A) PSE (B) Placebo (C) Pstda N LS Mean a (Average % change) b N LS Mean a (Average % change) b N LS Mean a (Average % change) b Baseline 362 2.65 368 2.65 360 2.67 Change from Baseline > [匕 Day 1 354 -0.36 (-12.8) 355 -0.48 (-17.8) 352 -0.32 (-11.9) 0.650 Day 2 361 -0.44 (-16.0) 365 -0.44 (-16.2) 359 -0.31 (-Π.4) 0.621 Day 3 361 -0.50 (-18.5) 365 -0.49 (-18.3) 359 -0.37 (-13.5) 0.642 Day 4 361 -0.56 (-20.7) 364 -0,53 (-19.6) 359 -0.42 (Ί5.4) 0.671 Days 1 to 8 361 -0.54 (20.1) 367 -0.54 (-20.2) 360 -0.42 (-15.6) 0.554 -26- 127803.doc 200838525
第9至15天 356 -0.71 (-26.0) 357 -0.78 (-28.9) 358 -0,56 (-20,7) 0.663 第1至15天 362 -0.61 (>22.8) 368 -0.65 (-24.1) 360 -0.49 (-17.9) 0.572 成對比feP值 95%詈信區P 3 A-B A-C B-C A-B A-C B-C 自基線之變1 f匕 第1天 0.011 0.510 0.001 (0.03, 0.22) (-0.13,0.06) (-0.25,-0.06) 第2天 0.921 0.007 0.005 (-0.09,0.10) (-0.22, -0.03) (-0.22,-0.04) 第3天 0.904 0.006 0.009 (-0.10,0.09) (-0.23, -0.04) (-0.22,-0.03) 第4天 0.613 0.006 0.024 (-0.12,0.07) (-0.24, -0.04) (-0.21,-0.01) 第1至8天 0.928 0.004 0.003 (-0.08, 0.08) (-0.20, -0.04) (-0.20,-0.04) 第9至15天 0.149 0.005 <.001 (-0.03,0.17) (-0.24, -0.04) (-0.31 11) 第1至15天 0.422 0.003 <•001 (-0.05,0.12) (-0.21,-0.04) (-0.24,-0.08) PSE=240毫克偽麻黃鹼錠劑。 a ·自具有治療及位點效應之雙向ANOVA模型獲得LS平 均值及Pstd(總標準偏差）。 b :平均百分比變化係原始平均數。 PM PRIOR鼻充血評分 PM PRIOR鼻充血評分表徵投藥後〇至i 2小時之日間症狀 緩解。該分析證實主要分析結果，即在第1至15天期間， LMC：之鼻充&評分自&線之平均降低較安慰劑在統計學上 .、、、員著（P G.GG4)更有效，且LMC與偽麻黃㈣無顯著差異。 其他療效變量 AM PNIF自基線之變化結果歸納於表3中，其顯示在整 口研九期間LMC與偽麻黃驗之效應彼此相似。pNiF評估係 瞬時評估，其表徵在評估日㈣之鼻腔氣流。在⑷、時投藥 127803.doc •27· 200838525 間期終點實施AM評價。在第2至15天（主要時間點）期間， PNIF自基線之平均增加對於LMC為10.64升/分鐘，對於偽 麻黃鹼為10.06升/分鐘，且對於安慰劑為5.05升/分鐘。分 析顯示，在第2至15天期間，LMC之AM PNIF自基線之增 加較安慰劑在統計學上顯著更有效（P<〇.〇〇1)。由於此係在 早上投藥前立即實施之瞬時評估，故LMC在整個投藥間期 維持其效應。Days 9 to 15 356 -0.71 (-26.0) 357 -0.78 (-28.9) 358 -0,56 (-20,7) 0.663 Days 1 to 15 362 -0.61 (>22.8) 368 -0.65 (-24.1 360 -0.49 (-17.9) 0.572 Contrast feP value 95% 詈信区 P 3 AB AC BC AB AC BC Change from baseline 1 f匕1st day 0.011 0.510 0.001 (0.03, 0.22) (-0.13,0.06) (-0.25, -0.06) Day 2 0.921 0.007 0.005 (-0.09, 0.10) (-0.22, -0.03) (-0.22, -0.04) Day 3 0.904 0.006 0.009 (-0.10,0.09) (-0.23, - 0.04) (-0.22, -0.03) Day 4 0.613 0.006 0.024 (-0.12, 0.07) (-0.24, -0.04) (-0.21, -0.01) Days 1 to 8 0.928 0.004 0.003 (-0.08, 0.08) ( -0.20, -0.04) (-0.20, -0.04) Days 9 to 15 0.149 0.005 <.001 (-0.03,0.17) (-0.24, -0.04) (-0.31 11) Days 1 to 15 0.422 0.003 <;•001 (-0.05,0.12) (-0.21,-0.04) (-0.24,-0.08) PSE=240 mg pseudoephedrine lozenge. a • LS mean and Pstd (total standard deviation) were obtained from a two-way ANOVA model with treatment and site effects. b: The average percentage change is the original average. PM PRIOR nasal congestion score The PM PRIOR nasal congestion score characterizes the symptom relief after 2 hours of administration. This analysis confirmed the main analysis results, that is, during the first to fifteenth days, the average reduction of the LMC: nasal charge & score from & line was statistically compared with placebo (P G.GG4) More effective, and there is no significant