TW201212907A - Inhaled combination product for asthma - Google Patents

Abstract

An inhalant pharmaceutical composition containing primary active ingredients of beta2-agonist and corticosteroids is provided. The pharmaceutical compositions disclosed in the present invention is to be inhaled by a patient when needed as a reliever, or administrated in an eccentric way as a controller. The eccentric way control therapy could create a low blood concentration period during the day and minimize the acute tolerance phenomenon (or so called tachyphylaxis) for bronchodilator-beta2-agonists in treating asthma or other obstructive respiratory disorders.

Description

201212907 六、發明說明： I發明所屬之技術領域] 本發明係關於一種複方組合物，特別關於一種包含 吸入性皮質類固醇搭配乙二型協同劑之複方組合物。 【先前技術】 傳統上以吸入性劑型治療氣喘（Asthma)或慢性肺 阻塞（Chronic Obstructive Pulmonary Disease，COPD)為 較佳之選擇’因為用藥量低病人身體負擔較低。常用之 吸入性劑型藥物包括皮質固醇類（corticosteroids)、乙二 型協同劑（beta-2 agonists)、抗乙醢膽鹼藥物 (anticholinergics)，或是上述藥物組成之複方。 市售之吸入性皮質類固醇藥物，包括有氟替卡松丙酸 酯（Fluticasone propionate)、布***（Budesonide)、環 索奈德（Ciclesonide)、糠酸莫美他松（Momethasone fiiroate)亦稱為 Mometasone、丙酸倍氯米松 (Beclomethasone dipropionate)、丙酮去炎松 (Triamcinolone acetonide)以及替潑尼旦（Tipredane)等。 乙二型交感神經興奮劑（beta2 agonists)或稱為乙 二型協同劑，市售之乙二型協同劑（β2 agonists)包括硫 酸阿布叔醇（Albuterol sulfate)或稱硫酸沙丁胺醇 (Salbutamol sulphate)、鹽酸普魯卡地魯（Procaterol hydrochloride)、菲諾特洛氫溴酸鹽 （Fenoterol hydrobromide)、鹽酸瑞普特羅（Repr〇teiOl hydrochloride)、服莫喘（Formoterol)、、硫酸特布他林 (Terbutaline sidphate)、沙美特羅昔萘酸酯（Salmeterol xinafoate) ° 201212907 其中Formoterd'Sahnet—為長效型乙二型 (LABA^Long acting beta2 agonists) ’ 作用時間長 時，必須合併吸入型類固醇，用於改善中度持續到重度 持續氣喘病患之症狀及肺功能《單獨長期使用，與短效 乙二型協關細_-樣，均已被證實對病人病情不 利。故不適宜單獨運用於治療氣喘病。因其本身抗發炎 之作用不強，單獨使用僅能短暫緩解症狀.，但長期會遮 蔽氣道之發炎症狀，導致氣喘更不昜控制之嚴重後果。201212907 VI. INSTRUCTIONS: TECHNICAL FIELD OF THE INVENTION The present invention relates to a combination composition, and more particularly to a combination composition comprising an inhaled corticosteroid in combination with an ethylene-type synergist. [Prior Art] It has been conventionally preferred to treat asthma (Asthma) or Chronic Obstructive Pulmonary Disease (COPD) with an inhaled dosage form as a preferred option because the patient has a low physical burden. Commonly used inhaled dosage forms include corticosteroids, beta-2 agonists, anticholinergics, or a combination of the above. Commercially available inhaled corticosteroids, including Fluticasone propionate, Budesonide, Ciclesonide, Momethasone fiiroate, also known as Mometasone, Beclomethasone dipropionate, Triamcinolone acetonide, and Tipredane. Beta agonists or beta-type synergists, and commercially available beta agonists include Albuterol sulfate or Salbutamol sulphate. Procaterol hydrochloride, Fenoterol hydrobromide, Repr〇teiOl hydrochloride, Formoterol, terbutaline sulfate Terbutaline sidphate), Salmeterol xinafoate ° 201212907 where Formoterd'Sahnet—Larse acting beta2 agonists' must be combined with inhaled steroids for long periods of time To improve the symptoms and lung function of patients with moderate to severe persistent asthma, "long-term use alone, and short-acting type B-type associations have been confirmed to be unfavorable to the patient's condition. Therefore, it is not suitable for the treatment of asthma alone. Because its anti-inflammatory effect is not strong, it can only relieve symptoms for a short time. However, it will mask the symptoms of inflammation of the airway for a long time, which may cause serious consequences of asthma control.

Fenotercl' Aalbutercl、Terbutaline 或 Procaterol 等屬Genus Fenotercl' Aalbutercl, Terbutaline or Procaterol

於短中效快速作用β2_乙二型協同劑，作用時間約3至& 小時或4至8小時，臨床應用主要是單方用於緊急氣管 收縮症狀之快速解除，有需要時可一日使用三至四次。 先技術上’雖然本國200303767公開號揭示福莫特羅 (Formoterol)之超微細配方係含有0.003_0 192〇/〇 w/v間之 (R，RH±>福莫特羅反丁烯二酸鹽，專利第329387號揭示 之含單方摩美他松（Mometasone)糠酸鹽之治療呼吸道 及肺部疾病之醫藥組合物。大陸CN1305380公告號揭示 含有福莫特羅和布***組合物在預防和治療急性氣喘 疾病中之應用。美國專利第5,972,919號揭示，含有效量 活性Formoterol與Budesonide成分之摩爾比例為 1:4〜1:70。美國專利第 6,932,962 號、6,799,572 號、 6,638,495 號、6,962，151 號、7,321,059 號，已經揭示有 關吸入性固醇類（inhaled corticosteroids)藥物之複方， 包括選用 Budesonide、Fluticasone、Mometasone、Rapidly acting as a short-acting and moderate-acting β2_B-type synergist, the action time is about 3 to & hours or 4 to 8 hours. The clinical application is mainly for the rapid release of emergency tracheal contraction symptoms, and can be used once a day if necessary. Three to four times. Technically 'Although the National Publication No. 200303767 discloses that the ultrafine formulation of Formoterol contains between 0.003_0 192 〇/〇w/v (R, RH±> formoterol fumaric acid Salt, a pharmaceutical composition containing unilateral mometasone citrate for the treatment of respiratory and pulmonary diseases disclosed in Patent No. 329387. The mainland CN1305380 announcement number reveals the use of formoterol and budesonide in the prevention And in the treatment of acute asthmatic diseases. U.S. Patent No. 5,972,919 discloses a molar ratio of effective amount of active Formoterol to Budesonide components of 1:4 to 1:70. U.S. Patent Nos. 6,932,962, 6,799,572, 6,638,495, 6,962, No. 151, No. 7,321,059, has revealed a combination of inhaled corticosteroids, including Budesonide, Fluticasone, Mometasone,

Beclomethasone、Ciclesonide等固醇類，乙二型交感神經 接受體興奮劑（beta-2 agonists)選用如Fenoterol、 Albuterol、Procaterol、Salmeterol 及 Formoterol 等藥物。 而美國專利第 7,244,742 號、7,481,995、6,596,261 號， 201212907 更揭示吸入性固醇類搭配乙二型協同劑藥物之複方内添 加Ipratropium之抗乙醢膽鹼藥物（Anticholinergics)，但 W 所論及的，都是製劑學上的技術，而非本發明所欲揭示 、 的利用藥物作用時效、劑量、用法上組合變化，來改善 臨床治療效能。Beclomethasone, Ciclesonide and other steroids, beta-2 agonists use drugs such as Fenoterol, Albuterol, Procaterol, Salmeterol and Formoterol. U.S. Patent Nos. 7,244,742, 7,481,995, 6,596,261, and 201212907 disclose the addition of Ipratropium anticholinergic drugs to a combination of inhaled steroids and an ethylene-type synergistic drug, but all of them are discussed by W. It is a medicinal technique, rather than a combination of aging, dose, and usage changes of the drug to be disclosed in the present invention to improve clinical therapeutic efficacy.

