201016215 六、發明說明： 【發明所屬之技術領域】 本發明係關於藉由經口吸入或經鼻内投予抗病毒活性藥 劑以冶療、減少、儘量降低或預防患者之哮喘惡化。 【先前技術】 小核糖核酸病毒家族之病毒包括鼻病毒與腸病毒。鼻病 毒為病毒性呼吸道感染（VRI)(包括普通感冒）之主要原因。 在美國（us)每年有約十億例感冒。⑺普通感冒患者之年齡 • 分佈傾向於年輕人。雖然範圍變化廣泛，但成年人一年感 冒兩至四次。女性（尤為彼等年齡20至30歲）得感冒多於男 性，可能係因為彼等與兒童更緊密接觸之故。年長於6〇歲 之個體平均每年經歷少於一次。感冒最流行於年幼兒童， 彼等每年經歷約六至十次感冒。 普利康那利（pleconaril)為一種抗病毒活性藥劑，一互細 小核糖核酸病毒進入細胞内，其即阻止該病毒脫殼 (UnC〇ating)，而選擇性抑制細小核糖核酸病毒；普利康那 利亦藉由整合入病毒衣殼中之特定疏水位點而阻止一些細 小核糖核酸病毒粘附於寄主細胞。現在市場上沒有其他化 合物具有與普利康那利相同之作用機制。 普利康那利稱為1，2,4-噁二哇3_[3,5-二甲基-4-[3-(3-甲 基-5-異噁唑基）丙氧基]苯基]_5_(三氟甲基）。其具有其他 名稱，諸如PICOVIR®，VP 63843與Win 63843。普利康那 利為一種細小核糖核酸病毒複製抑制劑，除其他疾病外還 適用於治療病毒誘發的上呼吸道與下呼吸道感染、病秦性 141755.doc 201016215 腦膜炎、及諸如慢性腦膜炎、新生兒腸道疾病、小兒麻痺 症和心肌炎之生命威脅性疾病。 根據默克指弓丨（Merck Index)，其可根據美國專利案第 5,464,848號製得，其揭示内容已以引用的方式併入。 已發展一種普利康那利口服調配物，並已對該口服調配 物進行臨床試驗，證實普利康那利於減少普通感冒症狀嚴 重度和持續性之能力。普利康_解除感冒症狀的時間比 安慰劑縮短25%，且在該等m期研究之前即已達到所設定 的預定目標。在接受錠劑調配物治療5或7天的成年患者 中’普利康那利總體上具良好耐受性；最f報告的不良事 件為頭痛（24%)、腹瀉（8%)、及噁心（6%)。 哮喘惡化可能與普通感冒相關。哮喘惡化包括咳漱、氣 喘與啤吸急促。彼等罹患哮喘惡化的人們，f通感f尤其 會造成問題且可能威脅生命。201016215 VI. Description of the Invention: [Technical Field] The present invention relates to the treatment, reduction, minimization or prevention of asthma exacerbation in a patient by oral inhalation or intranasal administration of an antiviral active agent. [Prior Art] Viruses of the picornavirus family include rhinoviruses and enteroviruses. Nasal toxicity is the leading cause of viral respiratory infections (VRI), including the common cold. There are about one billion colds a year in the United States (us). (7) Age of common cold patients • Distribution tends to young people. Although the scope varies widely, adults have two to four times a year. Women (especially those aged 20 to 30) have a cold more than men, probably because they are in closer contact with children. Individuals older than 6 years old experience less than once a year on average. Colds are most prevalent among young children, who experience about six to ten colds a year. Pleconaril is an antiviral active agent, a microRNA is introduced into the cell, which prevents the virus from uncoating (UnC〇ating), and selectively inhibits the picornavirus; Pricanali Some picornaviruses are also prevented from adhering to host cells by integration into specific hydrophobic sites in the viral capsid. No other compounds on the market now have the same mechanism of action as Pricanali. Precanali is called 1,2,4-oxo-wow 3_[3,5-dimethyl-4-[3-(3-methyl-5-isoxazolyl)propoxy]phenyl] _5_(trifluoromethyl). It has other names such as PICOVIR®, VP 63843 and Win 63843. Pricanali is a small ribonucleic acid replication inhibitor that is suitable for the treatment of viral-induced upper and lower respiratory tract infections, other diseases, dysentery 141755.doc 201016215 meningitis, and such as chronic meningitis, newborns Life-threatening diseases of intestinal diseases, polio and myocarditis. According to the Merck Index, which is made in accordance with U.S. Patent No. 5,464,848, the disclosure of which is incorporated herein by reference. A Pricanali oral formulation has been developed and clinical trials have been conducted on this oral formulation to demonstrate the ability of Pricanali to reduce the severity and persistence of the common cold symptoms. Plexicon _ relieved the symptoms of colds by 25% less than placebo and achieved the set goals before the m-phase study. 'Pricanali is generally well tolerated in adult patients who have been treated with lozenge formulations for 5 or 7 days; the most reported adverse events are headache (24%), diarrhea (8%), and nausea ( 6%). Asthma exacerbations may be associated with the common cold. Asthma worsens, including coughing, asthma, and shortness of beer. People with asthma exacerbations can cause problems and can be life-threatening.
