TW470647B - Composition and pharmaceutical combination kit comprising formoterol and budesonide - Google Patents

Composition and pharmaceutical combination kit comprising formoterol and budesonide Download PDF

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Publication number
TW470647B
TW470647B TW086114371A TW86114371A TW470647B TW 470647 B TW470647 B TW 470647B TW 086114371 A TW086114371 A TW 086114371A TW 86114371 A TW86114371 A TW 86114371A TW 470647 B TW470647 B TW 470647B
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Taiwan
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active ingredient
patent application
budesonide
composition
scope
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TW086114371A
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Chinese (zh)
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Jan Trofast
Anders Ullman
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Astra Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Abstract

The invention provides a composition or kit having as a first active ingredient formoterol, or a salt or solvate derivative thereof, and having as a second active ingredient budesonide, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, and the use of the composition and kit in the treatment of respiratory disorders.

Description

ο 7 4 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（1 ) 發明範畴 本發明提供醫藥活性物質之新组合，其具治療呼吸疾病 之用途，特別是對氣喘。 發明背景 儘管最近對氣喘了解之進展與強力及有效之抗氣喘藥物 之引介，氣喘仍係所知有限而且通常難以治療之疾病。由 於認知氣喘係慢性發炎疾病，近來在治療該病已有進展。 目前之治療旨在控制症狀並減低發炎，症狀包括未控制之 氣道發炎，其可能造成黏膜損傷與結構變化，可能造成氣 道無法復原之窄化與肺纖維變性。 症狀或許可藉点2-腎上腺素受體拮抗劑控制，諸如舒喘寧 、紗馬得洛、特普他林（terbutaline)與福馬得洛，福馬得洛 較佳，因其效果持續久，其作用快而且不太會使人夜間轉 醒。 預防治療通常係藉提供類固醇，諸如倍氯美松 diproprionate、氟的可松、fluticasone丙酸醋與布得索奈，其 中又以布得索奈較優，因爲其可給高吸入劑量（達每日2毫 克）但只具低的全身效應。對成人與兒童之長期臨床研究顯 示吸入之布得索奈整體安全性極佳。 發明摘要 根據本發明，其提供一種组合物，包括成混合物狀態之： (a) 第一種活性成份，其係福馬得洛、福馬得洛之醫藥可接 受之鹽或溶劑合物或此種鹽之溶劑合物；與 (b) 第二種活性成份，其係布得索奈； _-4 -_ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） I---------装------訂 (請先閱讀背面之注意事項再填寫於頁) 470647 經濟部中央標準局員工消費合作社印製 五、發明説明（2 ) -中第種活性成份對第二種活性成份之莫耳數比係由 1 :30至1 :36，又以約i :32 5較佳 根據本發明，其進_步提供—種套件，包括： (D-種容器，其包含第一種活性成份， ㈤-種容器，其包含第二種活性成份，與 (11)依序或刀開施予需此之病人第-與第二種活性成份之指 丁其中第-種活性成份對第二種活性成份之莫耳數比 係由1.3 0至1: 3 6，又以約j : 3 2 5較佳。 由吸入而施予根據本發明之組合物可治療罹患諸如氣 喘之呼吸疾病之病人。替代地治療此種病人可經由吸入而 依序或分開施用： (i)某劑量之第一種活性成份，與 (ϋ)某劑量之第二種活性成份； 其中第-種活性成份對第二種活性成份之莫耳數比係由 1: 3 0至1 ·· 3 6，又以約！ ： 3 2 5較佳。 員發現根據本發明之活性成份的组合係、具優點的，因爲 其與已知之冶療比較具有顯著改善之抗-發炎效果。國際專 利公告唬碼WO 93 / 1 1 773揭示具廣大重量比例範圍之布得 索，與福馬得洛組合。本文件中對本發明之系統揭示之组 合最切近的實例爲福馬得洛反丁晞二酸鹽二水合物對布得 索奈重量比爲〇.〇6:1，亦即莫耳數比爲1:16 3。根據本發 明之活性成份組合當用於治療罹患氣喘之病人時與此已知 組合比較，其結果出奇地好。 孩套件乙第一與第二種活性成份於治療呼吸疾病時可依 本紙張尺度適用中國國家標^ ( CNS〉A4規格（210X297公蔆了 ' I..... - I m. 1 - 1..... I :衣!i ! - - - i —^^1 (請先閱讀背面之注意事項耳填寫I頁〕 470647 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（3 ) 序或分別施用，依序施用意指施用第一與第二種活性成份 時係個濟接另一個’若是分別施用亦具所需效果，但必 須小於12小時，離2小時之内較佳，差距3〇分鐘内更佳。 較佳條件爲施用之第—種活性成份提供由1〇至25〇毫微莫 耳日劑量（由15至120毫微莫耳較佳）而施用之第二種活性成 份提供由0.1至10微莫耳之日劑量（〇 2至5微莫耳較佳）或由 39至4300微克之第二種活性成份（由86至215〇微克較佳）須 符合罘一種活性成份對第二種活性成价之莫耳數比落在由 1:30至1:36之範圍的原則。 福馬得洛適合之生理可接受的鹽包括衍生自無機與有機 酸之酸加成鹽，例如氯化鹽、溴化鹽、硫酸鹽、磷酸鹽、 順丁埽二酸鹽、反丁埽二酸鹽、酒石酸鹽、檸檬酸鹽、苄 酸鹽、4 -甲氧基苄酸鹽、2_或4_羥基苄酸鹽、4_氣苄酸鹽 、對-甲苯磺酸鹽、甲烷續酸鹽、抗壞血酸鹽、乙酸鹽、琥 珀酸鹽、乳酸鹽、或二酸鹽、葡糖酸鹽、三羰丙烯酸鹽、 羥基S _羧酸鹽或油酸鹽或其溶劑合物。第一種活性成份以 福馬得洛反丁烯二酸鹽較佳，尤其是二水合物。 W弟種活性成伤爲福馬件洛反丁 '烯二酸鹽二水合物時 ’則第一種活性成份之較佳日劑量爲由4至1 〇 〇微克，由6至 5 0微克更佳（須符合第一種活性成份對第二種活性成份之莫 耳數比係爲由1: 3 〇至1: 3 6之範圍的原則）。 