Austria等人，揭示臨床上對於7〜18歲經常性氣喘 病患併用 Procaterol 與 Budesonide (Chest，2005)，以口 服Procaterol添加低劑量或高劑量吸入性Budesonide之 控制療法（Control therapy)，可改善病情，唯患者數量太 鲁 少’兩組之間無差異。另外，曰本2010年4月14曰揭 示以 Procaterol 吸入液 15 或 30 meg 與 Budesonide 吸 入懸浮液.250 meg併用於氣霧機’一日2次治療一週後 改用單方Budesonide治療經常性青少年氣喘病。上述兩 種呼吸治療方式，係運用口服乙二型協同劑藥物搭配吸 入性皮質固醇類藥物’或兩種藥物以氣霧機（nebulizer) 產生連續氣霧的治療案例，與本發明之複方定量喷霧吸 士劑或乾粉吸入劑不同。其間以氣霧機配吸入液之給 藥方式，病患每次需吸入藥物達1〇〜15分鐘，所給予病 鲁患之藥物量，與口服投藥所投與藥物劑量，遠高於定量 喷霧劑或乾粉吸入劑之投藥劑量，且為一曰2次均等式 控制療法，與本發明偏極性控制療法(eccentric 所提供之較低及一日内不均等之藥物血中濃度不同。 涉及氣喘及慢性阻塞性肺病（C〇PD)之呼吸道疾 病’係隨著社會都市化所帶來之環境污染問題，此類呼 吸道疾病已成為全球化之主要疾病之一。許多研究結 果，顯示氣喘死亡率之居高不下，與低診斷率及治療不 ，有關。世界衛生組織和美國國家衛生院於1993年遨請 軋而專豕研讨防治軋喘之道，組成全球氣喘創議組織 201212907 (Global Initiative for Asthma^ GINA)理事會之經常性組 織。每間隔幾年該組織根據醫療證據.，隨著臨床之新# 據不斷更新治療觀念，撰寫氣喘診治之最新指引.，= 國醫護人員參考。 目前GINA之治療準則係採取階梯式上下調整之 治療觀念，亦即依據病情，調整增減劑量方式以掌控 患之狀況： " 1. 最輕微之第一級病人： 僅於發作時，給與短效快速作用之乙二型協同 劑（Pragonist)以解除症狀； 2. 第二級輕度病人： 曱、控制治療：給與a.低劑量之吸入性皮質類 固醇藥物或b.白三稀抑制劑。 、 乙、解除症狀:發作時給與短效快速作用之乙二 型協同劑（P2-agonist); 3. 第三級中度病人： 甲、控制，療:：選擇投與a/‘低劑量吸入性皮質 ，固醇藥物搭配長效乙二型協同劑”、b.中 南劑量吸入性皮質類固醇藥物、c•“低劑量吸 入，皮質類固醇藥物搭配白三烯抑制劑，，或 d•低劑量吸入性皮質類固醇藥物搭配長效 性茶鹼，，。 乙、_解除症狀：發作時給與短效快速作用之乙 一型協同劑 ®2-agonist); 4. 第四級重度病人： 甲、控制治療：選擇給與a. “中高劑量吸入性 皮^類固醇藥物搭配長效乙二型協同劑”、b. 白三缔抑制劑、c.長效茶鹼或選擇性投與其 201212907 中2種。 乙、解除症狀：發作時給與短效快速作用之乙 二型協同劑（P2-agonist); 5.第五級的嚴重急性發作： 曱、控制治療：第四級控制治療藥物加入口服 皮質類固醇藥物或抗IgE免疫療法， 乙、解除症狀：發作時給與短效快速作用之乙 二型協同劑（p2-agonist);。 由文獻資料可知’雖然乙二型協同劑具有擴張氣管 之作用’但無論呈現短效或長效作用藥物，均不建議單 獨做為病人慢性控制治療藥物。主要原因係以高劑量高 頻率單獨地使用此類藥物時，會導致病人產生急性耐藥 性（Tachyphylaxis)現象，使病人需快速增加劑量，來達 成同樣的控制效果，或有時會用藥時無效，甚至於病症 更容易發作，因此增加病患之急性發作比率、住院率及 死亡率。 一般認為乙二型協同劑，顯現急性财藥性之機制， 係β2接受體之快速向下調節（β2 recept〇r down regUiati〇n) 所致。另已知某些基因型病患，在乙二型協同劑之療程 中，較易顯現急性而f藥性之發作。而吸入性皮質類固醇 藥物’因呈現部份反制02接受體快速向下調節之能力， 所以，目前將吸入性皮質類.固醇藥物搭配藥效12小時以 上的長效乙二型協同劑的，，複方組合物，，，係主要治療氣 喘之組合物，例如Budesonide搭配Formoterol fumarate > Fluticasone propionate 搭配 Salmeterol xinafoate，Fluticasone propionate 搭配 Formoterol fiini3rate ’ Ciclesonide 指'配 F ormotcrol fiunarstc y 201212907Austria et al., revealed that clinically controlled asthma patients with 7 to 18 years of age with Procaterol and Budesonide (Chest, 2005) with low-dose or high-dose inhaled Budesonide in oral Procaterol can improve the condition. Only the number of patients is too small. There is no difference between the two groups. In addition, 曰 4 4 4 4 4 4 4 4 4 Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro . The above two methods of respiratory therapy are treatment cases in which a continuous aerosol is produced by using an oral inhaled corticosteroid or an inhaled corticosteroid or both drugs, and a compound aerosol of the present invention. Spray suction or dry powder inhalation is different. In the meantime, the aerosol machine is equipped with the inhalation solution, and the patient needs to inhale the drug for 1 to 15 minutes each time, and the amount of the drug to be administered to the patient is compared with that of the oral administration. The dosage of the aerosol or dry powder inhaler, and is a one-time equal-ordination control therapy, which is different from the blood concentration of the drug of the present invention, which is lower in eccentric and less unequal in one day. Respiratory diseases of chronic obstructive pulmonary disease (C〇PD) are environmental pollution problems caused by social urbanization. These respiratory diseases have become one of the major diseases of globalization. Many studies have shown that asthma mortality High in the world, related to low diagnostic rate and treatment. The World Health Organization and the National Institutes of Health in 1993 invited the company to specialize in the prevention and treatment of asthma, forming a global asthma initiative 201212907 (Global Initiative for Asthma^ GINA) The regular organization of the Board of Directors. Every few years, the organization is based on medical evidence. With the new clinical concept, the diagnosis and treatment of asthma is written. New guidelines., = References for national medical staff. At present, GINA's treatment guidelines are based on the concept of step-by-step adjustment, that is, according to the condition, adjust the dose increase and control methods to control the situation: " 1. The slightest first Grade patients: Pragonist is given short-acting and rapid effects to relieve symptoms only at the time of onset; 2. Mild patients in the second stage: sputum, controlled treatment: given a. low dose inhalation Corticosteroids or b. leukotriene inhibitors. B. Decompression symptoms: P2-agonist for short-acting and rapid effects at the onset; 3. Moderately moderate patients: A, control, Treatment:: Choose to invest in a/' low-dose inhaled cortex, steroid drug with long-acting type B synergist, b. Mid-South dose inhaled corticosteroids, c• “low-dose inhalation, corticosteroids with white Triene inhibitor, or d• low-dose inhaled corticosteroids with long-acting theophylline, B. _ relieve symptoms: short-acting rapid effects of the type II synergist®2-agonist; 4 Fourth level weight Patient: A, controlled treatment: choose to give a. "medium high dose inhaled skin steroid drugs with long-acting type B synergist", b. white three-inhibitor, c. long-acting theophylline or selective investment 2 kinds in 201212907. B. Dispelling symptoms: P2-agonist with short-acting and rapid action at the time of attack; 5. Severe acute attack at the fifth level: 曱, control treatment: the fourth-level control drug is added to oral corticosteroids Or anti-IgE immunotherapy, B, relieve symptoms: a short-acting rapid effect of the type 2 synergist (p2-agonist); It can be seen from the literature that although the type II synergist has the effect of expanding the trachea, it is not recommended to be a chronic control drug for patients, regardless of whether it exhibits a short-acting or long-acting effect. The main reason is that when these drugs are used alone at high doses and high frequency, the patient will develop acute resistance (Tachyphylaxis), so that patients need to increase the dose quickly to achieve the same control effect, or sometimes invalid during medication. Even the disease is more likely to attack, thus increasing the acute attack rate, hospitalization rate and mortality rate of the patient. It is generally believed that the type II synergist exhibits an acute drug-characteristic mechanism and is caused by the rapid down-regulation of the β2 receptor (β2 recept〇r down regUiati〇n). It is also known that some genotype patients are more likely to develop acute and f-medicated episodes during the course of the B-type synergist. Inhaled corticosteroids, because of the ability to rapidly down-regulate some of the anti-02 receptors, are currently inhaled corticosteroids with long-acting B-type synergists for more than 12 hours. , combination composition,, is the main treatment for asthma, such as Budesonide with Formoterol fumarate > Fluticasone propionate with Salmeterol xinafoate, Fluticasone propionate with Formoterol fiini3rate 'Ciclesonide ' with F ormotcrol fiunarstc y 201212907

Momethasone fiiroate 搭配 Formoterol fhmarate， Beclomethasone 搭配 Formoterol ftimarate 或;Fluticasone ' 如*oate搭配Vilanterol trifenatate等，劑型則主要是乾粉 、 吸入劑（DpI，Dry Powder Inhaler)或定量喷霧吸入劑 (MDI，Metered Dose Inhaler)，此等藥物組合物，均已成 為目前主要研究開發之方向。 此等複方組合物之乙二型協同劑，如j?orm〇ter〇l fUmarate 及 Salmeterol xinafoate，均為每日給予二次以 維持24小時藥效之藥物，而vilanterol trifenatate則係每曰 φ 給予一次之更長效之藥物。Momethasone fiiroate with Formoterol fhmarate, Beclomethasone with Formoterol ftimarate or; Fluticasone ' such as *oate with Vilanterol trifenatate, etc., the dosage form is mainly dry powder, inhalant (DpI, Dry Powder Inhaler) or metered dose inhaler (MDI, Metered Dose Inhaler) These pharmaceutical compositions have become the main research and development direction. The type II synergists of such combination compositions, such as j?orm〇ter〇l fUmarate and Salmeterol xinafoate, are drugs administered twice daily for 24 hours, while vilanterol trifenatate is administered per φ A longer-lasting drug.

Papi，A.等人，於20〇7年揭示Beclomethasone搭配短 效乙二型協同劑Albuterol，用於輕度氣喘治療之複方組 合物，其所使用的複方控制療法也是一日二次之用法。 此外’除上述之文獻之外’尚有美國專利第5,270,305 號、5,658,549 號、5,674,472 號、5,674,860 號、6,123,924 號、6，143,277 號、6251368 號、6,253,762 號、6,315,173 號、6,510,969 號、6,524,555 號、6,546,928 號、6,641，800 號、RE40045 號、7,067,502 號、20100008997 號、 20090274771 號、20090258075 號、20090047336 號、 • 20080279788 號、20080078382 號、20080066741 號、 20080066739 號、20070196285 號、20060054166 號、 20050085445 號、20040241103 號、20040105819 號、 20040101483號，雖揭示許多“吸入性皮質類固醇藥物搭 配乙二型協同劑”之配方技術或傳遞技術發明，但均未論 及吸入性皮質類固醇藥物與中短效快速作用乙二型協同 劑如Procaterol HC1等之併用及使用方法。 美國專利資料庫中，揭示將乙二型協同劑Procaterol HC1與吸入性皮質類固醇藥物併用之專利，如專利第 201212907 6,503,537號、7,387,794號涉及附聚物粉末之製備、 7,244,414 號、7,658,949 號、7,687,073 號、7,694,676 號、 7,736,628號則涉及乾粉吸人劑而7，172,752號係合併粉 粒之相關發明’ 7,55〇，133號為吸入濃縮藥物.，7，1〇9,247 號為奈米粒子之懸液，6,814,953號則用於氣霧器。 6,932,962號係含有烷基醣之氫氟烷類 (hydrofluoroalkanes，HFA)喷霧劑，7,244,742 號再添加 抗膽鹼藥物，7,267,813號含有結晶球形攜入顆粒， 7,459，146號係用於經修飾之聚乙二醇（peg)、奈米顆粒Papi, A., et al., revealed that Beclomethasone was combined with the short-acting type B synergist Albuterol in the year of 20, 7 for a combination therapy for mild asthma therapy, and the combination control therapy used was also used twice a day. Further, in addition to the above-mentioned documents, there are U.S. Patent Nos. 5,270,305, 5,658,549, 5,674,472, 5,674,860, 6,123,924, 6,143,277, 6,251,368, 6,253,762, 6,315,173, 6,510,969, 6,524,555, 6,546,928. No. 6,641,800, RE40045, 7,067,502, 20100008997, 20090274771, 20090258075, 20090047336, 20080279788, 20080078382, 20080066741, 20080066739, 20070196285, 20060054166, 20050085445, 20040241103, 20040105819, 20040101483, although many of the "inhalation corticosteroids with B2 synergist" formula technology or transmission technology invention, but did not discuss the inhaled corticosteroid drugs and the short-acting rapid effect of type B synergy The combination of Procaterol HC1, etc., and the method of use. The U.S. Patent Database discloses a patent for the use of a combination of a prosthetic agent Procaterol HC1 and an inhaled corticosteroid, such as Patent Nos. 201212907 6,503,537, 7,387,794, relating to the preparation of agglomerate powders, 7,244,414, 7,658,949, 7,687,073. 7,694,676, 7,736,628 are related to dry powder inhalation and 7,172,752 are related inventions of combined powder '7,55〇,133 is inhaled concentrated drug. 7,7〇9,247 is the suspension of nano particles Liquid, 6,814,953 is used for the aerosol device. 6,932,962 is a hydrofluoroalkanes (HFA) spray containing alkyl sugar, 7,244,742 is added with anticholinergic drugs, 7,267,813 contains crystalline spherical particles, and 7,459,146 is used for modified polyethylene. Alcohol (peg), nanoparticle