difference between LMC and pseudoephedrine (four). Other efficacy variables The results of AM PNIF changes from baseline are summarized in Table 3, which shows that the effects of LMC and pseudoephedrine tests are similar to each other during the entire study. The pNiF assessment is an instantaneous assessment that characterizes the nasal airflow on the assessment day (D). The AM evaluation was performed at the end point of (4), when the drug was administered 127803.doc •27·200838525. During the 2nd to 15th day (major time point), the average increase in PNIF from baseline was 10.64 L/min for LMC, 10.06 L/min for pseudoephedrine, and 5.05 L/min for placebo. Analysis showed that the increase in AM PNIF from baseline for LMC was statistically significantly more effective than placebo during days 2 to 15 (P<〇.〇〇1). Since this is an instantaneous assessment performed immediately prior to administration in the morning, LMC maintains its effect throughout the administration interval.
在第2至1 5天期間，偽麻黃鹼之AM PNIF自基線之增加 較安慰劑在統計學上亦顯著更有效（Ρ=〇·〇〇1)。然而，在第 2至1 5天之主要時間點或所分析任一其他時間點AM PNIF 自基線之變化方面，LMC與偽麻黃鹼間無顯著差異。 表3·鼻腔最大吸氣流量（升/分鐘）分析結果：受試者-評價 AM(所有隨機受試者）。During the second to fifteenth day, the increase in AM PNIF from pseudoephedrine from baseline was statistically significantly more effective than placebo (Ρ=〇·〇〇1). However, there was no significant difference between LMC and pseudoephedrine in terms of changes in AM PNIF from baseline at major time points from day 2 to day 15 or at any other time point analyzed. Table 3. Nasal Maximum Inspiratory Flow (L/min) Analysis Results: Subject - Evaluation AM (all random subjects).
LMC (A) PSE (B) 安慰劑(C) LS (平均％ LS (平均％ LS (平均％ N 平均值a 變化)b N 平均值a 變化)b N 平均值a 變化)b Pstda 基線 361 91.80 366 96.27 360 94.99 自基線之變化 第2天 361 5.15 (9.1) 362 3.68 (5.8) 358 1.19 (3.6) 23.36 第3天 361 6,87 (11.5) 365 6.35 (9.7) 358 1.81 (4.6) 23.45 第4天 361 7.47 (12.9) 364 7.53 (10.9) 358 1.09 (4.4) 24.23 第2至8天 361 8.56 (13.3) 365 7.85 (11.1) 358 3.43 (7.0) 19.97 第9至15天 355 12.85 (19.2) 357 12.70 (16.9) 357 6.92 (11.4) 24.68 第2至15天 361 10.64 (16.2) 366 10.06 (13.7) 360 5.05 (9.0) 20.54 成對比較P 值 95%置信區間 A-B A-C B-C A-B A-C B-C -28 - 127803.doc 200838525 自基線之變化 第2天 0.399 0.023 0.153 (-1.95, 4.89) (0.54, 7.39) (-0.93,5.92) 第3天 0.766 0.004 0.009 (-2.91，3.95) (1.62, 8.51) (1.11，7.98) 第4天 0.974 <•001 <.001 (-3.60, 3.48) (2.83, 9.94) (2.89, 9.99) 第2至8天 0.633 <.001 0,003 (-2.21,3.63) (2.20, 8.06) (1.50,7.34) 第9至15天 0.933 0.001 0.002 (-3.49, 3.80) (2.29, 9.57) (2.14,9.41) 第2至15天 0.703 <.001 0.001 (•2.42, 3.58) (2.59, 8.60) (2.01,8.01) LMC=1()毫克氯雷他定/10毫克孟魯司特組合錠劑； PSE=240毫克偽麻黃鹼錠劑。 a ：自具有治療及位點效應之雙向ANOVA模型獲得 LS(最小顯著性）平均值及Pstd(總標準偏差）。 b ：平均百分比變化係原始平均數。 其他次要療效變量（即RQLQ、治療反應之聯合評價、及 SAR整體病況之聯合評價）之分析顯示與安慰劑相比， LMC在統計學上顯著（Ρ<0·005)更有效且LMC與偽麻黃鹼間 無顯著差異。 表4歸納在任一治療組中2%或更多受試者出現的不良事 件。經LMC治療受試者之不良事件總發生率（15.2%)低於 經PSE治療受試者（23 ·0%)且與經安慰劑治療受試者之發生 率（17.6%)相當。在任一治療組的2%以上受試者中，除口 乾燥、噁心、頭痛、及失眠外未報道不良事件。在PSE治 療組中口乾燥及噁心以較LMC組（0.6%，0.3%)或安慰劑組 (0.6%，0%)顯著更高之發生率（4.9%，2.2%)發生。頭暈僅 在經PSE治療受試者中發生（6，1.6%)。