最佳條件爲本發明之组合物或套件包括6微克福馬得洛反 丁烯二酸鹽二水合物與2〇〇微克布得索奈，或4 5微克福馬 得洛反丁烯二酸鹽二水合物與160微克布得索奈，其中之— _ - 6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ' " ""— 1-!· ...... II I - I n I I I - - I I 1!.. 1! 丁 (請先閱讀背面之注意事項#·填寫本頁) 470647 經濟部中央檩準局員工消費合作杜印製 A7 -------— B7 五、發明説明（4 ) 可施予達每天4次。 替代地，本發明之组合物或套件包括12微克福馬得洛反 丁烯二酸鹽二水合物4〇〇微克布得索奈或爲9微克福馬得洛 反丁烯二酸鹽二水合物與32〇微克布得索奈，二者皆每日施 用一或二次。 較佳者係使用活性成份時混合以一或多種醫藥可接受添 加劑、稀釋劑或載體，較佳者係其量爲每個劑量5 〇微克至 25毫克，更佳者是其量爲由5〇微克至1〇毫克，最佳是其量 馬由100至2000微克。適合的稀釋劑或載體之實例包括乳 糖、葡聚糖、甘露醇與葡萄糖。較佳者係使用乳糖，尤其 是單水合物。 吾人應明瞭在所给之每種活性成份量之時，其皆是測定 量。當施用活性成份時，病人吸入之每一成份之量皆可與 測足量有別，例如由於活性成份存留於吸入裝置中之情形 。甚且，當分開；!周配活性成份時，個別之施用量未必要依 比例減少。因此，活性成份之施用比例可與測定比例有別 ’但施用比例以落在上述之特定測定比例者較佳。 本發明所用之一或多種活性成份的乾粉型式較佳，成微 小顆粒者更佳，例如微細化乾粉，例如所具之大略平均直 徑不逾10微米，例如1至5微米，成團狀之微細乾粉更佳， 相對於或團狀之替代方法，該微細化之活性成份可爲混合 一或多種醫藥可接受添加物、稀釋劑或載體之處方型式。 處方混合物係微細活性成份與醫藥可接受添加物、稀釋劑 或载體之粗顆粒的組合。本發明所用成份可利用熟諳此藝 ^^1' fn ·: ϋ^— m n , ^ϋ· ^^^1 ^^^1 ^^^1 n^i ^^^1--aJ. (請先閱讀背面之注意事項#填寫t頁) 470647 、發明説明（5 ) 已知方法製成這些較佳型式。 根據本發明，其進-步提供使㈤根據 套件製造用以治療呼吸疾病，仞4 ^ Λ 乙組口物或 像吁及疾届，例如氣喘之藥物。本發明亦 3供使用布得索奈或福馬得洛製造根據本發明之套件或组 合物作爲治療呼吸疾病例如氣喘之用途。 ， 施用方法可經口服或鼻内吸入，較佳者係將該成份改成 由乾粉吸人器，加壓之測定劑量吸人器或嘴霧劑施用。 當將组合物或套件内成份改成由加壓吸人器施用時，立 以微細化型式較佳。其係溶解或者較佳者係懸浮於液能推 進劑混合物。所用之推進劑得包括氟氯化碳、烴或氣化燒 類。特佳之推進劑爲Pl34a(四氟乙幻與卩⑵（七氣丙幻 ’其皆可各別或組合使用。他們可視情形組合—或多種其 他推進劑與/或一或多種界面活性劑與/或一或多種其他 賦型劑使用例如乙醇、潤滑劑抗氧化劑與/或安定劑。 當改變本發明組合物或套件成份於經噴霧劑施用時，其 可爲噴霧之溶液懸浮劑或溶液型式加或不加適合的pH或張 力調整，並可爲單位劑量或多劑量裝置。 該组合物或套件可視情形分成丨至4次之分別劑量型式施 用’而以一天一次或兩次較佳。 本發明可藉下列實例加以説明，但其並非在限制應用範 園。在實例中，微細化係採傳統方式進行，可使每種成份 之顆粒大小範圍適於吸入施係Astra AB之商標。 實例1 和重6份之福馬得洛反丁烯二酸鹽二水合物混合以重7 9 4 -8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） I---------士表------1T (請先閲讀背面之注意事項界填寫I頁) ο 7 4 4 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（6 ) 份之乳糖單水合物。利用高壓空氣噴射研磨微細化該混合 物，然後利用EP-A-717 616之方法調整之，利用混合方式將 重200份之微細化的布得索奈添加至該調整過之產物並藉低 壓噴射研磨使之均質化。然後，利用EP-A-721 331之方法使 該混合物成球體並充填入T u r b u h a 1 e r之辟存間隔内。 實例2 將重4.5份之福馬得洛反丁烯二酸鹽二水合物混合以重 83 5份之乳糖單水合物。利用高壓空氣喷射研磨微細化該混 合物，然後利用EP-A-717 616之方法調整之。利用混合方式 將重1 6 0份之微細化的布得索奈添加至該調整過之產物並藉 低壓噴射研磨使之均質化。然後，利用EP-A-721 331之方法 使該混合物成球禮並充填入T u r b u h a 1 e r之貯存間隔内。 實例3 將重1 2份之福馬得洛反丁烯二酸鹽二水合物混合以重5 8 8 份之乳糖單水合物。利用高壓空氣喷射研磨微細化該混合 物，然後利用EP-A-717 616之方法調整之，利用混合方式將 重4 0 0份之微細化的布得索奈添加至該調整過之產物並藉低 壓噴射研磨使之均質化。然後，利用EP-A-721 331之方法使 該混合物成球體並充填入T u r b u h a 1 e r之貯存間隔内。 實例4 將重6份之福馬得洛反丁烯二酸鹽二水合物混合以重9 9 4 份之乳糖單水合物《利用高壓空氣噴射研磨微細化該混合 物，然後利用EP-A-717 616之方法調整之。然後，利用EP-A-721 331之方法使該混合物成球體並充填入Turbuhaler之貯存 間隔内。 ^^^1 nn· nn mu nn Tm I— —1— Ml 1^^^ m·— u ml 1^1^1-' A^、v'口 (請先閱讀背面之注意事項#·填寫t頁) 本紙張尺度適用中國國家標隼（CNS ) A4規格（210XM7公釐） 470647 A7 經濟部中央標準局員工消費合作社印製 B7五、發明説明（7 ) 將重2 0 0份之微細化的布得索奈混合物以重8 0 0份之乳糖 單水合物。利用高壓空氣噴射研磨微細化該混合物，然後 利用EP-A-717 616之方法調整之。然後，利用EP-A-721 331之 方法使該混合物成球體並充填入Turbuhaler之貯存間隔内。 實例5 將重4.5份之福馬得洛反丁烯二酸鹽二水合物混合以重 9 9 5份之乳糖單水合物。利用高壓空氣噴射研磨微細化該混 合物，然後利用EP-A-717 616之方法調整之。然後，利用EP-A-721 331之方法使該混合物成球體並充填入Turbuhaler之 貯存間隔内。 將重1 6 0份之微細化的布得索奈混合以重8 4 0份之乳糖單 水合物。利用高壓空氣噴射研磨微細化該混合物，然後利 用EP-A-717 616之方法調整之。然後，利用EP-A-721 331之方 法使該混合物成球體並充填入Turbuhaler之貯存間隔内。 實例6 將重1 2份之福馬得洛反丁烯二酸鹽二水合物混合以重9 8 8 份之乳糖單水合物。利用高壓空氣噴射研磨微細化該混合 物，然後利用EP-A-717 616之方法調整之。然後，利用EP-A-721 3 31之方法使該混合物成球體並充填入T u r b u h a 1 e r之貯 存間隔内。 將重4 Ο 0份之微細化的布得索奈混合 以重6 0 0份之乳糖 單水合物。利用高壓空氣噴射研磨微細化該混合物，然後 利用EP-A-717 616之方法調整之。然後，利用EP-A-721 331之 方法使該混合物成球體並充填入Turbuhaler之貯存間隔内。 ^^^1 fln_^i mu I n^— ι^ϋ ^^^^1 -'J (請先閱讀背面之注意事項'再填寫l頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 47 47ο 7 4 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (1) The scope of the invention The present invention provides a new combination of medicinal active substances, which has the purpose of treating respiratory diseases, especially for asthma. BACKGROUND OF THE INVENTION Despite recent advances in understanding asthma and the introduction of powerful and effective anti-asthmatic drugs, asthma is a disease with limited knowledge and often difficult to treat. Because of the chronic inflammatory disease of the cognitive asthma system, progress has recently been made in treating the disease. Current treatments are designed to control symptoms and reduce inflammation. Symptoms include uncontrolled airway inflammation, which may cause mucosal damage and structural changes, may cause narrowing of the airways and pulmonary fibrosis. Symptoms may be controlled by 2-adrenoceptor antagonists, such as Shuchuanning, samadrol, terbutaline, and formadrol. Formadrol is better because its effects last for a long time. It is fast and does not wake people up at night. Prophylactic treatment is usually provided by steroids such as beclomethasone diproprionate, flucortisone, fluticasone propionate and budesonide, of which budesonide is preferred because it can give high inhaled doses 2 mg per day) but with only low systemic effects. Long-term clinical studies in adults and children have shown that inhaled budesone is extremely safe. SUMMARY OF THE INVENTION According to the present invention, there is provided a composition comprising: (a) the first active ingredient, which is formadrol, a pharmaceutically acceptable salt or solvate of formadrol, or such a salt Solvates; and (b) the second active ingredient, which is Budesonide; _-4 -_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) I ----- ---- Install ------ Order (please read the notes on the back before filling in the page) 470647 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (2)-The first active ingredient pair The molar ratio of the second active ingredient is from 1:30 to 1:36, and preferably about i: 32 5 according to the present invention, which further provides a kit including: (D- container, It contains the first active ingredient, a kind of container, which contains the second active ingredient, and (11) is administered to a patient in need of the order of the first or the second active ingredient. The molar number ratio of one active ingredient to the second active ingredient is from 1.30 to 1: 3 6 and preferably about j: 3 2 5. The root is administered by inhalation. The composition of the present invention can treat patients suffering from respiratory diseases such as asthma. Alternatively, such patients can be administered sequentially or separately by inhalation: (i) a dose of the first active ingredient, and (ii) a dose The second active ingredient; the molar number ratio of the first active ingredient to the second active ingredient is from 1: 30 to 1 ·· 3 6 and again approx.: 3 2 5 is better. The combination of active ingredients according to the present invention is advantageous because it has significantly improved anti-inflammatory effects compared to known metallurgical treatments. International Patent Bulletin WO 93/1 1 773 discloses fabrics with a wide range of weight ratios Desox, combined with formadrol. The closest example of the combination disclosed in this document to the system of the present invention is formadrol transbutanedioate dihydrate to budesonide weight ratio of 0.06: 1. That is, the molar ratio is 1:16 3. The active ingredient combination according to the present invention is surprisingly good when compared with this known combination when used in the treatment of patients suffering from asthma. Kid Kit B First and Second Active ingredients can be used in the treatment of respiratory diseases Paper size applies to Chinese national standard ^ (CNS> A4 specification (210X297 male diamond 'I .....