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TW201138862A - Beta-blocking active ingredient capsules and polyunsaturated fatty acid esters - Google Patents

Beta-blocking active ingredient capsules and polyunsaturated fatty acid esters Download PDF

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TW201138862A
TW201138862A TW099139982A TW99139982A TW201138862A TW 201138862 A TW201138862 A TW 201138862A TW 099139982 A TW099139982 A TW 099139982A TW 99139982 A TW99139982 A TW 99139982A TW 201138862 A TW201138862 A TW 201138862A
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pharmaceutical composition
group
polymer
acid
microcapsules
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TW099139982A
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Duena Antonio Parente
Paolo Carminati
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Gp Pharm Sa
Defiante Farmaceutica Sa
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    • A61K9/1629—Organic macromolecular compounds
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    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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Abstract

Pharmaceutical composition for oral administration which contains polyunsaturated fatty acid alkyl esters (PUFA) and active pharmaceutical ingredients for the treatment and/or prevention of cardiovascular diseases.

Description

201138862 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種用於口服施用的醫藥組成物，其包 含聚合性微膠囊懸浮在含有多不飽和脂肪酸酯（PUFA ) 的油中之懸浮液，其中該微膠囊包含至少一種聚合物和 /3 -阻斷活性成分，及係關於其用於治療和/或預防心血 管疾病之用途。 【先前技術】 最常用以治療心血管疾病的活性醫藥成分係0 -阻斷 劑。 β -阻斷劑係/3 ·腎上腺素能受體的競爭性拮抗劑且用 於治療心血管疾病，如高血壓、狹心症、心律不整、心肌 梗塞和心衰竭。它們亦用於控制酒精戒斷症候群、焦慮症 、甲狀腺機能亢進和自發性震顫，及偏頭痛預防和與門脈 高壓相關的靜脈曲張出血。 多不飽和脂肪酸酯（PUFA )亦對於預防心血管疾病 具有已知的有利效果且通常用於罹患一些類型的心肌梗塞 的患者之合倂治療。有許多關於PUF Α的抗高血壓、降低 血清膽固醇、抗三酸甘油酯、抗心律不整、抗凝血和抗炎 效果的硏究[Bucher H.C.等人，jm.J. A/d. 112: 298-304 ( 2002 ) ; Benatti Ρ·等人，J · A m. C oil. Ν utr : 28 1 -3 02 ( 2004 ) ;Lee J.H.等人，Μα少o C/ίη. /Voc. 8 3 : 3 24-332 ( 2008 ) ;Heinz R. Adv. Ther.26 ： 675-690 ( 2009 )]。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition for oral administration comprising a suspension of polymerizable microcapsules suspended in an oil containing polyunsaturated fatty acid ester (PUFA). A solution wherein the microcapsules comprise at least one polymer and/or a blocking active ingredient, and the use thereof for the treatment and/or prevention of cardiovascular diseases. [Prior Art] The active pharmaceutical ingredient 0-blocker which is most commonly used for the treatment of cardiovascular diseases. A β-blocker system/3 a competitive antagonist of adrenergic receptors and is used to treat cardiovascular diseases such as hypertension, angina, arrhythmia, myocardial infarction and heart failure. They are also used to control alcohol withdrawal syndrome, anxiety disorders, hyperthyroidism and spontaneous tremors, as well as migraine prevention and variceal bleeding associated with portal hypertension. Polyunsaturated fatty acid esters (PUFAs) also have known beneficial effects in the prevention of cardiovascular diseases and are commonly used in the treatment of patients suffering from some types of myocardial infarction. There are many studies on the antihypertensive effect of PUF 、, lowering serum cholesterol, anti-triglyceride, anti-arrhythmia, anticoagulant and anti-inflammatory effects [Bucher HC et al., jm. J. A/d. 112: 298-304 (2002); Benatti Ρ· et al., J. A m. C oil. Ν utr : 28 1 -3 02 ( 2004 ) ; Lee JH et al., Μα少o C/ίη. /Voc. 8 3 : 3 24-332 (2008); Heinz R. Adv. Ther.26: 675-690 (2009)].