失眠，PSE之一般 副作用，在8名（2.2%)經PSE治療受試者中發生，與之相 127803.doc -29- 200838525 比，經LMC治療受試者無一發生失眠且2名（〇6%)經安慰 劑治療受試者發生失眠。 所有不良事件之歸納顯示如下。 表4任-治療組中報告2%或更多受試者（所有隨機受試者） 事件之匯總 身體系統/器官類別 不良事件 數量(%) LMC (n=363) PSE (n=369) 安慰劑 任一不良事件 55 (15·2) _ (n-363) 胃腸病症 85 (23.0) 64(17.6) 口乾燥 口惡心 2 (0.6) 18(4.9) 2 (0.6) 神經系統病症 1 (0.3) 8 (2.2) 0 頭痛 8 (2.2) 0 精神病症 失眠 7(1.9) 9(2.5) LMC=l〇毫克氯雷他定/1〇毫克孟 PSE-240¾克偽麻黃驗錠劑。 -- 魯司特組 —_2(0.6) 合錢劑； 此外LMC (A) PSE (B) Placebo (C) LS (average % LS (mean % LS (mean % N mean a change) b N mean a change) b N mean a change) b Pstda baseline 361 91.80 366 96.27 360 94.99 Change from baseline Day 2 361 5.15 (9.1) 362 3.68 (5.8) 358 1.19 (3.6) 23.36 Day 3 361 6,87 (11.5) 365 6.35 (9.7) 358 1.81 (4.6) 23.45 4 Day 361 7.47 (12.9) 364 7.53 (10.9) 358 1.09 (4.4) 24.23 Days 2 to 8 361 8.56 (13.3) 365 7.85 (11.1) 358 3.43 (7.0) 19.97 Days 9 to 15 355 12.85 (19.2) 357 12.70 (16.9) 357 6.92 (11.4) 24.68 Days 2 to 15 361 10.64 (16.2) 366 10.06 (13.7) 360 5.05 (9.0) 20.54 Pairwise comparison P value 95% confidence interval AB AC BC AB AC BC -28 - 127803. Doc 200838525 Change from baseline on day 2 0.399 0.023 0.153 (-1.95, 4.89) (0.54, 7.39) (-0.93, 5.92) Day 3 0.766 0.004 0.009 (-2.91, 3.95) (1.62, 8.51) (1.11, 7.98 ) Day 4 0.974 <•001 <.001 (-3.60, 3.48) (2.83, 9.94) (2.89, 9.99) Days 2 to 8 0.633 <.001 0,003 (-2.21, 3.63) (2.20, 8.06 ) (1.50, 7.34) No. 9 15 days 0.933 0.001 0.002 (-3.49, 3.80) (2.29, 9.57) (2.14, 9.41) Days 2 to 0.7 0.703 <.001 0.001 (•2.42, 3.58) (2.59, 8.60) (2.01, 8.01) LMC= 1 () mg of loratadine/10 mg montelukast combination lozenge; PSE = 240 mg pseudoephedrine lozenge. a : LS (least significant) mean and Pstd (total standard deviation) were obtained from a two-way ANOVA model with treatment and site effects. b: The average percentage change is the original average. Analysis of other secondary efficacy variables (ie, RQLQ, combined evaluation of treatment response, and combined assessment of overall SAR conditions) showed that LMC was statistically significant (Ρ<0·005) more effective than LMO and LMC was There was no significant difference between pseudoephedrine. Table 4 summarizes the adverse events that occurred in 2% or more of the subjects in either treatment group. The overall incidence of adverse events (15.2%) in subjects treated with LMC was lower than those treated with PSE (23.0%) and was comparable to the incidence of placebo-treated subjects (17.6%). No adverse events were reported except for dry mouth, nausea, headache, and insomnia in more than 2% of subjects in either treatment group. Oral dryness and nausea occurred in the PSE treatment group at a significantly higher incidence (4.9%, 2.2%) than the LMC group (0.6%, 0.3%) or the placebo group (0.6%, 0%). Dizziness occurred only in subjects treated with PSE (6, 1.6%). Insomnia, the general side effects of PSE occurred in 8 (2.2%) subjects treated with PSE, compared with 127803.doc -29- 200838525, none of the subjects treated with LMC had insomnia and 2 (〇 6%) Insomnia occurred in subjects treated