-I m. 1-1 ..... I: clothing! I!---I — ^^ 1 (Please read the notes on the back first and fill in page I) 470647 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy When the active ingredient is used, it is effective if it is applied separately, but it must be less than 12 hours, better within 2 hours, and better within 30 minutes. The preferred condition is that the first active ingredient provided provides a daily dose of 10 to 25 nanomoles (preferably from 15 to 120 nanomoles) and the second active ingredient provided provides 0.1 to 10 micromoles. Mohr's daily dose (preferably 02 to 5 micromoles) or 39 to 4300 micrograms of the second active ingredient (preferably 86 to 2150 micrograms) must meet the following criteria: The principle that the mole ratio of price falls in the range from 1:30 to 1:36. Suitable physiologically acceptable salts of formaldehyde include acid addition salts derived from inorganic and organic acids, such as chlorides, bromides, sulfates, phosphates, maleate, fumarate Salts, tartrates, citrates, benzates, 4-methoxybenzates, 2- or 4-hydroxybenzates, 4-gas benzates, p-toluenesulfonates, methanates , Ascorbate, acetate, succinate, lactate, or diacid, gluconate, tricarbonylacrylate, hydroxy S_carboxylate, or oleate, or a solvate thereof. The first active ingredient is formaldehyde fumarate, especially dihydrate. When the active ingredient of F. spp. Is fumarate, but ''s oxalate dihydrate, the preferred daily dose of the first active ingredient is from 4 to 100 micrograms, more preferably from 6 to 50 micrograms. (It must meet the principle that the molar ratio of the first active ingredient to the second active ingredient is in the range from 1:30 to 1:36). The best conditions are that the composition or kit of the present invention includes 6 micrograms of formmadelo fumarate dihydrate and 200 micrograms of budesonide, or 45 micrograms of formamalo fumarate dihydrate Hydrate and 160 micrograms of Budssonai, among which — _-6-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) '" " " — 1-! · ... .. II I-I n III--II 1! .. 1! Ding (please read the notes on the back # · Fill this page first) ----- B7 V. Description of Invention (4) It can be administered up to 4 times a day. Alternatively, the composition or kit of the present invention includes 12 micrograms of formmadelo fumarate dihydrate, 400 micrograms of budesonide, or 9 micrograms of formmadelo fumarate dihydrate and 32 micrograms of budesone, both were applied once or twice daily. Preferably, the active ingredient is mixed with one or more pharmaceutically acceptable additives, diluents or carriers. The preferred amount is 50 micrograms to 25 milligrams per dose, and the more preferred amount is 50 micrograms. Micrograms to 10 milligrams, most preferably the amount is from 100 to 2000 micrograms. Examples of suitable diluents or carriers include lactose, dextran, mannitol and glucose. Preferably, lactose is used, especially monohydrate. I should be aware that when each active ingredient amount is given, it is a measured amount. When