S -5- 201138862 PUFA是典型的脂肪酸且應可得自人類的膳食。取決 於第一個不飽和位置（分別是η-3和n_ 6 )，它們分成ω -3 和ω-6。主要的ω-3脂肪酸發現於魚油中，如二十碳五烯 酸（ΕΡΑ)、二十二碳六烯酸（DHA ) "PUFA可以三酸甘 油酯或烷酯形式存在。ω-3脂肪酸酯的市售組成物之脂肪 酸的純度和含量不同且通常以ΕΡ Α和D Η Α含量表示。 P UFA，在其任何形式中，易被氧化且必須儲存在惰 性環境中且避光。市售組成物含有抗氧化劑以使其分解作 用最小化。 已經知道以脂質爲基礎的調合物提高某些活性醫藥成 分的生物利用性。經由使用PUF A提高活性成分之生物利 用性的調合物的例子述於文獻，其通常爲乳液調合物。藉 生物可相容的油（如二十碳五烯酸（EPA ))的奈米粒子 形成的微乳液之製備述於WO 2006/135415 A2，這些含有 活性醫藥成分，尤其如/3-阻斷劑。US 2007009559 A1中 ，提出在水中的溶解度欠佳之不同的活性醫藥成分（尤其 是卡維地洛（carvedilol))的生物利用性之改良，此經 由將它們摻入含有不飽和脂肪酸（如亞麻油酸或亞麻油酸 乙酯）和水、界面活性劑、多元醇和磷脂之組成物中而達 成。所有的這些情況中，與PUFA或與調合物賦形劑的接 觸爲無法避免，然該接觸造成這些活性成分分解。 已經知道前述/3 -阻斷活性成分的不安定性。在/3 -阻 斷劑中，存在於相對於羥基的α位置的二級胺基造成它們 化學不安定性，此因與賦形劑可能的交互作用之故，且此 -6- ⑧ 201138862 代表在其儲存期間內會發生問題。因此，-阻斷劑的胺 基會與醛或酯官能基反應，此如同，例如，WO 2005/051383 A1中關於卡維地洛（carvedilol)之描述。 得到具有含有兩種活性成分（PUFA和Θ -阻斷劑）的 安定調合物爲有利的，其避免在相對於/3 -阻斷劑的羥基 爲α位置的反應性胺官能基與PUFA的酯官能基之交互作 用所引發的分解反應。 WO 2 0 0 7/ 1 0 3 5 5 7 Α2中，提出在硬或軟明膠膠囊中組 份的物理隔絕作爲解決具有二或更多種活性成分的組成物 之化學不相容性問題的方式。此膠囊應含有第一活性成分 (如ω-3脂肪酸）和一或多種內部膠囊包衣，其中它們的 至少一者由聚合物與其他活性成分合倂組成，而含有此活 性成分的包衣應與膠囊隔絕並選擇性地藉額外包衣與外界 隔離。W0 200 8/063 3 23 Α2中，藉含有ω-3脂肪酸的膠囊 的連續內部包衣和包含抗心律不整的活性成分（含括卢_ 阻斷劑）的包衣達到合倂治療。因爲明膠包衣的易碎性和 在水中的溶解度及須要嚴格控制塗覆期間內的沉積溫度和 速率’所以製程複雜。 W0 2006/08 1 5 1 8 Α2中’欲達到多重活性成分（含括 点-阻斷劑）的經修飾釋出，製備活性成分與離子交換樹 脂（樹脂酸鹽）之複合物，經或未經聚合方式塗覆，並懸 浮於非離子和非含水媒液（“NINA”媒液，如醇、多元醇 、聚醚、油、三酸甘油酯或蠟，含括ω _3 )中。所用 “NINA”媒液的類型得以控制樹脂與水之接觸。前述文獻S -5- 201138862 PUFA is a typical fatty acid and should be available from human diets. Depending on the first unsaturation (η-3 and n_6, respectively), they are divided into ω -3 and ω-6. The main omega-3 fatty acids are found in fish oils such as eicosapentaenoic acid (ΕΡΑ) and docosahexaenoic acid (DHA). PUFA can be present as a triglyceride or an alkyl ester. The fatty acid of the commercially available composition of the omega-3 fatty acid ester differs in purity and content and is usually expressed in terms of ΕΡ and D Η 。. P UFA, in any form, is susceptible to oxidation and must be stored in an inert environment and protected from light. Commercially available compositions contain antioxidants to minimize their decomposition. Lipid-based blends are known to increase the bioavailability of certain active pharmaceutical ingredients. An example of a blend that enhances the bioavailability of the active ingredient via the use of PUF A is described in the literature, which is typically an emulsion blend. The preparation of microemulsions formed from nanoparticles of biocompatible oils such as eicosapentaenoic acid (EPA) is described in WO 2006/135415 A2, which contain active pharmaceutical ingredients, especially such as /3-blocking Agent. In US 2007009559 A1, improvements in the bioavailability of different active pharmaceutical ingredients (especially carvedilol) which are poorly soluble in water are proposed, by incorporating them into unsaturated fatty acids (such as linseed oil). It is achieved by the composition of acid or linoleic acid ethyl ester) with water, a surfactant, a polyol and a phospholipid. In all of these cases, contact with the PUFA or with the blending excipient is unavoidable, but the contact causes the decomposition of these active ingredients. It is known that the aforementioned /3 - blocks the instability of the active ingredient. In the /3 -blocker, the secondary amine groups present in the alpha position relative to the hydroxyl group cause their chemical instability, which may be due to possible interaction with the excipient, and this -6-8 201138862 represents Problems occur during the storage period. Thus, the amine group of the -blocker will react with the aldehyde or ester functional group as described, for example, in Car 2005/051383 A1 for carvedilol. It is advantageous to obtain a stability blend having two active ingredients (PUFA and hydrazine-blocker) which avoids esters of reactive amine functional groups with PUFA at the alpha position relative to the hydroxyl group of the /3 -blocker The decomposition reaction caused by the interaction of functional groups. WO 2 0 0 7/ 1 0 3 5 5 7 Α2, the physical isolation of components in hard or soft gelatin capsules is proposed as a way to solve the chemical incompatibility problem of compositions having two or more active ingredients . The capsules should contain a first active ingredient (such as an omega-3 fatty acid) and one or more internal capsule coatings, at least one of which consists of a combination of a polymer and other active ingredients, and the coating containing the active ingredient should be Isolated from the capsule and optionally isolated from the outside by additional coating. W0 200 8/063 3 23 Α2, a continuous internal coating of a capsule containing omega-3 fatty acids and a coating comprising an antiarrhythmic active ingredient (including a _ blocker) to achieve a combined treatment. The process is complicated because of the friability of the gelatin coating and its solubility in water and the need to strictly control the deposition temperature and rate during the coating period. W0 2006/08 1 5 1 8 Α2 'To achieve the modified release of multiple active ingredients (including the point-blocker), to prepare a complex of the active ingredient and the ion exchange resin (resin), with or without It is applied by polymerization and suspended in nonionic and non-aqueous media ("NINA" media such as alcohols, polyols, polyethers, oils, triglycerides or waxes, including ω_3). The type of "NINA" vehicle used controls the contact of the resin with water. The aforementioned literature

S -7- 201138862 的例子中，這些調合物完全藉局部途徑施用。樹脂酸鹽用 於口服施用有爭議存在，此因施用大量離子交換劑或離子 交換劑長時間用於臨床治療會改變胃腸液的離子力並造成 電解質失衡之故。 因此，源自於此技術的問題須尋求包含心血管用途的 兩種活性成分（如/3 -阻斷劑和PUFA )且其製備較簡單且 不會引發所述問題之用於口服施用之安定的醫藥組成物。 本發明提出的解決方案係包含所述試劑之用於口服施用的 醫藥組成物，其活性成分藉聚合物隔離，且其不須使用會 在慢性治療上造成負面二次影響的賦形劑。 本發明的標的係用於口服施用的醫藥組成物，其包含 /5 -阻斷活性成分在含有多不飽和脂肪酸烷酯的油中的微 膠囊之懸浮液。此組成物提供0 -阻斷活性醫藥成分防禦 其與PUFA烷酯之化學交互作用、及提供防禦濕氣、光和 氧化劑的較大保護。 【發明內容】 因此，本發明係關於新穎之用於口服施用的醫藥組成 物，其避免阻斷活性成分與含有PUFA烷酯之油調合在 一起時，/3 -阻斷活性成分的分解問題。 【實施方式】 第一方面，本發明係關於一種用於口服施用的醫藥組 成物，其包含聚合性微膠囊之懸浮液，該微膠囊包含至少 -8- 201138862 一種聚合物和/3 -阻斷活性成分，這些微膠囊懸浮於含有 多不飽和脂肪酸烷酯的油中。該微膠囊之聚合物構成其外 部部分並提供用於經包封的活性醫藥成分的完整包衣。 本發明之醫藥組成物中，發現/3 -阻斷活性成分在聚 合性微膠囊內部，而該聚合性微膠囊於含有PUF A烷酯之 油中之懸浮液中。藉由易在胃腸介質中分解的聚合物， /5 -阻斷活性成分與外部介質和PUF A烷酯隔絕。如同合倂 治療中之活性醫藥成分的合倂施用，本發明之醫藥組成物 使得/5 -阻斷活性成分與PUF A烷酯隔離。聚合性包衣提供 這些Θ -阻斷劑安定性，防止因爲在相對於羥基爲α位置 的反應性胺基官能與PUF Α烷酯的酯基之交互作用而形成 分解產物。 較佳地，PUF A烷酯的脂肪酸屬於ω -3系列。