HFA推進劑氣霧吸入劑，亦均與本發明不相同。 文獻資料亦顯示，添加吸入性皮質類固醇之複方組 合藥物，僅可緩解部份乙二型協同劑急性耐藥性現象， 因為事貫上乙二型協同劑，僅投與一次過高劑量，就足 以產生急性耐藥性，顯示尚有其它因素，可誘發急性耐 藥性之產生。 依據相關文獻’發現此急性耐藥性之機制，可能與 乙一型協同劑，係經由間接消耗體内一些内因性氣管擴 張物質，暇現之氣管舰侧有關連性，如大量增加 細胞内環腺苷單磷酸鹽㈣咖 =n=sphate，cAMp)濃度，着被蛋白晦作用，產 連串反應，促使氣管擴張。所以，大量投予乙二型 Ϊ同ίϊ Γ，相對地該内因性氣管擴張物質亦隨之消 ，發之自身補充低於餘速度時’足以 誘發急性耐樂性現象。 日都亦顯示’氣喘病人之肺功能狀況，並非整 而下午16:00最好。依據此 之新治瘅方^錢制’_翻人研魏喘或慢性肺阻塞 〜、/。發明人經過悉心試驗與研究，並一本鍥 201212907 用於氣喘之複方組合 ^不捨之精神，終構思出本案「 」，以解決習知技術之缺失。 I發明内容】 之一構想係提供一種吸入性複方組合物，其包 之一乙二型協同劑搭配一有效量之皮質類固醇 樂物’必要時搭配藥學上可接受之載體。 本案之另一構想係提供一種吸入性喷霧劑或乾粉吸 • 組合物’其包含有效量之-乙二型協同劑搭配-有 六里之皮質類固醇藥物，必要時搭配藥學上可接受之載 體。 ^根據上述構想’其中該乙二型協同劑係選自阿布叔 醇（Albuterol)、菲諾特洛（Fen〇ter〇1)、普魯卡地魯 (Procater〇l)、特布他林（Terbutaline)及其鹽基藥物硫酸阿 布叔醇（Albuterol sulfate)、鹽酸普魯卡地魯（procater〇i HC1)、菲諾特洛氫溴酸鹽 fen〇ter〇i hytjrobromide)、及 疏酸特布他林（Terbutaline sulphate)至少其中之一。 根據上述構想，其中該皮質類固醇藥物係選自布地 鲁奈德（Budesonide)、氟替卡松（Fluticasone)、莫美他松 (Mometasone)、環索奈德（cidesonide)、倍氣米松 (Beclomethasone)、去炎松（Triamcinolone)、替潑尼旦 (Tipredane)等藥物及其鹽基形態氟替卡松丙酸酯 (Fluticasonepropionate)、丙酸倍氣米松（Beclomethasone dipropionate)、及丙_去炎松（Triamcinolone Acetonide) 至少其中之一。 本案之又一構想係提供一種用於氣喘複方組合 物，其目的之一，係使用於氣喘或慢性肺阻塞等疾病之 201212907 療。基於上述氣喘病人之肺功能狀況為不 藥之所，非均等固定式投 較佳之户疼掇ΐ ί (Γ apy) °偏極性療法係 士;段::1=之^恢 極性ΐ法=現if ”供必要時給藥之治療。因而偏 現仃—日二次之控制給藥方式，對病 八之長效乙二鶴關複方藥物，呈現更佳之選^性。又 【實施方式】 劑量及纽單贼用乙二型協同_ 聲響22性，及觀測皮_固醇藥物加入治療的 二實誘ξ小鼠氣喘之實驗模式進行相關試 一圖所示，依照控制群與投藥群兩系 ifί t 群進行實驗。控制群包括未致敏小鼠投 二、藥物)之正常對照組，致敏小鼠卻不投與藥 物/台療之氣喘控制組。投犖雜目丨丨你诚 — 、 J別’分別為單方乙二型i同劑不同劑i 1同 'ί藥组劑ii頻同齡配皮該_複方^物不; 先經過間隔十曰三次之腹腔白蛋白 # 26日&日採血’檢測IgE確認過敏體質後， λ蛋白’第30曰起氣管内給藥，分 華t切s 二次的7曰給藥組’最後一次投 n氣管插管’以儀器進行乙醯甲膽鹼 發之氣管收縮資料收集數據。以 了解本發月複方組合物之緩解作用，相對於致敏小鼠單 201212907 獨使用長效或短效乙二型協同劑（Salmeter〇]或 Formotero】）、相對於正常小鼠及對照組之反應。 實驗結果如第二圖〜第四圖所示，無論於長效之 Salmeterol或中短效外咖哪】之單獨或複方投藥，單次 給予過高劑量，均有令致敏化小鼠呈現氣管擴張能力下 急性耐藥性現象H顯示，有—適宜劑量之區間， 讓藥效較能發揮。-日二次投讀物，賴無 性耐藥性現象之產生，於適當劑量範圍内避:； Budesomde吸入性皮質類固醇藥物，可減緩急性耐藥 性、。但使用過高量之乙二型協同劑量時，貝,^ Budes〇nide 無法減緩急性耐藥性，顯示此時乙二型協同劑量已超過 ^體可負擔程度。此實驗結果，亦間接證明，本發明所 提出之“急性耐藥性係體内氣管擴張媒介物質被耗盡所 造成”之想法及假設。 相對於GINA準則中所列模式，單獨使用短效乙二 型協同劑，供各級患者緊急發作症狀之解除作用氣管 擴張劑。若更改短效乙二型協同劑之投藥方式，採取短 效乙二型協同劑搭配皮質類固醇之複方吸入劑，應為另 一投藥方式。亦即，採用本發明“吸入性皮質類g醇藥 物搭配中短效快速作用乙二型協同劑，，之複方組合物，提 供緊急發作之各級患者，以此賊管擴_解除緊急發 作之症狀。 第五級病患當病情嚴重發作時，需添加口服皮質類 固醇藥物以進-步控制病情之事實，顯示病情惡化發作 時’病患身體可能需要額外之皮質類轉藥物，以協助 病者恢復氣管擴張功能。 相關之研究，僅Chiesi公司贊助發表於NewHFA propellant aerosol inhalers are also different from the present invention. The literature also shows that the combination of inhaled corticosteroids can only alleviate the acute drug resistance of some type B synergists, because it is a high-dose dose. Sufficient to produce acute drug resistance, showing that there are other factors that can induce acute drug resistance. According to the relevant literature 'discovering the mechanism of acute drug resistance, it may be related to the type I synergistic agent, through indirect consumption of some endogenous tracheal dilating substances in the body, and the current tracheal ship side related, such as a large increase in intracellular loop glands The concentration of monophosphate (4) coffee = n = sphate, cAMp) is caused by peptone, which produces a series of reactions that promote tracheal expansion. Therefore, a large number of injections of type B Ϊ ϊ ϊ Γ Γ Γ Γ Γ Γ Γ 相对 相对 Γ Γ Γ Γ Γ Γ Γ Γ 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对 相对The Japanese also showed that the lung function of the asthmatic patients was not the best at 16:00 in the afternoon. According to this, the new treatment of 瘅方^钱制’_ 翻人研魏喘 or chronic lung obstruction ~, /. The inventor has carefully tested and researched, and a book of 201212907 for the combination of asthma and the spirit of reluctance, finally conceived the case "" to solve the lack of conventional technology. SUMMARY OF THE INVENTION One concept is to provide an inhaled combination composition comprising an effective combination of an effective amount of a corticosteroid and a pharmaceutically acceptable carrier. Another concept of the present invention is to provide an inhalation spray or dry powder absorption composition comprising an effective amount of a type II synergist - a six mile corticosteroid drug, if necessary with a pharmaceutically acceptable carrier . ^ According to the above concept, wherein the type II synergist is selected from the group consisting of Albuterol, Fen〇ter〇1, Procater〇l, and terbutaline ( Terbutaline) and its salt-based drug Albuterol sulfate, procater〇i HC1, fenoldate hydrobromide fen〇ter〇i hytjrobromide, and sulphuric acid At least one of the Terbutaline sulphate. According to the above concept, wherein the corticosteroid drug is selected from the group consisting of Budesonide, Fluticasone, Mometasone, cidesonide, Beclomethasone, and inflammation. Triamcinolone, Tipredane, and the like, and its salt form, Fluticasone propionate, Beclomethasone dipropionate, and Triamcinolone Acetonide, at least One. Another idea of the present invention is to provide a composition for an asthma compound, one of which is for use in the treatment of asthma such as asthma or chronic lung obstruction 201212907. Based on the above-mentioned asthma patients' lung function status is not the drug, the non-equal fixed type of preferred household pain ί (Γ apy) ° polar therapy therapist; paragraph:: 1 = ^ ^ polarity ΐ method = now If "" for the treatment of the necessary dose. Therefore, the second-time control of the drug delivery method, the long-acting E. sinensis compound drug of the disease eight, showing a better choice. Also [Implementation] dose and New single thief with the type II synergy _ sound 22, and observation of the skin _ sterol drugs added to the treatment of the two real temptation mice asthma model test results shown in the first picture, according to the control group and the drug group two lines if The t group was tested. The control group included the normal control group of the unsensitized mice, and the sensitized mice were not given the anti-asthmatic control group of the drug/therapeutic treatment. J 别 'is a single singular type II i with the same agent different agents i 1 with ' ί 药 group ii frequency with the same age with the skin _ compound ^ things; first through the interval of ten times three times abdominal cavity albumin # 26 & Blood collection 'detection of IgE confirmed allergic constitution, λ protein '30th 曰 from intratracheal administration, divided into t cut s twice 7曰administration group 'last cast n tracheal intubation' to collect data on tracheal contraction data of methotrexate from the instrument. To understand the mitigation effect of the compound composition of this month, compared to the sensitized mouse single 201212907 The long-acting or short-acting type B synergist (Salmeter〇) or Fortomero) was used alone, and the reaction was compared with normal mice and the control group. The experimental results are shown in the second to fourth figures, regardless of the long-term effect. Salmeterol or medium-short-acting coffee, which is administered alone or in combination, has a high dose in a single dose, and all of the sensitized mice exhibit acute drug resistance under the ability of tracheal expansion. H shows that there is a range of appropriate doses. Let the drug effect be more effective. - The second reading of the product, the emergence of the phenomenon of asexual drug resistance, within the appropriate dosage range to avoid:; Budesomde inhaled corticosteroid drugs, can reduce acute drug resistance, but used When high doses of B-type synergistic dose, B, ^ Budes〇nide can not alleviate acute drug resistance, indicating that the synergistic dose of type B has exceeded the affordability of the body. The results of this experiment also indirectly prove that the present invention The idea and hypothesis that “acute drug resistance is caused by the depletion of tracheal expansion mediators in the body”. Short-acting type B synergists are used alone for emergency attacks at all levels compared to the models listed in the GINA guidelines. Discharge of the symptoms of the tracheal dilator. If the mode of administration of the short-acting type B synergist is changed, the combination inhalation of the short-acting type B synergist with corticosteroid should be another method of administration. "Inhalation corticosteroids in combination with short-acting and rapid-acting type B synergistic agents, the combination of the composition, to provide emergency patients at all levels, with the thief tube expansion _ relieve the symptoms of emergency. When a fifth-grade patient has a serious episode, the need to add oral corticosteroids to control the condition further indicates that the patient may need additional corticosteroids to help the patient recover the trachea. Expansion function. Related research, only sponsored by Chiesi Company, published in New

England Journal of Medicine 2007 之文獻，涉及“吸入性皮 12 201212907 質類固醇藥物搭配矩效快速作用βρ乙二型協同 研究。其結果指出’於輕度氣喘病人.，長達6個月 蹤下，當病情發作時才給藥之“必要時給藥法，，投與 Beclomethasobne 搭配 Albuterol 之複方，顯 ^、The literature of the England Journal of Medicine 2007 relates to the "inhalation skin 12 201212907 steroid drug combination with the rapid effect of the rapid effect of βρ ethylene type II. The results indicate 'in mild asthma patients., up to 6 months, when "If necessary, the drug is administered at the time of the onset of the disease, and the combination of Beclomethasobne and Albuterol is shown.