administering the active ingredient, the amount of each ingredient inhaled by the patient may be different from the measured amount, for example due to the fact that the active ingredient remains in the inhalation device. Furthermore, when divided into separate active ingredients, it is not necessary to reduce the application rate in proportion. Therefore, the application ratio of the active ingredient may be different from the measurement ratio, but it is preferable that the application ratio falls within the specific measurement ratio described above. The type of dry powder of one or more active ingredients used in the present invention is better, and it is more preferable to form small particles. For example, micronized dry powder, for example, has a roughly average diameter of not more than 10 micrometers, such as 1 to 5 micrometers. The dry powder is better. Compared to the alternative method of agglomerates, the miniaturized active ingredient may be a formula in which one or more pharmaceutically acceptable additives, diluents or carriers are mixed. A prescription mixture is a combination of finely divided active ingredients and coarse particles of a pharmaceutically acceptable additive, diluent or carrier. The ingredients used in the present invention can be cooked using this technique ^^ 1 'fn ·: ϋ ^ — mn, ^ ϋ · ^^^ 1 ^^^ 1 ^^^ 1 n ^ i ^^^ 1--aJ. (Please first Read the notes on the back #Fill in page t) 470647, invention description (5) Known methods to make these better types. According to the present invention, it further provides a kit for treating respiratory diseases according to the present invention, which is a group 4 mouthpiece or a medicine that appeals to a disease such as asthma. The present invention is also intended for use in the manufacture of a kit or composition according to the present invention for the treatment of respiratory diseases such as asthma using budesone or formadrol. The method of administration can be by oral or intranasal inhalation. The preferred method is to change the ingredient to dry powder inhaler, pressurized dose inhaler or mouth spray. When the composition or the contents of the kit are changed to be applied by a pressure inhaler, a miniaturization type is preferred. It is dissolved or preferably suspended in a liquid energy propellant mixture. The propellant used may include CFCs, hydrocarbons, or gasifiers. Particularly good propellants are Pl34a (tetrafluoroacetic acid and thallium (seven-qi propionic acid), which can be used individually or in combination. They can be combined according to the situation-or a variety of other propellants and / or one or more surfactants and / Or one or more other excipients using, for example, ethanol, lubricant antioxidants and / or stabilizers. When the composition or kit ingredients of the present invention are changed for spray application, it can be a sprayed solution suspension or solution type plus Or without suitable pH or tonicity adjustment, and can be a unit dose or a multi-dose device. The composition or kit may be divided into 丨 to 4 separate dosage forms, and is preferably administered once or twice a day. The present invention The following examples can be used to illustrate, but it is not limited to the application of the garden. In the example, the miniaturization is performed in a traditional manner, which can make the particle size range of each component suitable