較佳地 ，PUFA選自（全順式）-5,8, 11,14,17-二十碳五烯酸或二 十碳五烧酸（ΕΡΑ)、或二十碳五稀酸（timnodonic acid )或二十碳五烯酸（icosapent) (C20: 5 n-3)、（全順 式）-4,7,10, 13,16,19-二十二碳六烯酸或二十二碳六烯酸 (DHA)或二十二碳六烯酸（cerv〇nic acid)或二十二碳 六烯酸（C22: 6 n-3)和/或它們的混合物’尤其是In the example of S -7-201138862, these compositions are administered entirely by topical route. The use of resinate for oral administration is controversial because the application of a large amount of ion exchanger or ion exchanger for a long period of time for clinical treatment changes the ionic strength of the gastrointestinal fluid and causes electrolyte imbalance. Therefore, problems arising from this technique require the search for two active ingredients (such as /3 -blockers and PUFAs) for cardiovascular use and their preparation is relatively simple and does not cause the problem of stability for oral administration. Pharmaceutical composition. The solution proposed by the present invention is a pharmaceutical composition comprising the agent for oral administration, the active ingredient is isolated by a polymer, and it does not require the use of an excipient which would cause a negative secondary effect on chronic treatment. The subject matter of the present invention is a pharmaceutical composition for oral administration comprising a suspension of /5-blocking microcapsules of the active ingredient in an oil containing a polyunsaturated fatty acid alkyl ester. This composition provides a 0-blocking active pharmaceutical ingredient that protects against its chemical interaction with PUFA alkyl esters and provides greater protection against moisture, light and oxidants. SUMMARY OF THE INVENTION Accordingly, the present invention is directed to a novel pharmaceutical composition for oral administration which avoids blocking the decomposition of the active ingredient when the active ingredient is blended with the PUFA alkyl ester-containing oil. [Embodiment] In a first aspect, the present invention relates to a pharmaceutical composition for oral administration comprising a suspension of polymerizable microcapsules comprising at least -8-201138862 a polymer and /3 - blocking The active ingredient, these microcapsules are suspended in an oil containing a polyunsaturated fatty acid alkyl ester. The polymer of the microcapsules constitutes the outer portion thereof and provides a complete coating for the encapsulated active pharmaceutical ingredient. In the pharmaceutical composition of the present invention, it was found that the /3 - blocking active ingredient was inside the polymerizable microcapsules, and the polymerizable microcapsules were suspended in the oil containing the PUF A alkyl ester. The /5-blocking active ingredient is isolated from the external medium and the PUF A alkyl ester by a polymer that readily decomposes in the gastrointestinal medium. The pharmaceutical composition of the present invention isolates the/5-blocking active ingredient from the PUF A alkyl ester, as is the combined application of the active pharmaceutical ingredient in the combination therapy. The polymeric coating provides these oxime-blocker stability to prevent decomposition products from forming