141755.doc 已研九經口投予之普利康那利（諸如口服錠劑）對哮喘惡 化之預防。在該研究中，在哮喘患者出現普通感冒症狀 後’給予兩種劑型之普利康那利或安慰劑。處理對象1 化為主要終點’其定義為在3週 對象為214歲且FEV1預設值為 其出現普通感冒預示症狀不超過18小 對象參與本研究。普利康那利組與安 點上沒有出現差異。六十三名對象對 且僅5名對象經歷哮喘惡化，其使得 ，確定經口投予的普利康那利對哮喘 201016215 惡化不具有效果。 因此，需要一種能預防咸少 氣夕治療或儘量降低帶有細 小核糖核酸病毒（諸如鼻病毒 ，人t 之人類之哮喘惡化之方法或 組合物。 【發明内容】 已驚奇發現抗病毒活性藥密丨 一 賴在經口吸入或鼻内投予時， 對哮喘症狀具有顯著效果。鞞定 将疋έ之，已發現抗鼻病毒活 ❿ 參 性醫藥活性劑（諸如普利康那利 、 丨⑺）可有效預防、治療、減少 或儘量降低哮喘相關症狀（諸如虚 一病毒性或感冒症狀相關 聯的哮喘惡化）。 一些本發明之實施例提供一 種m療、減少或儘量降低對 鼻病毒呈PCR+患者之哮喘惡化之方法，其包括對患者經 W藥上有效量之㈣康那利。需要諸等治療、減少 或儘量降料喘,β化的Μ患者⑽料具㈣喘惡化病 史或容易出現哮喘惡化之患者。㈣康那利可藉由鼻喷霧 器、氣霧器或加壓計量吸入器或其他任—可接受之遞送裝 置投予。普利康那利之治療上有效量為約i mg至約600 mg 間；約Irng至約100mgfa1 ; m〇mg至約5〇mg間；約職 約30 mg間之量；或約24 。 在本發明之多項實施例中，接受普利康那利治療之對鼻 病毒呈PCR+之患者之哮喘惡化機率比對鼻病毒呈⑽之 患者低三倍。因此，本發明之多種方法可使對 P C R +患者之哮喘惡化機率比對鼻病毒呈p c r _之患者聲低 三倍。 _ 141755.doc 201016215 f、化係由#生精或在哮喘上出現 顯者，化問卷由6個評估白天與夜間域症狀之變化、 急救藥物使用之增加、活力受限的問題組成’· A C Q得分數 亦考慮肺功能之變化（最高流量或Fevi)。 普利康那利可以每曰投予兩次；每鼻孔喷4劑；約15 劑。因此每曰投藥共喷16劑。普利康那利可投予至少7 天或至少14天，亦可每日投予一次或每日兩次。 進-步的實施例提供一種治療、減少或儘量降低對鼻病 毒呈PCR+患者之球喘惡化之方法，丨包括每曰投予兩次 約24 mg之普利㈣利。普利康那利可藉由每鼻孔喷4劑投 〇 更進-步的實施例提供—種治療、減少或儘量降低對鼻 病毒呈PCR+患者之哮喘惡化之方法，其包括對患者經口 吸入投予治療上有效量之普利康那利。需要諸等治療、減 少或儘量降低哮喘惡化的典型患者為彼等具有哮喘惡化病 史或容易出現哮喘,¾化者。普利康那利鼻噴霧劑（作為預 防劑）對哮喘症狀及肺功能具有重要影響。普利康那利可 藉由乾粉吸入器、氣霧器或加壓計量吸入器給予。 用於經口吸入時’每日之普利康那利劑量為約2〇〇 mg至 約5〇〇 mg間；約300 mg至約400 mg間；約350 mg至約450 mg間之量；或約4〇〇 mg。用於經口吸入投予時，普利康那 利可每日兩次或每日三次投予。 夕種其他實施例提供一種治療、減少或儘量降低對鼻病 毒呈PCR+患者之哮喘惡化之方法，其包括由需要該治 141755.doc 201016215 療、減少或儘量降低哮喘惡化之患者經口吸入或經鼻内投 予治療上有效量之抗鼻病毒活性藥劑。該等方法適用於具 有哮喘惡化病史或容易出現哮喘惡化之患者。 本發明之多種實施例將可預防、減少治療或儘量降低 PCR+之對象中與慢性阻塞性肺疾病（c〇pD)相關之症狀或 惡化。 另些實施例提供一種適用於治療、減少或儘量降低對鼻 病毒呈PCR+患者之哮喘惡化之組合物，其中該組合物包 括/α療上有效里之普利康那利，為約1 至約600 間之 1。進一步的實施例提供一種藥品，其包括鼻腔噴霧器、 乾粉吸入器、氣霧器或加壓計量吸入器與該普利康那利組 合物。 有些本發明實施例提供一種治療、減少或儘量降低對鼻 病毋呈PCR+患者之哮喘惡化之方法，其包含投予一種包 括治療上有效量之普利康那利之吸入組合物。人類對象可 _ 能谷易、敏感或具有哮喘惡化病史及/或哮喘惡化。該組 合物可經鼻内或經口吸入。該組合物可於調配物中，其可 藉由鼻腔噴霧器、乾粉吸入器、氣霧器或加壓計量吸入器 投予。普利康那利之含量可在約i mg至約6〇〇 或約2〇〇 ' mg至約400 mg之範圍内。 其他實施例提供一種治療、減少或儘量降低對鼻病毒呈 PCR+患者之哮喘惡化之方法，其包括每日兩次投予包括 治療上有效量（約i mg至約6〇〇 mg間之量）之普利康那利吸 入組合物。進一步的實施例提供一種治療、減少或儘量降 141755.doc 201016215 低對鼻病毒呈PCR+患者之哮喘惡化之方法，其包括每曰 兩次經鼻内吸入投予包括醫藥上有效量（約i mg至約6〇〇 mg間之量）之普利康那利組合物。 又進一步之實施例具有一種治療、減少或儘量降低對鼻 病毒呈PCR+患者之哮喘惡化之方法，其包括每日兩次經 口吸入投予包括醫藥上有效量（約】mg至約6〇〇 mg間之量） 之普利康那利組合物。其他實施例提供一種治療、減少或 儘罝降低對鼻病毒呈PCR+患者之哮喘惡化之方法，其包 括每日兩夂投予吸入組合物，其包括至少7天用量之醫藥 上有效量之普利康那利。 又進-步之實施例提供—種治療、減少或儘量降低對鼻 病毒呈PCR+患者之哮喘惡化之方法，其藉由投予一種吸 入組合物，其包括醫藥上有效量之抗鼻病毒活性藥劑。 另些實施例提供-種適用於治療、減少或儘量降低對鼻 病毒呈PCR+患者之哮喘惡化之組合物，纟包括投予一種 包括治療上有效量（約【mg至約_叫間之量或約_叫 至約400 mg間之量）之普利康那利之吸入組合物。該組合 物可於調配物+，藉由鼻腔喷霧器、乾粉吸入器或 量吸入器投予。 【實施方式】 對比於早期研究，已驚奇發現抗病毒活性㈣在作為吸 入產品投予時，對哮喘症狀具有顯著效果。該抗病毒活性 藥劑可為抗細小核糖核酸病毒劑（諸如抗鼻病毒⑷。特定 言之’已發現抗鼻病毒活性藥劑（諸如普利康那利）可有效 141755.doc 201016215 治療、減少及儘量降低哮 w ^ „ ia M ⑼料“關症狀（諸如與病毒性或感 R症狀相關之哮喘惡化卜 又特疋s之，已發現吸入性普 利康那利適用於預防、洛 之症狀惡化。 減少或儘量降低與哮喘相關 因此’本發明之多種實施例提供一種預防、治療、減少 或儘量降低諸如哮喘惡化之哮喘症狀之方法，其係經口吸 入或經鼻内投予包含治療上有效量之普利康那利之調配 物。141755.doc Pricanali (such as oral lozenges) administered by the Oral Administration has been studied for the prevention of asthma deterioration. In this study, two doses of pricanali or placebo were given after the onset of common cold symptoms in asthmatic patients. Treatment target 1 was converted to the primary endpoint', which was defined as 3 weeks. The subject was 214 years old and the FEV1 default value was that the appearance of the common cold showed no more than 18 small subjects involved in the study. There was no difference between the Precanali group and the security point. Sixty-three subjects and only five subjects experienced asthma exacerbations, which made it clear that oral administration of Pricanali was not effective in the progression of asthma 201016215. Therefore, there is a need for a method or composition that can prevent salty stagnation or minimize the deterioration of asthma with a picornavirus (such as rhinovirus, human t). [Summary] Surprisingly found antiviral active drug secret丨 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在It is effective to prevent, treat, reduce or minimize asthma-related symptoms (such as asthma-associated asthma-associated asthma exacerbations). Some embodiments of the present invention provide a treatment, reduction or minimization of rhinovirus-like PCR+ patients A method for aggravating asthma, which comprises administering an effective amount of (a) Connali to a patient. It is necessary to treat, reduce or reduce asthma, and to treat a patient with phlegm (10) (4) a history of asthma exacerbation or prone to asthma Deteriorating patient. (4) Connelin can be administered by nasal spray, aerosol or pressurized