for inhalation of the trademark of Astra AB. Example 1 and 6 parts by weight of Formallo fumarate dihydrate mixed with weight 7 9 4 -8-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) I ------- --- watch ------ 1T ( Please read the notes on the back page and fill in page I) ο 7 4 4 A7 B7 printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (5) invention description (6) parts of lactose monohydrate. Use high-pressure air jet milling to refine this The mixture was then adjusted by the method of EP-A-717 616, and 200 parts by weight of finely divided budesone was added to the adjusted product by a mixing method and homogenized by low-pressure jet milling. Then, using The method of EP-A-721 331 made the mixture into a sphere and filled it into the storage interval of Turbuha 1 er. Example 2 4.5 parts by weight of formmadero fumarate dihydrate were mixed with a weight of 83 5 Parts of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. Using a mixing method, 160 parts by weight of finely refined budesone was added to the mixture. The adjusted product was homogenized by low-pressure jet milling. Then, the mixture was ball-shaped using the method of EP-A-721 331 and filled into the storage interval of Turbuha 1 er. Example 3 The weight will be 12 parts Fomad The fumarate dihydrate is mixed to weigh 5 8 8 parts of lactose monohydrate. The mixture is refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. 400 parts of finely divided budesone were added to the adjusted product and homogenized by low-pressure jet milling. Then, the mixture was sphered and filled with Turbuha by the method of EP-A-721 331. Within a storage interval of 1 er. Example 4 6 parts by weight of fumadol fumarate dihydrate were mixed to weigh 9 94 parts by weight of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then Use EP-A-717 616 to adjust it. Then, the mixture was sphered by the method of EP-A-721 331 and filled into the storage interval of Turbuhaler. ^^^ 1 nn · nn mu nn Tm I— —1— Ml 1 ^^^ m · — u ml 1 ^ 1 ^ 1- 'A ^, v' mouth (please read the note on the back first # · fill in t Page) This paper size is applicable to China National Standard (CNS) A4 (210XM7mm) 470647 A7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs B7 V. Invention Description (7) It will be 200 micro parts in fine detail The budesonide mixture is 800 parts by weight of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. Then, the mixture was sphered by the method of EP-A-721 331 and filled into the storage interval of Turbuhaler. Example 5 4.5 parts of fumadol fumarate dihydrate was mixed to give 995 parts by weight of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. Then, the mixture was sphered by the method of EP-A-721 331 and filled into the storage interval of Turbuhaler. 160 parts by weight of finely divided budesone were mixed to obtain 840 parts by weight of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. Then, the mixture was sphered by the method of EP-A-721 331 and filled into the storage interval of Turbuhaler. Example 6 12 parts by weight of fumadol fumarate dihydrate were mixed to obtain 98.8 parts by weight of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. Then, the mixture was formed into a sphere by the method of EP-A-721 3 31 and filled into the storage interval of Tu r b u h a 1 e r. 4 parts by weight of finely divided budesonide were mixed to 600 parts by weight of lactose monohydrate. The mixture was refined by high-pressure air jet milling, and then adjusted by the method of EP-A-717 616. Then, the mixture was sphered by the method of EP-A-721 331 and filled into the storage interval of Turbuhaler. ^^^ 1 fln_ ^ i mu I n ^ — ι ^ ϋ ^^^^ 1 -'J (Please read the notes on the back 'before filling in page l) This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 47 47