Albuterol單獨使用，可更能控制病情及較少嚴重發H 住院次數。雖然此研究’只探討於輕度氣喘病人之狀況， 而未探討中重度病人於常規控制用藥下之發作時緊魚 藥狀況，但已顯示病人發作時，除乙二型協同劑之^卜， 給予較多之皮質固醇類藥物有益於病情之控制。Albuterol alone can be used to control the condition and the number of hospitalizations that are less severe. Although this study only explores the condition of patients with mild asthma, but does not discuss the state of tight fish in the onset of moderately severe patients under routine control medication, it has been shown that in addition to the type II synergist, Giving more corticosteroids is beneficial to the control of the disease.

故本發明之添加皮質固醇類藥物之短效快速作用 乙二型協同劑複方，可供所有等級氣喘病患之發作時緊 急用藥’提供更佳之選擇。此等額外給予之皮質固醇類 藥物’能以其抗發炎作用，協助病患緩解病情。 依照本發明實施例配方之複方組合物，運用之中短 效乙二型協同劑 Procatero卜 Fenoterol、Terbutaline 或Therefore, the short-acting rapid action of the corticosteroid-added drug of the present invention is a combination of the type B synergistic agent, which provides a better choice for emergency medication in the onset of all grades of asthmatic patients. These additional corticosteroids can be used to help patients relieve their disease by their anti-inflammatory effects. A compound composition formulated according to an embodiment of the present invention, using a short-acting type B synergist Procatero Bu Fenoterol, Terbutaline or

Albuterol及其鹽基藥物，如採取吸入劑方式初次單方 投藥時’氣管擴張藥效約達6〜8小時。若每曰使用3〜4 次’雖產生急性耐藥性現象’唯擴張氣管藥效之留存3〜4 小時隨即降低。併用吸入性皮質類固醇Budesonide藥 物，且於睡前及起床後之偏極性使用’藥效則可回復維 持到6〜8小時。因此配合病症，俟症候發作必要時再使 用本發明之複方組合物所呈現之緩解效果，有助於長期 控制病患之病症。 通常以藥效作用為3至8小時之Procaterol HC1、 Procaterol、Albuterol、Albuterol sulfate、Fenoterol、 Fenoterolhydrobromide等乙二型協同劑，搭配吸入性皮 質類固醇藥物，如布***（Budesonide)、氟替卡松 (Fluticasone)、倍氯米松（Beclomethasone)、莫美他松 13 201212907 (Mometasone)、環索奈德(Cides〇nide)、或去炎松 (Triamcinolone)等藥物及其鹽基形態等，所形成的複方 定量吸入劑型或乾粉吸入劑《乙二型協同劑與此等吸入 性皮質類固醇藥物之用藥重量比例約1:2 w/w〇/〇到 l:70w/w% ’較佳之範圍為1:5論％到1:6〇 w/w % 〇Albuterol and its salt-based drugs, such as the initial unilateral administration by inhalation, have a tracheal expansion effect of about 6 to 8 hours. If it is used 3 to 4 times per ’, although the phenomenon of acute drug resistance occurs, only the expansion of the tracheal effect will remain for 3 to 4 hours. Inhaled corticosteroid Budesonide is used, and it can be recovered for 6 to 8 hours by using the drug effect before bedtime and after getting up. Therefore, in combination with the condition, the symptomatic effect of the compound composition of the present invention, if necessary, can be used to control the condition of the patient for a long time. Procaterol HCl, Procaterol, Albuterol, Albuterol sulfate, Fenoterol, Fenoterolhydrobromide, etc., usually with a pharmacodynamic effect of 3 to 8 hours, combined with inhaled corticosteroids such as Budesonide and Fluticasone. Compound inhalation, such as beclomethasone, mometasone 13 201212907 (Mometasone), Cides〇nide, or Triamcinolone, and their salt forms. Formulation or dry powder inhaler The weight ratio of the type II synergist to these inhaled corticosteroids is about 1:2 w/w〇/〇 to l:70w/w%. The preferred range is 1:5 on %. To 1:6〇w/w % 〇

臨床上用法，是睡前及睡醒時用藥，配合氣喘病情 發作時使用1其優點是可提供病人在下午之肺部功能較 佳的階段，身體有足夠時間的恢復累積體内氣管擴張之 媒介物，以因應下次給藥之需求，並使乙二型協同劑 急性耐藥性現象降至最低，來幫忙病人穩定控制病情。 相對於其他短效乙二型協同劑單方藥物，添加吸入 性皮質類固醇藥物 procatero 卜 Albutefd、Tefbutaline、 F^n_〇l其鹽基藥物之複方·，由於搭配具有抗發炎及減 緩乙二型協同劑產生急性耐藥性之吸入性皮質類固_藥 物成份。相對僅终乙二型協同劑之單方 發作時緊急提供__，有助於病情之祕及減少長 期間之嚴重發作次數。 #本發明應用於吸入性乙二型協同劑搭配皮質類垣 =物複方之偏極性投細型，可選擇氫氟絲進劑吳 置噴霧劑（HFA MDI)或乾粉吸入劑（DH，_ p〇wde 之給藥途徑。上述”藥學上可接受之載體，，係令 衣備乙一型協同劑搭配皮質類固醇藥物複方之各劑型对 賦形趣統，令其投與祕或人類猶於造成不良 敏或其它不適當反應。载體或賦形劑系統亦可 面活性劑、溶劑、助懸劑以及推進劑助 ίϋη礙狀缝絲進縦量讀吸入劑 =MDI)之配方通常採用】，u，2 (Tetraflu_thane，HFA 13^ HFC 134a)或 u山2 3,3^ 14 201212907 七氟丙院(Heptafluoro-n-propane, HFC 2276¾ HFC 227, 227) ’亦可視必要時選擇HFA134a與HFA 227並 用之定量喷霧製劑。乾粉吸入劑可經由單劑量吸入器， • ，擇採用無載體之主成分藥物直接充填於膠囊内，或含 乳酷為載體經由單劑量吸入器給藥之製劑。 活性實驗方法： 選用Balb/c小鼠’區分為正常對照組（Normal control group)、氣喘控制組（〇va contr〇i 设0即）1 每組 • 2〜28隻(前期劑量探索階段隻數較少，後期劑量確認後， 重覆確認實驗隻數較多），’各組之飲水、飼料供應相同。 於氣喘控制組先間隔10天採取腹腔注射卵白蛋白 (OVA)如第一圖所示，使之產生過敏體質。第24天從 眼窩採企，.以IgEElisa定量檢測，確認小鼠呈現過敏體 質。正常對照組，未致敏且投予食鹽水。經致敏之氣喘 控制群，同樣投予食鹽水卻不投與藥物治療。投藥前三 天，連續鼻腔内給予OVA .，.強化過敏體質。 各群老鼠先依照不同藥物、不同劑量分組，每組依 φ 照1次給藥（one dose)以及每日1次（qd)或2次給藥 (bid) 7日而區分為不同投藥組。將食鹽水或食鹽水所調 配Procaterol搭配Budesonide形成之混核藥物均直接投 予小鼠喉頭。 15 201212907 表一 群/組/編碼 給藥方式 小鼠(隻） 正常對照組 (Normal control group) 一次劑量 18 一日2次X 7天 19 氣喘控制組 (Ova control group) 一次劑量 21 一日1次X7天 14 一日2次X 7天 28 Budesonide 9.0 pg/kg搭配 Procaterol 0.5 pg/kg (B9+P0.5) 一次劑量 7 一日2次X 7天 13 Budesonide 19.0 pg/kg搭配 Procaterol 1.0 pg/kg (B19+P1) 一次劑量 11 一日2次X 7天 19 Budesonide 27.0 pg/kg搭酉己 Procaterol 1·5 pg/kg (B27+P1.5) 一次劑量 6 一日2次X 7天 12 Budesonide 45.0 pg/kg搭配 Procaterol 2.5 pg/kg (B45+P2.5) 一次劑量 8 一日2次X 7天 15 Budesonide 90.0 pg/kg 搭 配 Procaterol 5.0 pg/kg (B90+P5) 一次劑量 10 一日2次X 7天 25 Budesonide 180.0 pg/kg 搭 配 Procaterol 10.0 pg/kg (B180+P10) 一次劑量 10 Budesonide 200.0 pg/kg 搭 酉己 Procaterol 12.5 pg/kg (B200+P12.5) 一日1次X7天 3 Budesonide 225.0 pg/kg 搭 酉己 Procaterol 12.5 pg/kg (B225+P12.5) 一日2次X 7天 2 16 201212907 表一（續) 群/組/編碼 給藥方式 小鼠(隻） Budesonide 540.0 pg/kg 搭 配 Procaterol 30.0 pg/kg (B540+P30) 一日1次X7天 2 Budesonide 900.0 pg/kg 搭 配 Procaterol 50.0 pg/kg (B900+P50) 一次劑量 2 Procaterol 0.5 pg/kg (P0.5) 一次劑量 7 一日2次X 7天 12 Procaterol 1.0 pg/kg (PI) 一次劑量 13 一日2次X7天 10 Procaterol 1.5 pg/kg (PI.5) 一次劑量 7 一日2次X7天 15 Procaterol 2.5 pg/kg (P2.5) 一次劑量 5 一日2次X 7天 9 Procaterol 5.0 pg/kg (P5) 一次劑量 5 一日2次X 7天 14 JProcaterol 10.0 pg/kg (P10) 一次劑量 5 一日2次X 7天 10 Salmeterol Xinafoate 50.0 pg/kg (S50) 一次劑量 5 一日1次X7天 2 一日2次X 7天 8 Salmeterol Xinafoate 100.0 \igjkg (SI00) 一日1次X7天 3 Salmeterol Xinafoate 200.0 Kg/kg (S200) 一次劑量 6 一日1次X7天 6 一日2次X 7天 9 Salmeterol Xinafoate 500.0 kg/kg (S500) 一次劑量 3 一日1次X7天 2 一日2次X 7天 8 17 201212907 最後一次投藥後，麻醉下切開小鼠氣管，裝入測氣 管阻力儀器，以乙醯甲膽鹼（Methacholine，MCh)氣霧 刺激氣管收縮並以SCIREQ FlexiVent.機器測試肺部氣 管阻力。 下列實施例係將各成分混合後溶入氫氟烷類之賦形 劑系統製備成定量喷霧吸入劑，或直接充填於膠囊内、 或製成乾粉吸入劑經由單劑量吸入器給藥。Clinically, it is used before bedtime and during waking, and it is used in combination with asthma. It has the advantage of providing patients with better lung function in the afternoon, and the body has enough time to recover the medium of accumulated tracheal expansion in the body. In order to meet the needs of the next administration, and to minimize the acute drug resistance of the type II synergist, to help patients stabilize the disease. Compared with other short-acting type B synergistic agents, the addition of inhaled corticosteroids procatero, Albutefd, Tefbutaline, F^n_〇l, a compound of its base-based drugs, due to its anti-inflammatory and slow-responding type B synergy The agent produces an acutely inhaled corticosteroid-drug component. The __ is urgently provided in the unilateral episode of the final type B synergist, which helps the secret of the disease and reduces the number of serious episodes during the long period. # The invention is applied to the inhalation type B type synergistic agent combined with the cortical type 物= compound compound, and the selective polarity type can be selected, and the hydrofluoric acid injection agent (HFA MDI) or dry powder inhaler (DH, _ p〇) can be selected. The route of administration of wde. The above-mentioned "pharmaceutically acceptable carrier, which is a combination of the preparation of the type I synergistic agent and the corticosteroid drug compound, makes it difficult to cause it to be secret or human. Or other inappropriate reaction. The carrier or excipient system may also be formulated with a surfactant, a solvent, a suspending agent, and a propellant to prevent the amount of the thread from being inhaled (MDI). 2 (Tetraflu_thane, HFA 13^ HFC 134a) or ushan 2 3,3^ 14 201212907 Heptafluoro-n-propane (HFC 22763⁄4 HFC 227, 227) 'Also select HFA134a and HFA 227 if necessary Quantitative spray preparations. Dry powder inhalers can be directly filled into capsules via a single-dose inhaler, or a drug containing a main ingredient without a carrier, or a preparation containing a milk-cooled carrier via a single-dose inhaler. : Using Balb/c mice' Divided into normal control group (Normal control group), asthma control group (〇va contr〇i set to 0) 1 Each group • 2~28 (only the number of pre-dose exploration stages is small, after the late dose confirmation, repeat confirmation There were only a large number of experiments), 'The drinking water and feed supply of each group were the same. In the asthma control group, the intraperitoneal injection of ovalbumin (OVA) was taken 10 days apart, as shown in the first figure, to produce allergies. On the 24th day The eye socket was collected, and IgEElisa quantitative test confirmed that the mice showed allergic constitution. The normal control group was not sensitized and administered saline. The sensitized asthma control group was also given saline but not given medication. In the first three days, OVA was given continuously in the nasal cavity to strengthen allergies. Each group of mice was first grouped according to different drugs and different doses, and each group was dosed one dose and once a day (qd) or Two doses (bid) were divided into different administration groups on the 7th. The mixed drugs formed by Procaterol and Budesonide in saline or saline were directly administered to the throat of the mice. 15 201212907 Table group/group/coded administration Small way (only) Normal control group One dose 18 times 2 times X 7 days 19 Ova control group One dose 21 One day X7 days 14 Days 2 times X 7 days 28 Budesonide 9.0 Pg/kg with Procaterol 0.5 pg/kg (B9+P0.5) One dose 7 2 times 2 times X 7 days 13 Budesonide 19.0 pg/kg with Procaterol 1.0 pg/kg (B19+P1) One dose 11 times a day 2 times X 7 days 19 Budesonide 27.0 pg/kg Pro Pro Procaterol 1·5 pg/kg (B27+P1.5) One dose 6 2 times 2 times X 7 days 12 Budesonide 45.0 pg/kg with Procaterol 2.5 pg/kg (B45 +P2.5) One dose 8 times 2 times X 7 days 15 Budesonide 90.0 pg/kg with Procaterol 5.0 pg/kg (B90+P5) One dose 10 times 2 times X 7 days 25 Budesonide 180.0 pg/kg with Procaterol 10.0 pg/kg (B180+P10) One dose 10 Budesonide 200.0 pg/kg Procaterol 12.5 pg/kg (B200+P12.5) Once a day X7 days 3 Budesonide 225.0 pg/kg Procaterol 12.5 pg /kg (B225+P12.5) 2 times a day X 7 days 2 16 201212907 Table 1 (continued) Group/group/coded mode of administration of mice (only) Bud Esonide 540.0 pg/kg with Procaterol 30.0 pg/kg (B540+P30) once a day X7 days 2 Budesonide 900.0 pg/kg with Procaterol 50.0 pg/kg (B900+P50) One dose 2 Procaterol 0.5 pg/kg (P0. 5) One dose 7 2 times a day X 7 days 12 Procaterol 1.0 pg/kg (PI) One dose 13 2 times 2 times X7 days 10 Procaterol 1.5 pg/kg (PI.5) One dose 7 2 times 2 times X7 days 15 Procaterol 2.5 pg/kg (P2.5) One dose 5 times 2 times X 7 days 9 Procaterol 5.0 pg/kg (P5) One dose 5 2 times 2 times X 7 days 14 JProcaterol 10.0 pg/kg (P10) Once Dosage 5 2 times a day X 7 days 10 Salmeterol Xinafoate 50.0 pg/kg (S50) One dose 5 Day 1 X 7 days 2 Day 2 X 7 days 8 Salmeterol Xinafoate 100.0 \igjkg (SI00) 1 time X7 Day 3 Salmeterol Xinafoate 200.0 Kg/kg (S200) One dose 6 One day X7 days 6 Days 2 times X 7 days 9 Salmeterol Xinafoate 500.0 kg/kg (S500) One dose 3 One day X7 days 2 Days 2 times X 7 days 8 17 201212907 After the last administration, the mouse trachea was cut under anesthesia, and the measuring instrument for measuring the trachea was taken. Methacholine (MCh) aerosol stimulates tracheal contraction and tests lung tracheal resistance with a SCIREQ FlexiVent. machine. The following examples are prepared by mixing the ingredients and dissolving the hydrofluorocarbon-forming excipient system into a metered dose inhaler, either directly in a capsule or as a dry powder inhaler via a single dose inhaler.