metered-dose inhaler or any other acceptable delivery device. The therapeutically effective amount is between about i mg to about 600 mg; from about Irng to about 100 mg fa1; m 〇 mg to about 5 〇 mg; about 30 mg between about 30 mg; or about 24. In various embodiments of the invention In the case, patients who received Pricanali treatment for rhinovirus with PCR+ had a three-fold lower risk of asthma exacerbation than patients with rhinovirus (10). Therefore, the various methods of the present invention can aggravate the asthma in patients with PCR+ Compared with patients whose rhinovirus is pcr_, the patient's voice is three times lower. _ 141755.doc 201016215 f, the system is produced by #生精生 or in asthma, the questionnaire is composed of 6 assessments of daytime and nighttime symptoms, first aid The increase in drug use and the limitation of vitality constitute '· ACQ scores also take into account changes in lung function (maximum flow or Fevi). Pricanali can be administered twice per sputum; 4 doses per nostril; about 15 doses Therefore, a total of 16 doses are administered per dose. Precanaliril can be administered for at least 7 days or at least 14 days, or once daily or twice daily. The advanced embodiment provides a treatment, reduction or Minimize the side of the rhinovirus with PCR + patients with asthma丨 曰 曰 曰 约 约 约 约 约 约 约 约 约 约 约 约 约 约 约 约 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普 普The virus is a method of PCR + exacerbation of asthma in a patient, which comprises administering a therapeutically effective amount of pricanolide to the patient by oral inhalation. Typical patients who need treatment, reduce or minimize asthma exacerbation are those with a history of asthma exacerbation Or prone to asthma, pricanolide nasal spray (as a prophylactic) has an important effect on asthma symptoms and lung function. Pricanali can be inhaled by dry powder inhaler, aerosol or pressurized metering For daily oral inhalation, the daily dose of pricandine is between about 2 mg to about 5 mg; between about 300 mg and about 400 mg; between about 350 mg and about 450 mg. Amount; or about 4 〇〇 mg. For oral inhalation administration, Pricanali can be administered twice daily or three times daily. Other embodiments provide a method of treating, reducing, or minimizing asthma exacerbation of a rhinovirus in a PCR+ patient, comprising orally inhaling or passing through a patient in need of treatment, reducing or minimizing asthma exacerbations. A therapeutically effective amount of an anti-rhinoviral active agent is administered intranasally. These methods are indicated for patients with a history of asthma exacerbations or prone to asthma exacerbations. Various embodiments of the invention will prevent, reduce, or minimize the symptoms or exacerbations associated with chronic obstructive pulmonary disease (c〇pD) in subjects with PCR+. Still other embodiments provide a composition suitable for treating, reducing or minimizing the exacerbation of asthma in a rhinovirus-inducing PCR+ patient, wherein the composition comprises pl or concanx in a therapeutically effective form, from about 1 to about 600. 1 in between. A further embodiment provides a medicament comprising a nasal nebulizer, a dry powder inhaler, an aerosol or a pressurized metered dose inhaler and the Pricanali composition. Some embodiments of the present invention provide a method of treating, reducing or minimizing asthma exacerbation in a PCR+ patient for rhinorrhea, comprising administering an inhaled composition comprising a therapeutically effective amount of pricanolide. Human subjects can be susceptible, sensitive or have a history of asthma exacerbation and/or asthma exacerbations. The composition can be inhaled intranasally or orally. The composition can be administered in a formulation which can be administered by a nasal nebulizer, a dry powder inhaler, an aerosol device or a pressurized metered dose inhaler. The amount of Pricanaliol may range from about i mg to about 6 或 or from about 2 〇〇 'mg to about 400 mg. Other embodiments provide a method of treating, reducing, or