第8611437號專利申請案 中文補充說明書(88年8月） 方法： 852名經以布得索奈(每日兩次800毫克)治療四週之病患，在經以糖皮 質激素處理後，以隨機之方式，利用乾粉吸入器(Turbuhaler)每日施予2 次下列之藥劑：100微克布得索奈加安慰劑；100微克布得索奈加12微 克福馬得洛；400微克布得索奈加安慰劑；或400微克布得索奈加12微 克福馬得洛。視需要，可施用特普他林(terbutaline)。整個療程持續一 年，再比較四組中之氣喘之惡化頻率、症狀及肺功能。當病患需口服 糖皮質激素或當肺之高峯流量連續兩天較基準線值減少大於30%時， 則視為嚴重之惡化。 結果： 當將低劑量之布得索奈中添加福馬得洛時，其可分別降低％%及4〇〇/〇 之嚴重及輕度惡化頻率。當單獨施用較高劑量布得索奈時，嚴重及輕 度惡化頻率則可分別降低49%及37%。以福馬得洛及較高劑量布得索 奈治療之病患，其降低之程度最大一分別為63%及62%。當以含有福 馬得洛之藥劑及較鬲布得索奈之藥劑治療，其皆可改善氣喘之症狀及 肺功能，但以含有福馬得洛之藥劑其改善程度較大。 討論· 持續性具有氣喘症狀之病患’除可以吸入之糖皮質激素予以治療外， 以添加福馬得洛之布得索奈治療劑’或使用較高劑量之布得索奈皆會 有所幫助。添加福馬得洛之布得索奈治療齡可改善症狀及肺雜Y 亦不會減少對氣喘之控制。 U:\PTS\GAN\GANC\DOCUMENT\49858R1 DOCX22Supplementary Specification No. 8611437 for the Chinese Patent Application (August 88) Method: 852 patients treated with budesone (800 mg twice daily) for four weeks. After treatment with glucocorticoids, randomized By means of a dry powder inhaler (Turbuhaler), the following medicaments were administered twice daily: 100 micrograms of budesonega placebo; 100 micrograms of budesonega 12 micrograms of formadrol; 400 micrograms of budesonega placebo; Or 400 micrograms of Budesonica 12 micrograms of formaldehyde. If desired, terbutaline can be administered. The entire course of treatment lasted one year, and the frequency of exacerbations, symptoms, and lung function in the four groups were compared. When the patient needs oral glucocorticoids or when the peak lung flow decreases by more than 30% from the baseline value for two consecutive days, it is considered a severe deterioration. Results: When formamide was added to low-dose budesonide, it could reduce the frequency of severe and mild deterioration by %% and 400 / 〇, respectively. When a higher dose of budesonide was administered alone, the frequency of severe and mild deterioration was reduced by 49% and 37%, respectively. Patients treated with formalin and higher doses of budesonide experienced a maximum reduction of 63% and 62%, respectively. When treated with a drug containing formadrol and a drug that is more stable than budesonide, both can improve the symptoms of asthma and lung function, but the drug containing formadrol has a greater degree of improvement. Discussion · Patients with persistent asthma symptoms "in addition to inhalable glucocorticoids for treatment, addition of fumadrol to budesonide therapy" or higher doses of budesonide will help . The addition of budesonide to formate to improve the symptoms and lung miscellaneous Y does not reduce the control of asthma. U: \ PTS \ GAN \ GANC \ DOCUMENT \ 49858R1 DOCX22

Claims (1)