實施例一 Procaterol HC1 Budesonide HFA227 酒精 PEG 400 總量 實施例二 Procaterol HC1 Fluticasone propionate HFA 227 酒精 PEG 400 總量 實施例三 Procaterol HC1 Mometasone furoate HFA 227 0.014% W/W% 0.571% W/W% 98.664% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 0.014% W/W% 0.286% W/W% 98.95% W/W% 0.25% W/W% 0.50% WAV% 100.00% W/W% 0.014% W/W% 0.071% W/W% 99.164% W/W% 18 201212907Example 1 Procaterol HC1 Budesonide HFA227 Alcohol PEG 400 Total Example 2 Procaterol HC1 Fluticasone propionate HFA 227 Alcohol PEG 400 Total Example 3 Procaterol HC1 Mometasone furoate HFA 227 0.014% W/W% 0.571% W/W% 98.664% W /W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 0.014% W/W% 0.286% W/W% 98.95% W/W% 0.25% W/W% 0.50% WAV% 100.00 % W/W% 0.014% W/W% 0.071% W/W% 99.164% W/W% 18 201212907

酒精 0.25% WAV% PEG 400 0.50% W/W% 總量 100.00% W/W% 實施例四 Procaterol HC1 0.014% W/W% Fluticasone furoate 0.157% W/W% HFA 227 99.079% W/W% 酒精 0.25% W/W% PEG 400 0.50% W/W% 總量 100.00% W/W%Alcohol 0.25% WAV% PEG 400 0.50% W/W% Total 100.00% W/W% Example 4 Procaterol HC1 0.014% W/W% Fluticasone furoate 0.157% W/W% HFA 227 99.079% W/W% Alcohol 0.25 % W/W% PEG 400 0.50% W/W% Total 100.00% W/W%

實施例五 Procaterol HC1 0.0167% W/W% Budesonide 0.333% W/W% HFA 134a 99.57% W/W% 酒精 1% W/W% PEG 400 1% W/W% 總量 100.00% W/W% 實施例六 Budesonide 0.67% W/W% HFA 134a 99.57% W/W% 酒精 1% W/W% PEG 400 1% W/W% 總量 100.00% W/W% 19 201212907Example 5 Procaterol HC1 0.0167% W/W% Budesonide 0.333% W/W% HFA 134a 99.57% W/W% Alcohol 1% W/W% PEG 400 1% W/W% Total 100.00% W/W% Implementation Example 6 Budesonide 0.67% W/W% HFA 134a 99.57% W/W% Alcohol 1% W/W% PEG 400 1% W/W% Total 100.00% W/W% 19 201212907

Beclomethasone dipropionate HFA 227 酒精 PEG 400 總量 實施例七Beclomethasone dipropionate HFA 227 Alcohol PEG 400 Total Example 7

Fluticasone propionate HFA 134a 酒精 PEG 400 總量 實施例八 Procaterol HC1 Ciclesonide HFA 227 酒精 PEG 400 總量 實施例九 Procaterol HC1 0.417% W/W% 98.833% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 0.014% W/W% 0.286% W/W% 98.95% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 0.014% 0.071% 99.164% 0.25% 0.50% 100.00% W/W% W/W% W/W% W/W% W/W% W/W% 0.014% W/W% 0.143% W/W% 99.093% W/W% 0.25% W/W% 實施例十 Procaterol HC1 Beclomethasone dipropionate HFA 227 酒精 20 201212907 PEG 400 總量 0.50% W/W% 100.00% W/W%Fluticasone propionate HFA 134a Alcohol PEG 400 Total Example Eight Procaterol HC1 Ciclesonide HFA 227 Alcohol PEG 400 Total Example Nine Procaterol HC1 0.417% W/W% 98.833% W/W% 0.25% W/W% 0.50% W/W % 100.00% W/W% 0.014% W/W% 0.286% W/W% 98.95% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 0.014% 0.071% 99.164% 0.25 % 0.50% 100.00% W/W% W/W% W/W% W/W% W/W% W/W% 0.014% W/W% 0.143% W/W% 99.093% W/W% 0.25% W /W% Example 10 Procaterol HC1 Beclomethasone dipropionate HFA 227 Alcohol 20 201212907 PEG 400 Total 0.50% W/W% 100.00% W/W%

實施例十一 Procaterol HC1 Beclomethasone dipropionate HFA 227 酒精 PEG 400 總量 0.014% W/W% 0.286% W/W% 98.95% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W%Example 11 Procaterol HC1 Beclomethasone dipropionate HFA 227 Alcohol PEG 400 Total 0.014% W/W% 0.286% W/W% 98.95% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W %

實施例十二 Procaterol HC1 Budesonide HFA 227 酒精 PEG 400 總量 實施例十三 Procaterol HC1 Budesonide HFA 227 酒精 PEG 400 總量 0.014% W/W% 0.143% W/W% 99.093% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 0.014% W/W% 0.257% W/W% 98.98% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% 實施例十四 21 201212907 W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W%Example 12 Procaterol HC1 Budesonide HFA 227 Alcohol PEG 400 Total Example 13 Procaterol HC1 Budesonide HFA 227 Alcohol PEG 400 Total 0.014% W/W% 0.143% W/W% 99.093% W/W% 0.25% W/ W% 0.50% W/W% 100.00% W/W% 0.014% W/W% 0.257% W/W% 98.98% W/W% 0.25% W/W% 0.50% W/W% 100.00% W/W% Example 14 21 201212907 W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W% W/W%

Procaterol HC1 0.014%Procaterol HC1 0.014%

Fluticasone propionate 0.357% HFA227 98.879% 酒精 0.25% PEG 400 0.50% 總量 100.00% 實施例十五Fluticasone propionate 0.357% HFA227 98.879% Alcohol 0.25% PEG 400 0.50% Total 100.00% Example 15