minimizing asthma exacerbation of a rhinovirus in a PCR+ patient comprising administering twice daily, including a therapeutically effective amount (amount between about 1 mg to about 6 mg) Pricanali inhalation composition. A further embodiment provides a method of treating, reducing or minimizing 141755.doc 201016215 low rhinovirus by PCR+ asthma progression in a patient comprising intranasal inhalation administration twice per sputum including a pharmaceutically effective amount (about i mg To a dose of about 6 〇〇 mg of the Pricanali composition. Still further embodiments have a method of treating, reducing or minimizing asthma exacerbation of a rhinovirus in a PCR+ patient comprising administering twice daily oral inhalation comprising a pharmaceutically effective amount (about) mg to about 6 〇〇. The amount of mg of pricandine composition. Other embodiments provide a method of treating, reducing or minimizing the deterioration of asthma in a rhesus virus in a PCR+ patient comprising administering a daily inhaled composition comprising at least 7 days of a pharmaceutically effective amount of a prican Nali. Further embodiments provide a method of treating, reducing or minimizing asthma exacerbation of a rhinovirus in a PCR+ patient by administering an inhalation composition comprising a pharmaceutically effective amount of an anti-river active agent . Still other embodiments provide compositions suitable for treating, reducing or minimizing asthma exacerbation of rhinovirus in a PCR+ patient, comprising administering a therapeutically effective amount (about [mg to about _ called amount or An inhalation composition of Pricanali from about _ to about 400 mg. The composition can be administered to the formulation + by a nasal nebulizer, dry powder inhaler or metered dose inhaler. [Embodiment] Compared with earlier studies, it has been surprisingly found that antiviral activity (4) has a significant effect on asthma symptoms when administered as an inhaled product. The antiviral active agent may be an anti-microRNA virus agent (such as anti-rhinovirus (4). In particular, it has been found that an anti-rhinoactive agent (such as Pricanali) can be effective, 141755.doc 201016215 treatment, reduction and minimization Roar w ^ „ ia M (9) is expected to be “a symptom of asthma (such as asthma associated with viral or sensation of R). It has been found that inhaled Pricanali is suitable for prevention, and the symptoms of Luo are worse. Minimizing associating with asthma therefore 'a variety of embodiments of the present invention provide a method of preventing, treating, reducing or minimizing asthma symptoms such as asthma exacerbation by oral inhalation or intranasal administration comprising a therapeutically effective amount The formulation of the Concanali.
❷ 可根據本發明治療之族群包含12歲及以上、6歲及以上 之對象以及小於6歲之對象。本發明之多種實施例亦用於 成人及孩童之普通感冒。 本發明之多種實施例可用於預防、減少治療或儘量降低 與普通感冒相關之哮喘惡化。 希望本發明多種實施例可以預防、減少治療或儘量降低 PCR+對象中與慢性阻塞性肺疾病（c〇pD)相關之症狀或惡 化。 有效治療療程包括每日投藥一次或每日投藥兩次。洽療 時間可依需要持續延長’諸如至少3天、至少5天、至少7 天、或約5天或約7天或約1〇天或約14天。一種投藥療程可 為每日兩次（BID)持續7至14天或7天。 本發明之多種實施例有利於減少應用到急救療法、減少 醫生與急診室患者、改善哮喘控制及減少住院患者。 普利康那利可依每日單劑量或多劑量投予約1 mg至約 600 mg之量。 141755.doc 201016215 經口吸入時，每曰之普利康那利劑量可為約2〇〇 至約 5〇〇 mg ;約300 mg至約400 mg ;約35〇叫至約45〇叫之 量；或約400 mge經口吸入投予時，普利康那利可每日投 予兩次或每日投予三次。適用的經卩投藥裝置包含乾粉吸 入器（DPI)、計量吸入器（MDI)或氣霧器。 經鼻内投予時，每日之普利康那利劑量為丨mg至約1〇〇 mg ;約10 mg至約50 mg ;約20至約30 mg之量；或約24 mg。普利康那利可以每曰投予兩次；每鼻孔噴4劑；if mg/劑。因此每曰共喷16劑。 短語「治療上有效量」意指普利康那利與一或多種活性 藥劑之量’該用量可提供㈣或處理疾病或疾病狀態之治 療益處。 術語「患者」意指可能接受活性藥劑（諸如普利康那利） 投予之任一對象，且並未限於可能患有疾病或表現其症狀 之對象。 可使用多種劑型。劑型指以定計量或單位量提供組合物 之投藥形式，且包括至少一種治療劑與一種或多種包括遞 送系統（例如載劑、稀釋劑、及著色劑）之其他賦形劑。劑 型之實例包含凝膠、鼻喷霧劑、鼻滴劑、乳霜、粉末、供 吸入之定計量之氣霧劑、及定計量之液體。 可伴隨使用選自氣霧器、計量泵喷霧裝置、乾粉吸入器 與加壓計量吸入器之裝置進行投予。可選用單—加壓計量 吸入器，藉由簡單轉換一個設計用於經鼻遞送與設計用於 、-星口遞送之啟動器，用於經鼻内吸入途徑。遞送普利康那 141755.doc 201016215 利之農置類型將依目標吸入劑之類型決定。適用之裝置需 要提供計量一致之氣霧化醫藥組合物，供經口或鼻吸入遞 送至口腔呼吸道及肺部。 可使用任一適宜的泵喷霧器，諸如用於Schering_P1〇ugh 公司出售的NASONEX®及Schering-Plough公司出售的 AFRIN®的泵喷霧器。水性組合物（諸如彼等適用於鼻嘖霧 益）可特別含有水、輔劑及/或一種或多種賦形劑（諸如：懸 浮劑’例如微晶纖維素、羧曱基纖維素鈉、羥丙基甲基纖 維素；保濕劑，例如甘油與丙二醇；調節pH之酸、驗或緩 衝基質，例如檸檬酸、檸檬酸鈉、磷酸、磷酸鈉以及檸檬 酸鹽與磷酸鹽緩衝劑之混合物；表面活性劑，例如聚山梨 酸80 ;及抗微生物防腐劑，例如氣苄烷銨、苯乙醇及山梨 酸卸。） 