with placebo. The summary of all adverse events is shown below. Table 4 Reporting 2% or more subjects (all random subjects) in the treatment-treatment group. Summary of the number of adverse events in the body system/organ class (%) LMC (n=363) PSE (n=369) Consolation Any adverse events of the agent 55 (15·2) _ (n-363) Gastrointestinal disorders 85 (23.0) 64 (17.6) Dry mouth nausea 2 (0.6) 18 (4.9) 2 (0.6) Nervous system disorders 1 (0.3 8 (2.2) 0 Headache 8 (2.2) 0 Psychiatric Insomnia 7 (1.9) 9 (2.5) LMC = l 〇 mg loratadine / 1 〇 mg Meng PSE-2403⁄4 gram pseudo-anthraquinone tablet. -- Russ group —_2(0.6) money agent;
«个氏肀忏緦表中選出盥癡六 , 擬又感神經興奮性胺相 關之特異性不良事件（除失料）以確定治療組間該等事件 ^相對發生率。該等發生率歸納於表5中。咖組中該等事 件之發生率^LMC或安慰劑組。研究者將幾乎 事件皆視為治療相關的。 ^ 127803.doc -30- 200838525 表5與擬交感神經興奮性胺相關之不良事件（除失眠外）發生率 受試者數量(％) LMC PSE 安慰劑 不良事件 (n=363) (n=369) (n=363) 任一不良事件 眩暈 緊張不安 易激怒 頭暈 精神運動機能亢進 震顏 神經質 煩亂不安 3 (0.8) 0 0 2 (0.6) 0 0 0 0 1 (03) 14(3.8) 0 2 (0.5) 1 (0,3) 6(1.6) 1 (0.3) 0 3 (0.8) 1 (0.3) 4(1.1) 1 (0.3) 0 0 0 1 (0.3) 1 (0·3) 1 (0.3) 〇 LMC=l〇毫克氣雷他定/1〇毫克孟 PSE 24〇毫克偽麻黃驗鍵劑。 魯司特組 合錠劑； 等效内容The specific adverse events associated with sensory nerve excitatory amines (except for loss of material) were selected from the list of sputum sputum, to determine the relative incidence of such events between treatment groups. These incidences are summarized in Table 5. The incidence of such events in the coffee group ^LMC or placebo group. Researchers treat almost all events as treatment-related. ^ 127803.doc -30- 200838525 Table 5 Number of subjects with sympathomimetic excitatory amine-related adverse events (except insomnia) Number of subjects (%) LMC PSE Placebo adverse events (n=363) (n=369 (n=363) Any adverse event, dizziness, nervousness, irritability, dizziness, mental motor function, hyperthyroidism, neurotic disorder, 3 (0.8) 0 0 2 (0.6) 0 0 0 0 1 (03) 14 (3.8) 0 2 ( 0.5) 1 (0,3) 6(1.6) 1 (0.3) 0 3 (0.8) 1 (0.3) 4(1.1) 1 (0.3) 0 0 0 1 (0.3) 1 (0·3) 1 (0.3) 〇LMC=l〇mg gas statin/1〇mg Meng PSE 24〇mg pseudo-ephedrine test agent. Russert combination tablet; equivalent content
鲁發明尤其提供治療、減輕或預防與過敏性鼻炎相關之 鼻充血之方法。儘管已論述本發明之具體實施例，但上文 兒：係闡释性而非限制十生。閱讀此說明後，彼等熟習此項 :術者可明瞭本發明之許多變更。應參照申請專利範圍及 月曰來確疋本發明之完整範圍以及其等效内容之完整範 以及該等變更形式之完整範圍。 127803.doc -31 -In particular, the invention provides a method of treating, alleviating or preventing nasal congestion associated with allergic rhinitis. Although specific embodiments of the invention have been discussed, the foregoing is illustrative and not limiting. After reading this description, they are familiar with this: The practitioner will be able to clarify many variations of the invention. The full scope of the invention and the full scope of its equivalents, as well as the full scope of such modifications, should be 127803.doc -31 -
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| CN108125908A (en) * | 2017-12-14 | 2018-06-08 | 重庆西南医院 | A kind of Montelukast Sodium nose solution and preparation method thereof |
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