Procaterol HC1 0.014%Procaterol HC1 0.014%

Fluticasone propionate 0.071% HFA227 99.16% 酒精 0.25% PEG 400 0.50% 總量 100.00% 實施例十六 Procaterol HC1 Fluticasone furoate HFA 227 酒精 PEG 400 總量 0.014% 0.314% 98.921% 0.25% 0.50% 100.00% W/W% W/W% W/W% W/W% W/W% W/W% 實施例十七 W/W% W/W% W/W% W/W%Fluticasone propionate 0.071% HFA227 99.16% Alcohol 0.25% PEG 400 0.50% Total 100.00% Example Sixteen Procaterol HC1 Fluticasone furoate HFA 227 Alcohol PEG 400 Total 0.014% 0.314% 98.921% 0.25% 0.50% 100.00% W/W% W /W% W/W% W/W% W/W% W/W% Example 17 W/W% W/W% W/W% W/W%

Procaterol HC1 0.014%Procaterol HC1 0.014%

Fluticasone furoate 0.157% HFA 227 99.079% 酒精 0.25% 22 201212907Fluticasone furoate 0.157% HFA 227 99.079% alcohol 0.25% 22 201212907

PEG 400 0.50% 總量 100.00% 實施例十八 Procaterol HC1 2.439% Budesonide 97.561% 總量 100.00% 實施例十九 Procaterol HC1 16.667% Fluticasone propionate 83.333% 總量 100.00% 實施例二十 Procaterol HC1 9.091% Beclomethasone dipropionate 90.909% 總量 100.00% 實施例二十一 Procaterol HC1 0.133% Mometasone iuoate 1.333% Lactose 98.533% 總量 100.00% 實施例二十二 Procaterol HC1 0.133% Fluticasone fuoate 2.933% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% WAV% w/w% w/w% w/w% 23 201212907PEG 400 0.50% Total 100.00% Example 18 Procaterol HC1 2.439% Budesonide 97.561% Total 100.00% Example Nineteen Procaterol HC1 16.667% Fluticasone propionate 83.333% Total 100.00% Example Twenty Procaterol HC1 9.091% Beclomethasone dipropionate 90.909 % Total 100.00% Example 21 Procaterol HC1 0.133% Mometasone iuoate 1.333% Lactose 98.533% Total 100.00% Example Twenty-two Procaterol HC1 0.133% Fluticasone fuoate 2.933% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% w/w% WAV% w/w% w/w% w/w% 23 201212907