適用之裝置包括加壓計量吸入器（「MDI」），其遞送含 或不含其它賦形劑且懸浮於諸如CFC-11、CFC-12之氤氣 化碳推進劑或諸如氟化碳、HFC-134A或HFC-227之非氤氯 化碳或替代性推進劑之氣霧化顆粒。如熟悉此技術者已 知，此產品可含有兩個可互換啟動器。例如，其可含有一 個用於，經鼻内投予之啟動器及—個肖於經口投予之啟動 器。 在本發明的另一實施例中，遞送裝置可包括兩個分利用 於，二口及經鼻内遞送之可互換啟動器，以治療口與鼻兩個 有病母活性之位點β典型用於經鼻内遞送之啟動器可岛帶 有直钇、力1毫米開口的圓盤。用於經口遞送之啟動器可進 141755.doc 201016215 入口中，且該啟動器通常具有直徑約〇·5毫米之開口。 適用的調配物亦可經由乾粉吸入器投予，諸如Schering_The group to be treated according to the present invention comprises a subject 12 years of age and older, 6 years of age or older, and a subject younger than 6 years old. Various embodiments of the invention are also useful for the common cold of adults and children. Various embodiments of the invention can be used to prevent, reduce, or minimize the progression of asthma associated with the common cold. It is expected that various embodiments of the invention may prevent, reduce, or minimize the symptoms or deterioration associated with chronic obstructive pulmonary disease (c〇pD) in PCR+ subjects. Effective treatments include daily dosing or twice daily. The duration of the treatment may be extended as needed, such as at least 3 days, at least 5 days, at least 7 days, or about 5 days or about 7 days or about 1 day or about 14 days. One medication regimen can be twice daily (BID) for 7 to 14 days or 7 days. Various embodiments of the present invention are useful for reducing the application to first aid therapy, reducing physician and emergency room patients, improving asthma control, and reducing hospitalization. Precanaliril can be administered in a single or multiple doses of from about 1 mg to about 600 mg per day. 141755.doc 201016215 When inhaled by mouth, the dose of pricanolide per sputum may be from about 2 〇〇 to about 5 〇〇 mg; from about 300 mg to about 400 mg; from about 35 〇 to about 45 〇; When administered orally by about 400 mge, Pricanali can be administered twice daily or three times daily. Suitable warp-administered devices include dry powder inhalers (DPI), metered dose inhalers (MDI) or aerosols. For intranasal administration, the daily dose of pricanolide is from 丨mg to about 1 mg; from about 10 mg to about 50 mg; from about 20 to about 30 mg; or about 24 mg. Pricanali can be administered twice per sputum; 4 doses per nostril; if mg/dose. Therefore, a total of 16 doses per sputum. The phrase "therapeutically effective amount" means the amount of Pricanaliol and one or more active agents' that provides (d) or treats the therapeutic benefit of a disease or condition. The term "patient" means any subject to whom an active agent (such as Pricanali) may be administered, and is not limited to a subject who may have a disease or exhibit symptoms thereof. A variety of dosage forms are available. Dosage form refers to a form of administration that provides a composition in a given amount or unit quantity, and includes at least one therapeutic agent with one or more additional excipients including delivery systems (e.g., carriers, diluents, and colorants). Examples of dosage forms include gels, nasal sprays, nasal drops, creams, powders, aerosols for metered inhalation, and metered amounts of liquid. Administration can be carried out using a device selected from the group consisting of an aerosolizer, a metering pump spray device, a dry powder inhaler, and a pressurized metered dose inhaler. A single-pressure metered-dose inhaler can be used for the intranasal inhalation route by simply switching one of the actuators designed for nasal delivery and design for use in Star-to-Star delivery. Delivery of Preconna 141755.doc 201016215 The type of agricultural use will be determined by the type of target inhaler. Applicable devices require a metered, aerosolized pharmaceutical composition for oral or nasal inhalation for delivery to the oral respiratory tract and lungs. Any suitable pump sprayer can be used, such as the NARIN®® sold by Schering_P1〇ugh and the AFRIN® pump sprayer sold by Schering-Plough. Aqueous compositions, such as those suitable for nasal mist, may especially contain water, adjuvants and/or one or more excipients (such as suspending agents such as microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxy a propylmethylcellulose; a humectant such as glycerin and propylene glycol; an acid, pH or pH-adjusting substrate such as citric acid, sodium citrate, phosphoric acid, sodium phosphate, and a mixture of citrate and phosphate buffer; Active agents such as polysorbate 80; and antimicrobial preservatives such as benzalkonium chloride, phenylethyl alcohol and sorbic acid.) Suitable devices include pressurized metered dose inhalers ("MDI") with or without delivery Other excipients and suspended in a gasified carbon propellant such as CFC-11, CFC-12 or a non-tantalum chloride or alternative propellant such as carbon fluoride, HFC-134A or HFC-227 Particles. As is known to those skilled in the art, this product can contain two interchangeable actuators. For example, it may contain an actuator for intranasal administration and an actuator for oral administration. In another embodiment of the present invention, the delivery device can include two separate, two-port and intranasal delivery interchangeable actuators for treating both the oral and nasal sites of diseased activity β. The starter delivered intranasally can have a disc with a straight, 1 mm opening. The actuator for oral delivery can be placed in the inlet of 141755.doc 201016215, and the actuator typically has an opening of about 〇·5 mm in diameter. Suitable formulations can also be administered via a dry powder inhaler, such as Schering_
Plough公司之TWISTHALER®且其已描述於us 6,240,918 中，其全文係以引用的方式併入文中。 適用的調配物亦可經由氣霧器裝置投予。典型的可講得 的喷霧器裝置商品藉由兩種方法之一產生含在氣流中之分 散液滴。噴射氣霧器使用壓縮空氣源，藉由文丘里作用 (venturi action)吸引液體並引入流動氣流中，其後導致液TWISTHALER® of Plough Corporation and which is described in US 6,240,918, the entire disclosure of which is incorporated herein by reference. Suitable formulations can also be administered via an aerosol device. A typical negligible nebulizer device produces a discrete droplet contained in a gas stream by one of two methods. The jet aerosolizer uses a source of compressed air to attract liquid and introduce it into the flowing gas stream by a venturi action, which then leads to a liquid
體撞擊一或多個固定擋板來排除過大液滴。超音波氣霧器 使用電動轉換器，促使液體以高頻率震盪，產生可被夾帶 在移動氣流中的液滴喷霧；此等裝置較不適合遞送懸浮 液。有一種利用擠壓球供應空氣來霧化液體的手持式噴霧 器，但更廣泛使用的設備係併人—種電動壓縮器或與壓縮 氣體氣瓶相連。雖然可自商品購得之多種裝置對於特定醫 藥物之遞送效率上有極大變化，但其均適用於本發明之治 療法；因其各自送出的可吸人液滴之喷出量極不—致，: 處方中必需明確指出裝入每一特定裝置的醫藥調配物之精 適於氣霧器的懸浮液調配物含有可吸人粒徑之固體顆粒 (例如較佳為最大粒徑平均小於約5微米且更佳平均小 2微米）且最好在儲藏期間維持其懸浮粒度分佈。此外，、在 調配物氣霧化_形成的含顆粒液滴需具有適於在 吸系統區域沉積的大小。 而吁 亦可私用擠壓球供應空氣氣霧化液體的手持式氣霧器， 141755.doc -12· 201016215 但更廣泛適用的設備採用電動壓縮器或與壓縮空氣氣瓶相 連。雖然可自商品講得之多種裝置對某特定藥物的遞送效 率上有極大變化（因其分料出的可吸人液滴噴出量極不 -致），但若處方明確指明裝入每一特定裝置之醫藥調配 物之精確量時’任-種均可用於遞送本發明之藥物。 適於加至本發明多種實施例的組合物中之藥物包括但不 限於：抗病毒藥物、抗組胺藥物(諸如組胺Hi、Η:、％受 體拮抗劑）、祛痰劑、非類固醇消炎藥、抗膽驗能藥物， 醫藥上可接受之鋅鹽、抗生素、白三婦h拮抗劑、白三稀 抑制劑、P2Y激動劑、syk激酶類似物、紫錐花、維支素 =、、及維生素E。例如，調配物可含有㈣康那利與解充血 藥或皮質類固酵。含其他活性藥劑之普利康那利可同時或 先後投予，例如彼等可同時聯合投予，或可經依適宜順序 先後投予該等成份。 U防腐劑、抗氧化劑 '螯合劑及芳香物質，,、〜, (諸如甘油、聚乙-赔々廿 ' m 醇或其他二醇類、多醣類等 料）可抑制水從組合物散失，及亦增加濕濁品質。可用、= 芳香：質包含掉腦、薄荷醇、按樹腦等、及香料。通:: 入防腐劑，以確定及保持遠離病原菌；代表性組分包括苯 甲醇、對羥基苯甲酸 甲酸丁〜丁醇二= 本甲酸丙醋，基苯 酸果和队、亦為香料添加劑）、苯基醋 &述之本發明之多種實施例係本發明多種態樣之代表， 該組合物可含有任何數量之視需要選用的組分，諸如保 ❹ 保濕劑 141755.doc -13- 201016215 '、豸或限制所揭不的精確形式。熟悉此技術者將毫 :疑問地可進行多種㈣與改變。希望本發明之範圍將僅 受到所附請求項之限制。 實例 以下實例證實當普利康那利經吸入投予PCR+對象時之 7驚奇的適用性。本試驗之目標終點為在接觸感冒後之 預防乂減v成人與兒童（6歲及以上）的哮喘惡化發生率。 進行概念-驗證研究，在過去兩年中推定曾有上呼吸道 感染（腿)所誘發哮喘惡化病史之哮喘對象中評估含有普 利康那利的鼻喷霧劑。本研究之主要目的為評估普利康那 利鼻喷霧劑預防哮喘對象之哮喘惡化與普通感冒症狀之效 力’該哮喘對象已接觸過已出現與細小核糖核酸病毒呼吸 感染一致之症狀之家庭成員。 總共311名對象隨機分佈至本研究中〇54名普利康那利 組，及157名安慰劑組）；129名男性與182名女性丨年齡6 至65歲。對象在夏季/秋季當其無症狀時參與研究，隨後 直到他們接觸到有感冒症狀之家庭成員。一旦接觸到，對 象即隨機分佈成藥物組或安慰劑組，他們早已擁有藥物且 因此能立即開始使用普利康那利鼻噴霧劑。該普利康那利 鼻喷霧劑具有約1.5 mg/噴劑。每一對象每日接受兩次；每 鼻孔喷4劑之普利康那利投藥。因此，每天共噴16劑及投 予約24 mg之普利康那利。 哮喘惡化率係由醫生改變哮喘療程或ACq(哮喘控制調 查問卷）得分數之顯著變化之來界定。亦測定對象對鼻病 141755.doc •14- 201016215 毒呈PCR+或PCR-。 對於下呼吸道病症，患者之疾病狀態嚴重度可藉由客觀 肺功能測試定量，其包括測定對象在1秒内之用力呼氣流 量（FEV!)。當結果為預定值（使用考慮患者年齡、性別、 種族及體積之公式測定）之約65至79%時，呼吸道阻塞程度 視為溫和。若FEVi值為預定值之50至64%時，呼吸道阻塞 則視為中度；如果該值低於預定值之50%，則呼吸道阻塞 視為嚴重；且如果該值低於3〇%，則呼吸道阻塞視為非常 ❹ 嚴重。 結果 當評估所有隨機處理之患者後，在哮喘症狀與肺功能方 面觀察到組間差異。在兩個處理組中，在每個測定時間點 均測得FEV1減少。但在每個時間點，普利康那利經的 FEV1減少程度比安慰劑組低。FEvi的最大差異出現於第4 天（普利康那利組1.5%及安慰劑組51%，p=〇 〇35)，參 示 1-3。 在鼻病毒PCR+對象中觀察到最大效力。特定言之該 PCR陽性之普利康那利處理組對象的哮喘惡化程度較低。 