470647 第86114371號專利申請案 锰 中文申請專利範圍修正本(9〇年4月）gg470647 Patent Application No. 86114371 Manganese Chinese Patent Application Amendment (April 90) gg 經濟部中央標準局員工消費合作社印製 六、申請專利範圍 1. 一種用於治療呼吸疾病之组合物，其包括成混合物狀態 之： (a) 選定之第一種活性成份，其係福馬得洛（f〇rm〇ter〇1)， 其醫藥上可接受之鹽或溶劑合物及此類鹽之溶劑合 物，與 (b) 弟一種活性成份，其係布得索奈（budesonide)， 其中組合物中（a)對（b)之莫耳數比係由1:30至1:36。 2. 根據申請專利範圍第1項之組合物，其中該莫耳數比係約 1:32.5。 3·根據申請專利範圍第1或2項之組合物，其中該第一種活 性成份係福馬得洛反丁烯二酸鹽二水合物。 4. 根據申請專利範圍第1項之組合物，另外包括醫藥可接受 添加物，稀釋劑或載體，其可為乳糖、葡聚糖、甘露醇 或葡萄糖。 5. —種用於治療呼吸疾病之醫藥組合套件，其包括： (a) —種容器，其包含選自福馬得洛（form〇ter〇i)、其醫藥可 接受鹽類或溶劑合物，及此類鹽之溶劑合物之第一種 活性成份，與 (b) —種容器’其包含布得索奈（budesonide)並作為第二種 活性成份， (c) 依序或分開施予需此之病人第一與第二種活性成份之 指示， 其中第一種活性成份對第二種活性成份之莫耳數比係由 1 :30 至 1:36。 本紙張尺度逋用中國國家標準（CNS ) A4規格（210X297公釐） ' —^i^· i H —^^1 —^^1 I i I I ^^^1 ^^^1 ^^^1 HH —^ϋ、jxaJ i靖先閲讀背面之Vi意事項再填寫本耳j 圍範 -ΊΠΨ 專請 中 8 8 8 8 ABCD 4>s 6*根據申請專刺雜阁麵/ 比係約1:32·5。’:驚醫藥組合套件’其中該莫洱1 7. 根據申請專利範園第 活性成份係福馬得洛反;;醫::合套:物其中該 8. :=r_5,=::物另外包_ 接又添加物，稀釋劑或載體。 9·根據申請專利範圍 係細分之乾㈣^醫藥组合套件，其中每種成< 式而且每種容器俱為乾粉吸入器。 ---------'衣— (請先閱讀背面之注意事項再填寫本頁) 1T 經濟部中央標準局員工消費合作社印裝 -2· 本紙張尺度適用中國國家標準（CNS ) A4現格（210X297公釐）Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 6. Scope of Patent Application 1. A composition for the treatment of respiratory diseases, which includes a mixture of: (a) the first active ingredient selected, which is formaldehyde (F〇rm〇ter〇1), its pharmaceutically acceptable salts or solvates and solvates of such salts, and (b) a kind of active ingredient, which is budesonide, where The molar ratio of (a) to (b) in the composition is from 1:30 to 1:36. 2. The composition according to item 1 of the scope of patent application, wherein the molar number ratio is about 1: 32.5. 3. The composition according to item 1 or 2 of the scope of the patent application, wherein the first active ingredient is formadrol fumarate dihydrate. 4. The composition according to item 1 of the patent application scope, further comprising a pharmaceutically acceptable additive, diluent or carrier, which may be lactose, dextran, mannitol or glucose. 5. A pharmaceutical combination kit for the treatment of respiratory diseases, comprising: (a) a container comprising a substance selected from the group consisting of formatro, a pharmaceutically acceptable salt or solvate thereof, And the first active ingredient of a solvate of such salts, and (b) a container 'which contains budesonide as the second active ingredient, (c) is administered sequentially or separately The patient's indication of the first and the second active ingredient, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36. This paper uses Chinese National Standard (CNS) A4 specifications (210X297 mm) '— ^ i ^ · i H — ^^ 1 — ^^ 1 I i II ^^^ 1 ^^^ 1 ^^^ 1 HH — ^ Ϋ 、 jxaJ i Jing first read the Vi notice on the back and then fill in this j. Fan Fan-ΊΠΨ Special request 8 8 8 8 ABCD 4 > s 6 * According to the application, it is about 1:32 · 5. ': Surprise medicine combination kit' where the Mo 洱 1 7. According to the patent application Fanyuandi active ingredient is formaldehyde anti-;; Medical :: set: thing which the 8.:=r_5,= :: 物 Other package _ Additives, diluents or carriers. 9. According to the scope of the patent application, it is a subdivided dry medicine combination kit, each of which is < and each container is a dry powder inhaler. --------- 'Clothing — (Please read the precautions on the back before filling out this page) 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-2 · This paper size applies to Chinese National Standard (CNS) A4 Appearance (210X297 mm)
TW086114371A 1996-10-08 1997-10-02 Composition and pharmaceutical combination kit comprising formoterol and budesonide TW470647B (en)

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AU4578297A (en) 1998-05-05
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HUP9901674A2 (en) 1999-09-28
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