Lactose 96.933% w/w% 總量 100.00% w/w% 實施例二十三 Procaterol HC1 0.133% w/w% Budesonide 2.667% w/w% Lactose 97.200% w/w% 總量 100.00% w/w% 實施例二十四 Procaterol HC1 0.133% w/w% Ciclensonide 0.667% w/w% Lactose 99.200% w/w% 總量 100.00% w/w% 實施例 1. 一種吸入性複方組合物，其包含有效量之一乙二型協同 劑搭配一有效量之皮質類固醇藥物，必要時搭配藥學上 可接受之載體。 2·根據實施例1所述之複方組合物，係用於氣喘或慢性肺 阻塞病人氣喘發作之緊急用藥，睡前或睡醒之偏極性控 制用藥。 3.根據上述實施例中任意一個實施例所述之複方組合物， 其中該乙二型協同劑係選自阿布叔醇（Albuterol)、菲諾 特洛（Fenoterol)、普魯卡地魯（Procaterol)、特布他林 (terbutaline)及其鹽基藥物硫酸阿布叔醇（Albuterol sulfate)、鹽酸普魯卡地魯（ProcaterolHCl)、菲諾特洛氫 24 201212907 溴酸鹽（Fenoterol Itydrobromide)、及硫酸特布他林 (terbutaline sulphate)至少其中之一。 4. 根據上述實施例中任意一個實施例所述之複方組合物， 其中該皮質類固醇藥物係選自布***（Budesonide)、 氟替卡松（Fluticasone)、莫美他松（Mometasone)、環索 奈德（Ciclesonide)、倍氯米松（Beclomethasone)、去炎松 (Triamcinolone)，及其鹽基形態藥物氟替卡松丙酸酯 (Fluticasonepropionate)、丙酸倍氯米松（Becl〇methasone dipropionate)、及丙酿I去炎松（Triamcinolone Acetonide) 至少其中之一。 5. 根據上述實施例中任意一個實施例所述之複方組合物， 其中該乙二型協同劑搭配皮質類固醇藥物之比率為1:2 w/w%到 1:70 w/w%。 6. —種吸入性喷霧劑組合物’其包含藥學上可接受之載體; 以及有效量之一乙二型協同劑搭配一有效量之皮質類固 醇藥物。 ' 7. 根據實施例6所述之噴霧劑組合物，係用於氣喘或慢性 肺阻塞病人氣喘發作之緊急用藥，睡前或睡醒之偏極性 控制用藥。 8. 根據實施例6-7中任意一個實施例所述之喷霧劑組合 ，’其中該乙二型協同劑係選自阿布叔醇（Albuter〇^ 菲諾特洛（Fenoterol)、普魯卡地魯（Procater〇1)、特布 他林（Terbutaline)及其鹽基藥物硫酸阿布叔醇 (Albuterol sulfate)、鹽酸普魯卡地魯（Pr〇cater〇1 Ηα)、菲 諾特洛氫溴酸鹽（Fenoterol hydrobromide)、及硫酸特布 他林（Terbutaline sulphate)至少其中之一。 9. 根據實施例6-8中任意一個實施例所述之喷霧劑組合 物’其中該皮質類固醇藥物係選自布*** 25 201212907 (Budesonide)、氟替卡松（Fluticasone)、莫美他松 (Mometasone)、環索奈德（Ciclesonide)、倍氯米松 (Beclomethasone)、去炎松（Triamcinolone)，及其鹽基 形態藥物及其鹽基形態藥物氟替卡松丙酸酯 (Fluticasone propionate)、丙酸倍氯米松(Beclomethasone dipropionate)、及丙酮去炎松（Triamdnolone Acetonide) 至少其中之一。 10. 根據實施例6-9中任意一個實施例所述之喷霧劑組合 物，其中該乙二型協同劑搭配皮質類固醇藥物之比率為 l:4w/w%J'| 1.:50 w/w% β 11. 根據實施例6-10中任意一個實施例所述之喷霧劑組合 物’其中該藥學上可接受之載體必要時係選用氫氟烷推 進劑、表面活性劑、溶劑、助懸劑或乳醣。 12·根據實施例6-11中任意一個實施例所述之喷霧劑組合 物’其中該藥學上可接受之載體係選用氫氟烷推進劑、 表面活性劑、溶劑或助懸劑。 13. —種吸入性乾粉組合物，其包含藥學上可接受之載體；以 及有效量之一乙二型協同劑搭配一有效量之皮質類固醇 藥物。 14. 4艮據實施例13所述之乾粉組合物，係用於氣喘或慢性肺 阻塞病人氣喘發作之緊急用藥，睡前或睡醒之偏極性控 制用藥。 15. 根據實施例13-14中任意一個實施例所述之乾粉組合 物，其中該乙二型協同劑係選自阿布叔醇（Albuten)1)、 菲諾特洛（Fenoterol)、普魯卡地魯（Procaterol)、特布 他林（terbutaline)及其鹽基樂物硫酸阿布叔醇（Albuterol sulfate)、鹽酸普魯卡地魯（pr〇caterol HC1)、菲諾特洛氮 漠酸鹽（Fenoterol hydrobromide)、硫酸彳纟 _ % &amp; 26 201212907 (Terbutaline sulphate)至少其中之一。 16.根據實施例13-15中任意一個實施例所述之乾粉組合 物’其中該皮質類固醇藥物係選自布地^抻 (Budesonide)、氟替卡松、莫美:‘ (Mometasone)、環索奈德（ciclesonide)、倍 ^ 米^ (Beclomethasone)、去炎松（Ttiameinolone)，及其 形態藥物及其鹽基形態藥物氟替卡松丙 (Fluticasone propionate)、丙酸倍氯米松(Becl〇methas〇ne dipropionate)、及丙酮去炎松（Triamcinolone Aeet(mide) 至少其中之一。 17·根據實施例13-16中任意一個實施例所述之乾粉組合 物，其中該乙二型協同劑搭配皮質類固醇藥物之比率為 1:4 w/w%到 1:50 w/w% 〇 18. 根據實施例13-17中任意一個實施例所述之乾粉組合 物，其中該藥學上可接受之載體必要時係選用乳醣。 19. 根據上述實施例中任意一個實施例所述之組合物，其中 該乙二型協同劑為菲諾特洛(Fenoterol)，該皮質類固醇 藥物係選自布***（Budesonide)、敗替卡松 (Fluticasone)、莫美他松（Mometasone)、環索奈德 (Ciclesonide)、倍氣米松（Beclomethasone)、去炎松 (Triamcinolone)，及其鹽基形態藥物氟替卡松丙酸酯 (Fluticasonepropionate)、丙酸倍氯米松（Beclomethasone dipropionate)、及丙_去炎松（Triamcinolone Acetonide) 至少其中之一。 20. 根據上述實施例中任意一個實施例所述之組合物，其中 該乙二型協同劑為普魯卡地魯（Procaterol)，該皮質類 固醇藥物係選自布***（Budesonide)、氟替卡松 (Fluticasone)、莫美他松（Mometasone)、環索奈德 27 201212907 (C'iclesonide)、倍氣米松 、去炎松 (Triamcinolone) ’及其鹽基形態藥物氣替卡松丙酸醋 (Fluticasonepropionate)、丙酸倍氯米松 ggeci〇niethasone * dipropionate)、及丙鋼去炎松（Triamcinolone Acetonide) 至少其中之一。 21. 根據上述實施例中任意一個實施例所述之組合物，其中 該乙二型協同劑為阿布叔醇（Albuterol)，該皮質類固醇 藥物係選自布***（Budesonide)、氟替卡松 (Fluticasone)、莫美他松〇^[0111咖801^)、環索奈德 φ (cicles〇nide)、倍氣米松(Beci〇methasone)、去炎松 (Triamcinolone) ’及其鹽基形態藥物氟替卡松丙酸酯 (Fluticasonepropionate)、丙酸倍氯米松（Beclomethasone dipropionate)、及丙_去炎松（Triamcinolone Acetonide) 至少其中之一。 22. 根據上述實施例中任意一個實施例所述之組合物，其中 該乙二型協同劑為硫酸阿布叔醇（Albuterol sulfate)，該 皮質類固醇藥物係選自布***（Budesonide)、氟替卡 松（Fluticasone)、莫美他松（Mometasone)、環索奈德 (Ciclesonide)、倍氯米松（Beclomethasone)、去炎松 (Triamcinolone)，及其鹽基形態藥物氟替卡松丙酸酯 (Fluticasonepropionate)、丙酸倍氯米松（Beclomethasone dipropionate)、及丙g同去炎松（Triamcinolone Acetonide) 至少其中之一。 23. 根據上述實施例中任意一個實施例所述之組合物，其中 該乙二型協同劑為鹽酸普魯卡地魯（Procaterol HC1)，該 皮質類固醇藥物係選自布***（Budesonide)、氣替卡 松（Fluticasone)、莫美他松（Mometasone)、環索奈德 (Ciclesonide)、倍氣米松（Beclomethasone)、去炎松 28 201212907 (Triamcinolone)，及其鹽基形態藥物氟替卡松丙酸酉旨 (fluticasone propionate)、丙酸倍氣米松(Beclomethasone dipropionate)、及丙酮去炎松(Triamcinolone Acetonide)至 少其中之一。 24. 根據上述實施例中任意一個實施例所述之組合物，其中 該乙二型協同劑為菲諾特洛氫溴酸鹽（Fenoterol hydrobromide)，該皮質類固醇藥物係選自布*** (Budesonide)、氟替卡松（Fluticasone)、莫美他松 (Mometasone)、環索奈德（Ciclesonide)、倍氯米松 (Beclomethasone)、去炎松（Triamcinolone)及其鹽基形態 藥物氟替卡松丙酸醋（Fluticasone propionate)、丙酸倍氯 米松(Beclomethasone dipropionate)、及丙酮去炎松 (Triamcinolone Acetonide)至少其中之一。 25. 根據實施例M2中任意一個實施例所述之組合物，其中該 氫氟烷推進劑係選用HFA134a或HFA227。 26·根據實施例1-12中任意一個實施例所述之組合物，其中該 氫氟烷推進劑係選用HFA 134a與HFA 227並用之組 合。 雖然本發明已以較佳實施例揭露如上，然其並非用以限 定本發明之範圍，任何熟習此技藝者，在不脫離本發明之精 神和範圍内，當可作各種更動與潤飾，因此本發明之保護範 圍當視後附之申請專利範圍所界定者為準。 【圖式簡單說明】 第一圖:實驗流程圖。 第一圖:長效乙二型協同劑之劑量與效果反應。 29 201212907 A:正常對照組B:氣喘控制組 C： Salmeterol Xinafoate 50.0 一 次劑量 D: Salmeterol Xinafoate 50.0 pg/kg — 日 2 次 X 7 天 E: Salmeterol Xinafoate 200.0 pg/kg —次劑量 F: Salmeterol Xinafoate .200.0 pg/kg '日 2 次 X 7 天 G: Salmeterol Xinafoate 500.0 pg/kg 一 次劑量 H: Salmeterol Xinafoate 500.0 pg/kg ^一 日 2 次.X 7 天 I: Salmeterol Xinafoate 500.0 pg/kg —日 1 次 X 7 天 ###表示與正常對照組相比較p&lt;0.001 ; *表示與氣喘控制組相比較p&lt;0.05 ; 第三圖：中效乙二型協同劑Procaterol之劑量與效果反應。 A:正常對照組 B:氣喘控制組 C: Procaterol 0.-5 pg/kg —次劑量 D: Procaterol 0.5 pg/kg —日 2 次 X 7 天 E: Procaterol 1.0 pg/kg — 次劑量 F: Procaterol 1.0 pg/kg — 日 2 次 X 7 天 G: Procaterol 1.5 pg/kg — 次劑量 H: Procaterol 1.5 pg/kg —日 2 次 X 7 天 I: Procaterol 2.5 pg/kg —次劑量 J: Procaterol 2.5 pg/kg — 日 2次 X 7天 K: Procaterol 5.0 pg/kg — 次劑量 L: Procaterol 5.0 pg/kg —日 2次 X 7天 M: Procaterol 10.0 pg/kg — 次劑量 N: Procaterol 10.0 pg/kg — 日 2次 X 7天 ###表示與正常對照組相比較p&lt;0.001 ; **表示與氣喘控制組相比較Ρ&lt;〇.〇1 ; 30 201212907 第四圖:複方Rudesonide搭配Procaterol之劑量與效果反 應。 A:正常對照組 B:氣喘控制組 C: Budesonide 9.0 pg/kg 搭配 Procaterol 0.5 pg/kg —次劑量 D: Budesonide 9.0 pg/kg 搭配 Procaterol 0.5 μ^/kg —日 2 次 X 7天 E: Budesonide 19.0 pg/kg 搭配 Procaterol 1.0 pg/kg — 次劑量 F: Budesonide 19.0 jig/kg 搭配 Procaterol 1.0 pg/kg —日 2 次 X 7天 G: Budesonide 27.0 pg/kg 搭配 Procaterol 1.5 (Jg/kg .— 次劑量 H: Budesonide 27.0 pg/kg 搭配 Procaterol 1.5 pg/kg—日 2 次 X 7天 I: Budesonide 45..0 jxg/kg 搭配 Procaterol 2.5 pg/kg — 次劑量 J.: Budesoriide 45.0 pg/kg搭配Procaterol 2.5 pg/kg —日 2次 X 7天 K: Budesonide 90.0 pg/kg 搭配 Procaterol 5.0 pg/kg — 次劑量 L: Budesonide 90.0 pg/kg搭配 Procaterol 5.0 pg/kg—日 2次 X 7天 M: Budesonide 180.0 pg/kg搭配Procaterol 10.0 pg/kg— 次劑量 N: Budesonide 225.0 pg/kg搭酉己Procaterol 12_5 ue/kg—日 2次 X7天 O: Budesonide 540.0 pg/kg 搭配 Procaterol 30.0 μβ/kg —日 1 次 X7天 P: Budesonide 900.0 pg/kg 搭配 Procaterol .50,0 pg/kg —次劑量 ###表示與正常對照組相比較pO.OOl ; **表示與氣喘控制組相比較p&lt;0.01 ; ***表示與氣喘控制組相比較ρ&lt;0·001。 31 201212907 【主要元件符號說明】 無 參考文獻 1. Papi, A., G. W. Canonica, et al. (2007). ^Rescue Use ofLactose 96.933% w/w% Total 100.00% w/w% Example Twenty-three Procaterol HC1 0.133% w/w% Budesonide 2.667% w/w% Lactose 97.200% w/w% Total 100.00% w/w% Example Twenty-four Procaterol HC1 0.133% w/w% Ciclensonide 0.667% w/w% Lactose 99.200% w/w% Total 100.00% w/w% Example 1. An inhaled combination composition comprising an effective amount One of the type II synergists is combined with an effective amount of a corticosteroid drug, if necessary with a pharmaceutically acceptable carrier. 2. The combination composition according to Example 1 for use as an emergency medication for asthmatic episodes in patients with asthma or chronic lung obstruction, or for pre-sleep or wake-up. 3. The combination composition according to any one of the preceding embodiments, wherein the ethylene type 2 synergist is selected from the group consisting of Albuterol, Fenoterol, Procaterol ), terbutaline and its salt-based drug Albuterol sulfate, Procaterol HCl, phenotate hydrogen 24 201212907 bromate (Fenoterol Itydrobromide), and sulfuric acid At least one of terbutaline sulphate. 4. The combination composition according to any one of the preceding embodiments, wherein the corticosteroid drug is selected from the group consisting of Budesonide, Fluticasone, Mometasone, and ciclesonide. (Ciclesonide), Beclomethasone, Triamcinolone, and its salt form morphine Fluticasone propionate, Beclo〇methasone dipropionate, and C-inflammation At least one of Triamcinolone Acetonide. 5. The combination composition according to any one of the above embodiments, wherein the ratio of the type II synergist to the corticosteroid is from 1:2 w/w% to 1:70 w/w%. 6. An inhalable spray composition' comprising a pharmaceutically acceptable carrier; and an effective amount of one of the ethylenediformate synergists in combination with an effective amount of a corticosteroid. 7. The spray composition according to embodiment 6, which is an emergency medication for asthmatic episodes in patients with asthma or chronic lung obstruction, and a pre-sleep or wake-up polarity control medication. 8. The spray composition according to any one of embodiments 6-7, wherein the ethylene type II synergist is selected from the group consisting of albuterol (Albuter®^ Fenoterol, Prouka) Procater〇1, Terbutaline and its base drug Albuterol sulfate, Prucatelu (Pr〇cater〇1 Ηα), Fennotrol Hydrobromide At least one of Fenoterol hydrobromide and Terbutaline sulphate. 9. A spray composition according to any one of embodiments 6-8 wherein the corticosteroid system is Selected from budesonide 25 201212907 (Budesonide), Fluticasone, Mometasone, Ciclesonide, Beclomethasone, Triamcinolone, and its base The morphological drug and its base form drug, Fluticasone propionate, Beclomethasone dipropionate, and Triamdnolone Acetonide, at least one of them. 10. According to Examples 6-9 The spray composition according to any one of the embodiments, wherein the ratio of the type II synergist to the corticosteroid drug is 1:4 w/w% J'| 1.: 50 w/w% β 11. according to the embodiment The spray composition of any one of embodiments 6 to 10 wherein the pharmaceutically acceptable carrier is optionally a hydrofluorocarbon propellant, a surfactant, a solvent, a suspending agent or lactose. A spray composition according to any one of embodiments 6-11 wherein the pharmaceutically acceptable carrier is a hydrofluorocarbon propellant, a surfactant, a solvent or a suspending agent. An inhaled dry powder composition comprising a pharmaceutically acceptable carrier; and an effective amount of one of the ethylene-type synergists in combination with an effective amount of a corticosteroid drug. 14. 4. The dry powder composition of Example 13 An emergency medication for asthmatic episodes of asthmatic patients with asthma or chronic lung obstruction, a pre-sleep or wake-up eccentricity control medication. 15. The dry powder composition of any of embodiments 13-14, wherein the type B The synergist is selected from the group consisting of Albuten 1), Fenoterol, Procaterol, terbutaline and its salt-based music Albuterol sulfate, procacaterol hydrochloride (pr〇caterol HC1) ), at least one of Fenoterol hydrobromide, barium sulfate _ % &amp; 26 201212907 (Terbutaline sulphate). 16. The dry powder composition of any one of embodiments 13-15 wherein the corticosteroid drug is selected from the group consisting of Budesonide, fluticasone, Momei: '(Mometasone), ciclesonide ( Ciclesonide), Beclomethasone, Ttiameinolone, and its morphological drugs and its salt form morphological form Fluticasone propionate, Beclo methas 〇ne dipropionate, and A dry powder composition according to any one of embodiments 13-16, wherein the ratio of the ethylene-type synergist to the corticosteroid is 1 The dry powder composition of any one of embodiments 13-17, wherein the pharmaceutically acceptable carrier is selected from lactose if necessary. The composition according to any one of the preceding embodiments, wherein the ethylene ditype synergist is Fenoterol, the corticosteroid drug is selected from the group consisting of Budesonide, Pine (Fluticaso Ne), mometasone, Ciclesonide, Beclomethasone, Triamcinolone, and its salt form morphine fluticasone propionate, propionate times And a composition according to any one of the preceding embodiments, wherein the ethylene-type synergist is Proca Procaterol, the corticosteroid drug is selected from the group consisting of Budesonide, Fluticasone, Mometasone, ciclesonide 27 201212907 (C'iclesonide), bismuth, and go Triamcinolone' and its salt-based morphological drug, Fluticasone propionate, gegeci〇niethasone * dipropionate, and Triamcinolone Acetonide, at least one of them. The composition according to any one of the preceding embodiments, wherein the ethylene ditype synergist is Albuterol, the corticosteroid drug is selected from the group consisting of Budesonide and Fluticasone. , mometasone 〇 ^ [0111 805 801 ^), cicles 〇 nide, Beci 〇methasone, triamcinolone ' and its base form drug fluticasone propionic acid At least one of ester (Fluticasonepropionate), beclomethasone dipropionate, and Triamcinolone Acetonide. The composition according to any one of the preceding embodiments, wherein the ethylene-type synergist is Albuterol sulfate, the corticosteroid drug is selected from the group consisting of Budesonide and fluticasone ( Fluticasone), Mometasone, Ciclesonide, Beclomethasone, Triamcinolone, and its salt form morphine fluticasone propionate, propionate times At least one of beclomethasone dipropionate, and triamcinolone Acetonide. The composition according to any one of the preceding embodiments, wherein the type II synergist is procaloril hydrochloride (Procaterol HC1), the corticosteroid drug is selected from the group consisting of Budesonide, Fluticasone, Mometasone, Ciclesonide, Beclomethasone, Triamcinolone 201212907 (Triamcinolone), and its salt form fluticasone propionate At least one of fluticasone propionate, Beclomethasone dipropionate, and Triamcinolone Acetonide. The composition according to any one of the preceding embodiments, wherein the ethylene ditype synergist is Fenoterol hydrobromide, the corticosteroid drug is selected from the group consisting of Budesonide (Budesonide) ), Fluticasone, Mometasone, Ciclesonide, Beclomethasone, Triamcinolone and its salt form morphine fluticasone propionate (Fluticasone propionate) At least one of Beclomethasone dipropionate and Triamcinolone Acetonide. The composition of any one of embodiments M2, wherein the hydrofluorocarbon propellant is HFA 134a or HFA 227. The composition of any of embodiments 1-12, wherein the hydrofluorocarbon propellant is selected from the group consisting of HFA 134a and HFA 227. Although the present invention has been disclosed in the above preferred embodiments, it is not intended to limit the scope of the present invention, and various modifications and refinements may be made without departing from the spirit and scope of the invention. The scope of the invention is defined by the scope of the appended claims. [Simple description of the diagram] The first picture: experimental flow chart. First: Dose and effect response of long-acting type B synergist. 29 201212907 A: Normal control group B: Asthma control group C: Salmeterol Xinafoate 50.0 One dose D: Salmeterol Xinafoate 50.0 pg/kg - 2 times X 7 days E: Salmeterol Xinafoate 200.0 pg/kg - Sub-dose F: Salmeterol Xinafoate . 200.0 pg/kg 'day 2 times X 7 days G: Salmeterol Xinafoate 500.0 pg/kg One dose H: Salmeterol Xinafoate 500.0 pg/kg ^ 2 times a day. X 7 days I: Salmeterol Xinafoate 500.0 pg/kg - 1 time per day X 7 days ### indicates that compared with the normal control group, p&lt;0.001; * indicates p<0.05 compared with the asthma control group; and the third figure: the dose-effect response of the intermediate-effect type B synergist Procaterol. A: Normal control group B: Asthma control group C: Procaterol 0.-5 pg/kg - Sub-dose D: Procaterol 0.5 pg/kg - 2 times X 7 days E: Procaterol 1.0 pg/kg - Sub-dose F: Procaterol 1.0 pg/kg — twice daily X 7 days G: Procaterol 1.5 pg/kg — sub-dose H: Procaterol 1.5 pg/kg — twice daily X 7 days I: Procaterol 2.5 pg/kg — sub-dose J: Procaterol 2.5 pg /kg — twice daily X 7 days K: Procaterol 5.0 pg/kg — sub-dose L: Procaterol 5.0 pg/kg — twice daily X 7 days M: Procaterol 10.0 pg/kg — sub-dose N: Procaterol 10.0 pg/kg — 2 times X 7 days ### means compared with the normal control group p&lt;0.001; ** means compared with the asthma control group Ρ&lt;〇.〇1; 30 201212907 Fourth picture: the dose of compound Rudesonide with Procaterol Effect response. A: Normal control group B: Asthma control group C: Budesonide 9.0 pg/kg with Procaterol 0.5 pg/kg - sub-dose D: Budesonide 9.0 pg/kg with Procaterol 0.5 μ^/kg - 2 times X 7 days E: Budesonide 19.0 pg/kg with Procaterol 1.0 pg/kg — sub-dose F: Budesonide 19.0 jig/kg with Procaterol 1.0 pg/kg — twice daily X 7 days G: Budesonide 27.0 pg/kg with Procaterol 1.5 (Jg/kg .— times Dosage H: Budesonide 27.0 pg/kg with Procaterol 1.5 pg/kg-day 2 times X 7 days I: Budesonide 45..0 jxg/kg with Procaterol 2.5 pg/kg - sub-dose J.: Budesoriide 45.0 pg/kg with Procaterol 2.5 pg/kg - twice a day X 7 days K: Budesonide 90.0 pg/kg with Procaterol 5.0 pg/kg - sub-dose L: Budesonide 90.0 pg/kg with Procaterol 5.0 pg/kg - 2 times X 7 days M: Budesonide 180.0 pg/kg with Procaterol 10.0 pg/kg - sub-dose N: Budesonide 225.0 pg/kg Pro Pro Procaterol 12_5 ue/kg - 2 times X7 days O: Budesonide 540.0 pg/kg with Procaterol 30.0 μβ/kg - day 1 Times X7 days P: Budesonide 900.0 pg/kg with Procaterol .50,0 p g/kg - sub-dose### indicates pO.OOl compared with the normal control group; ** indicates p<0.01 compared with the asthma control group; *** indicates ρ&lt;0·001 compared with the asthma control group. 201212907 [Explanation of main component symbols] No reference 1. Papi, A., GW Canonica, et al. (2007). ^Rescue Use of

Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma.&quot; New England Journal of Medicine 356(20): 2040-2052. 2. Albers M, Schermer T, Van WC. Airflow limitation as a screening tool: too relevant to ignore, too conspicuous to apply? Chest 2005;128(4):1898-900. 3. CHEST /128 / 4 / October, 2005 Supplement.Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma.&quot; New England Journal of Medicine 356(20): 2040-2052. 2. Albers M, Schermer T, Van WC. Airflow limitation as a screening tool: too relevant to ignore, Too conspicuous to apply? Chest 2005;128(4):1898-900. 3. CHEST /128 / 4 / October, 2005 Supplement.

3232

Claims (1)

201212907 七、申請專利範圍： 1·一種吸入性複方組合物，其包含： 有效量之一乙二型協同劑搭配一有效量之皮質類固醇藥 物1必要時搭配藥學上可接受之載體。 2.如申請專利範圍第1項之複方組合物，係用於氣喘或慢性 肺阻塞病人氣喘發作之緊急用藥，睡前或睡醒之偏極性 控制用藥。 3·如申請專利範圍第1項之複方组合物，其中該乙二型協同 劑係選自阿布叔醇（Albuterol)、菲諾特洛（pen〇ter〇l)、 普魯卡地魯（Procaterol)、特布他林（Terbutaline)及其鹽 基藥物硫酸阿布叔醇（Albuterol sulfate)、鹽酸普魯卡地魯 (Procaterol HC1)、菲諾特洛氫溴酸鹽（Fenoterol hydrobromide)、及硫酸特布他林（Terbutaline sulphate)至 少其中之一。 4. 如申請專利範圍第1項之複方組合物，其中該皮質類固醇 藥物係選自布*** （Budesonide)、氣替卡松 (Fluticasone)、莫美他松（Mometasone)、環索奈德 (Ciclesonide)、倍氯米松（Beclomethasone)、去炎松 (Triamcinolone)及其鹽基形態藥物氟替卡松丙酸酯 (Fluticasone propionate)、丙酸倍氯米松（Beci〇methasone dipropionate)、及丙嗣去炎松（Triamcinolone Acetonide) 至少其中之一。 5. 如申請專利範圍第1項之複方組合物，其中該乙二型協同 劑搭配該皮質類固醇藥物之比率為1:2 w/w%到1:70 w/w% ° 33 201212907 6. 一種吸入性喷霧劑組合物，其包含： 藥學上可接受之載體;以及 有效量之一乙二型協同劑搭配一有效量之皮質類固醇藥 物。 7. 如申請專利範圍第6項之喷霧劑組合物，係用於氣喘或慢 性肺阻塞病人氣喘發作之緊急用藥，睡前或睡醒之偏極 性控制用藥。 8. 如申請專利範圍第6項之喷霧劑組合物，其中該乙二型協 同劑係選自阿布叔醇 （Albuterol)、菲諾特洛 (Fenoterol)、普魯卡地魯（Procaterol)、特布他林 (terbutaline)及其鹽基藥物硫酸阿布叔醇（Albuterol sulfate)、鹽酸普魯卡地魯（Procaterol HC1)、菲諾特洛氫 漠酸鹽（Fenoterol hydrobromide)、及硫酸特布他林 (Terbutaline sulphate)至少其中之一。 9. 如申請專利範圍第6項之喷霧劑組合物，其中該皮質類固 醇藥物係選自布***（Budesonide)、氟替卡松 (Fluticasone)、莫美他松（Mometasone)、環索奈德 (Ciclesonide)、倍氯米松(Beclomethasone)、去炎松 (Triamcinolone)及其鹽基形態藥物及其鹽基形態藥物氟 替卡松丙酸酯（Fluticasone propionate)、丙酸倍氣米松 (Beclomethasone dipropionate)、及丙酿I 去炎松 (Triamcinolone Acetonide)至少其中之一。 10. 如申請專利範圍第6項之喷霧劑組合物，其中該乙二型協 同劑搭配該皮質類固醇藥物之比率為1:4 w/w°/〇到1:50 w/w% 〇 34201212907 VII. Patent Application Range: 1. An inhaled combination composition comprising: an effective amount of an ethylene-type synergist in combination with an effective amount of a corticosteroid drug 1 if necessary with a pharmaceutically acceptable carrier. 2. The compound composition of claim 1 is used for emergency medication for asthmatic attacks in patients with asthma or chronic lung obstruction, and the pre-sleep or wake-up polarity control medication. 3. The compound composition of claim 1, wherein the type B synergist is selected from the group consisting of Albuterol, pennoterol, and Procaterol. ), Terbutaline and its salt-based drug Albuterol sulfate, Procaterol HC1, Fenoterol hydrobromide, and sulphate At least one of the Terbutaline sulphate. 4. The combination composition of claim 1, wherein the corticosteroid drug is selected from the group consisting of Budesonide, Fluticasone, Mometasone, and ciclesonide. Ciclesonide), Beclomethasone, Triamcinolone and its salt form morphine Fluticasone propionate, Beci〇methasone dipropionate, and B. sinensis Triamcinolone Acetonide) At least one of them. 5. The compound composition of claim 1, wherein the ratio of the type II synergist to the corticosteroid is 1:2 w/w% to 1:70 w/w% 33 201212907. An inhalable spray composition comprising: a pharmaceutically acceptable carrier; and an effective amount of one of the ethylene-type synergists in combination with an effective amount of a corticosteroid. 7. The spray composition of claim 6 is used for emergency medication for asthma attacks in patients with asthma or chronic obstructive pulmonary obstruction, and for extreme control before bedtime or wakefulness. 8. The spray composition of claim 6, wherein the type II synergist is selected from the group consisting of Albuterol, Fenoterol, Procaterol, Terbutaline and its salt-based drug Albuterol sulfate, Procaterol HC1, Fenoterol hydrobromide, and terbuta sulfate At least one of the forests (Terbutaline sulphate). 9. The spray composition of claim 6, wherein the corticosteroid drug is selected from the group consisting of Budesonide, Fluticasone, Mometasone, and Ciclesonide. ), beclomethasone, triamcinolone and its salt-based morphological drugs and its salt form morphological drug Fluticasone propionate, Beclomethasone dipropionate, and propyl I At least one of Triamcinolone Acetonide. 10. The spray composition of claim 6, wherein the ratio of the type B co-agent to the corticosteroid is 1:4 w/w°/〇 to 1:50 w/w% 〇 34