更特疋5之，對鼻病毒呈PCR+之普利康那利處理組對象 出現哮喘惡化之機率比對鼻病毒呈孤之患者小三倍。 普利康那利鼻喷霧劑對哮喘症狀及肺功能具有顯著影 :特疋^之，用於預防投藥之普利康那利鼻喷霧劑對哮 而症狀及肺功能尤其昇有顯著影響。較之安慰劑，普利康 j可改善哮％症狀及肺功能。在不考慮普利康那利對感 141755.doc -15, 201016215 冒症狀之效；/7 Τ 季節期間)，對C效力。在秋季(鼻病毒高峰 且耐受性良好。研究 利康那利鼻喷㈣ _九顯TF以曰 能影響。 ， ' 可顯著降低哮喘症狀與肺功 【圖式簡單說明】 圖1 FEV1從基線變化； 圖2哮喘症狀總分；及 圖3PCR+與PCR-對象之哮喘惡化。 141755.docThe body impacts one or more fixed baffles to remove excessive droplets. Ultrasonic Aerosols Use electric transducers to motivate liquids to oscillate at high frequencies, creating droplet sprays that can be entrained in moving air streams; these devices are less suitable for delivering suspensions. There is a hand-held sprayer that uses a squeeze ball to supply air to atomize the liquid, but the more widely used equipment is either an electric compressor or a compressed gas cylinder. Although a variety of devices commercially available from a commercial product vary greatly in the efficiency of delivery of a particular pharmaceutical product, they are all suitable for use in the treatment of the present invention; ,: It must be clearly stated in the formulation that the suspension formulation suitable for the aerosol formulation of the pharmaceutical formulation loaded into each particular device contains solid particles of inhalable particle size (for example, preferably the maximum particle size is less than about 5 on average). Micron and more preferably on average 2 microns) and preferably maintains its suspended particle size distribution during storage. In addition, the particle-containing droplets formed during aerosolization of the formulation need to have a size suitable for deposition in the area of the suction system. A hand-held aerosol device that can also be used to supply air-atomized liquid with a squeeze ball, 141755.doc -12· 201016215 But the more widely applicable equipment uses an electric compressor or is connected to a compressed air cylinder. Although the delivery efficiency of a particular drug can vary greatly from a variety of devices that can be derived from a product (since the amount of smearable droplets that are dispensed is extremely unacceptable), if the prescription clearly indicates the loading of each specific The precise amount of the pharmaceutical formulation of the device can be used to deliver the medicament of the present invention. Drugs suitable for addition to the compositions of the various embodiments of the invention include, but are not limited to, antiviral drugs, antihistamines (such as histamine Hi, sputum:, % receptor antagonists), expectorants, non-steroids Anti-inflammatory drugs, anti-cholinergic drugs, pharmaceutically acceptable zinc salts, antibiotics, white women's h antagonists, leukotriene inhibitors, P2Y agonists, syk kinase analogs, echinacea, vegetative = And vitamin E. For example, the formulation may contain (iv) concanal and decongestant or corticobacteria. Pricanaliol containing other active agents may be administered simultaneously or sequentially, for example, they may be administered simultaneously, or may be administered sequentially in a suitable order. U preservatives, antioxidants 'chelating agents and aromatic substances,, ~, (such as glycerin, polyethylidene-m-alcohol or other glycols, polysaccharides, etc.) can inhibit the loss of water from the composition, It also increases the wet turbidity quality. Available, = Aromatic: The quality includes brain, menthol, tree brain, etc., and spices. Pass: Preservatives to determine and keep away from pathogenic bacteria; representative components include benzyl alcohol, butylparaben-butanol = propyl acetonate, benzoic acid fruit and team, also a spice additive) Phenyl vinegar & various embodiments of the invention are representative of various aspects of the invention which may contain any number of optional components such as moisturizing humectants 141755.doc -13- 201016215 ', 豸 or limit the exact form that is not revealed. Those who are familiar with this technology will be able to make a variety of (four) and changes in doubt. It is intended that the scope of the invention be limited only by the appended claims. EXAMPLES The following examples demonstrate the surprising applicability of Pricanali when administered by inhalation to PCR+ subjects. The target end point of this trial was the prevention of deafness after exposure to a cold. The incidence of asthma exacerbations in adults and children (age 6 and older). A concept-validation study was conducted in which a nasal spray containing Pricanali was evaluated in asthmatic subjects who had been presumed to have a history of asthma exacerbations induced by upper respiratory tract infections (legs). The primary objective of this study was to evaluate the efficacy of Pricanali nasal spray in preventing asthma exacerbations and common cold symptoms in asthmatic subjects. The asthma subject has been exposed to family members who have developed symptoms consistent with picornavirus respiratory infections. A total of 311 subjects were randomly assigned to the study, 54 in the Pricanali group, and 157 in the placebo group; 129 men and 182 women, aged 6 to 65 years. Subjects participated in the study in the summer/autumn when they were asymptomatic, and then they were exposed to family members with symptoms of a cold. Once contacted, the subjects were randomly distributed into a drug or placebo group, and they already had the drug and were able to start using the Pricanali nasal spray immediately. The Pricanali nasal spray has about 1.5 mg/spray. Each subject received twice daily; 4 doses of Pricanali were administered per nostril. Therefore, a total of 16 doses per day and about 24 mg of pricanali were administered. The rate of asthma exacerbation is defined by a significant change in the number of doctors changing the course of asthma or the ACq (Asthma Control Survey Questionnaire). The subject is also tested for nasal diseases. 141755.doc •14- 201016215 Toxicity is PCR+ or PCR-. For lower respiratory tract conditions, the severity of the patient's condition can be quantified by an objective lung function test that includes the amount of forced expiratory flow (FEV!) within 1 second of the subject. When the result is about 65 to 79% of a predetermined value (determined using a formula that takes into account the patient's age, gender, race, and volume), the degree of airway obstruction is considered mild. If the FEVi value is 50 to 64% of the predetermined value, the airway obstruction is considered moderate; if the value is less than 50% of the predetermined value, the airway obstruction is considered serious; and if the value is less than 3〇%, then Airway obstruction is considered very serious. Results After all randomly treated patients were evaluated, differences between groups were observed for asthma symptoms and lung function. In both treatment groups, a decrease in FEV1 was measured at each measurement time point. However, at each time point, the rate of FEV1 reduction in the Precanic group was lower than in the placebo group. The largest difference in FEvi occurred on day 4 (1.5% in the Pricanali group and 51% in the placebo group, p=〇 〇 35), 1-3. Maximum efficacy was observed in rhinovirus PCR+ subjects. Specifically, the PCR-positive Pricanali treatment group had a lower degree of asthma exacerbation. More specifically, in the Pricanali treatment group with rhinovirus-like PCR+, the risk of asthma exacerbation was three times smaller than that of patients with rhinovirus. Precanali nasal spray has a significant effect on asthma symptoms and lung function: 普 之 , , , , , , , , , , , , , , , , , , , 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Compared with placebo, Prican j can improve the symptoms of snoring and lung function. Do not consider the effect of Pricanali on 141755.doc -15, 201016215; /7 Τ season period), work for C. In the fall (the rhinovirus peaks and is well tolerated. Studying the Concanali nasal spray (4) _ nine TF can affect the sputum. , ' can significantly reduce asthma symptoms and lung function [simplified diagram] Figure 1 FEV1 changes from baseline Figure 2 Total score of asthma symptoms; and Figure 3 PCR+ and PCR-substances asthma worsening. 141755.doc