due to the interaction of the reactive amino function at the alpha position relative to the hydroxy group with the ester group of the PUF decyl ester. Preferably, the fatty acid of the PUF A alkyl ester belongs to the omega-3 series. Preferably, the PUFA is selected from (transcis)-5,8,11,14,17-eicosapentaenoic acid or eicosapentaenoic acid (ΕΡΑ), or timnodonic acid Or eicosapent (C20: 5 n-3), (trans-cis)-4,7,10, 13,16,19-docosahexaenoic acid or twenty-two carbon Hexaenoic acid (DHA) or cev〇nic acid or docosahexaenoic acid (C22: 6 n-3) and/or mixtures thereof, especially

Omacor®、Lovaza® 或 Zodin®。較佳實施例中，EPA: DHA關係在介於1〇〇: 〇和〇: 1〇〇之間的範圍內’較佳介於 4 : 1和1 : 4之間，且更佳介於1 : 2和2 : 1之間。此P U F A 可以僅包含EPA或僅包含DHA。 較佳地，PUFA烷酯的烷基選自具1至8個碳原子的短 -9- 201138862 鏈烷基。較佳地，此烷基選自乙基、甲基、丙基、丁基和 /或彼等之混合物。更佳地，此烷基係乙基。 較佳地，含有PUFA烷酯的油係富含PUFA烷酯的油， 較佳地，此油含有超過50%PUFA烷酯，更佳超過 60%PUFA烷酯且又更佳地，超過85% PUFA烷酯。 較佳實施例中，本發明之醫藥膠囊中含有的PUFA烷 酯的量介於0.01和4克之間，較佳介於0.1和2克之間。 特別的實施例中，/5 -阻斷活性成分未限制地選自， 醋丁洛爾（acebutolol)、阿普洛爾（alprenolol)、氨擴 洛爾（amosulalol)、阿羅洛爾（arotinolol)、阿替洛爾 (atenolol )、倍他洛爾 （betaxolol)、貝凡洛爾 （ bevantolol)、比索洛爾（bisoprolol)、波卩引洛爾（ bopindolol )、布新狢爾（bucindolol)、布拉洛爾（ bupranolol )、卡拉洛爾（carazolol)、卡替洛爾（ carteolol)、卡維地洛（carvedilol)、塞利洛爾（ celiprolol )、塞坦洛爾（esatenolol)、艾司洛爾（ esmolol)、節諾洛爾（indenolol)、拉貝洛爾（labetalol )、蘭地洛爾（landiolol)、左布諾洛爾（levobunolol) 、甲 Π引洛爾（mepindolol)、美替洛爾（metipranolol)、 美托洛爾（metoprolol)、納多洛爾（nadolol)、奈必洛 爾（nebivolol)、氧燃洛爾（oxprenolol)、噴布洛爾（ penbutolol ) 、D引哄洛爾（pindolol)、普萘洛爾（ propranolol )、索他洛爾 （sotalol)、他林洛爾 （ tal inolol )、特他洛爾（tertatolol)、替利洛爾（ -10- 201138862 川—丨〇1 )、噻嗎洛爾（timol〇i )、布他沙明（ butoxamine)、和/或它們於醫藥上可接受的鹽類。 本發明之醫藥膠囊的微膠囊之聚合物未限制地選自’ 蛋白質、聚醣 '聚酯、聚丙烯酸酯、聚氰基丙烯酸酯、聚 乙一醇和/或彼等之混合物。較佳地，此微膠囊的聚合物 選自明膠、白蛋白、藻酸鹽、鹿角膠、果膠、阿拉伯膠、 聚葡萄胺糖、羧甲基纖維素、乙基纖維素、羥丙基甲基纖 維素（Η P M C )、硝基纖維素、纖維素乙酸酯丁酸酯、纖 維素乙酸酯酞酸酯、羥丙基甲基纖維素酞酸酯、羥丙基甲 基纖維素乙酸酯-丁酸酯、聚乙酸乙烯酯酞酸酯、聚（ 己內酯）、聚（對·二噁酮）、聚（<5 ·戊內酯）、聚（ 召-羥基丁酸酯）、聚（Θ -羥基丁酸酯）共聚物和万_羥 基戊酸酯共聚物 '聚（/3 -羥基丙酸酯）、甲基丙烯酸共 聚物（Eudragit® L和S )、甲基丙烯酸二甲胺基乙酯共聚 物（Eudragit® E)、甲基丙烯酸三甲錢乙酯共聚物（（ Eudragit® RL和RS))'乳酸和羥乙酸的聚合物和共聚物 、乳酸和羥乙酸和聚乙二醇的聚合物和共聚物和/或彼等 之混合物。更佳地’該聚合物係甲基丙烯酸的共聚物（ E u d r a g i t ® L和S )、乳酸和羥乙酸的聚合物和共聚物 '乳 酸和羥乙酸和聚乙二醇的聚合物和共聚物和/或彼等之混 合物。 選擇性地’此發明的醫藥膠囊之微膠囊的聚合物包含 塑化劑添加劑。該塑化劑添加劑未限制地選自檸檬酸的|完 酯（如檸檬酸三乙酯、檸檬酸三丁酯、檸檬酸乙醯基三丁Omacor®, Lovaza® or Zodin®. In a preferred embodiment, the EPA:DHA relationship is in the range between 1 〇〇: 〇 and 〇: 1〇〇, preferably between 4:1 and 1:4, and more preferably between 1:2. Between 2 and 1. This P U F A may contain only EPA or only DHA. Preferably, the alkyl group of the PUFA alkyl ester is selected from the group consisting of short -9-201138862 alkyl groups having from 1 to 8 carbon atoms. Preferably, the alkyl group is selected from the group consisting of ethyl, methyl, propyl, butyl and/or mixtures thereof. More preferably, the alkyl group is an ethyl group. Preferably, the PUFA alkyl ester-containing oil is a PUFA alkyl ester-rich oil. Preferably, the oil contains more than 50% PUFA alkyl ester, more preferably more than 60% PUFA alkyl ester and, more preferably, more than 85%. PUFA alkyl ester. In a preferred embodiment, the pharmaceutical capsule of the present invention contains the PUFA alkyl ester in an amount between 0.01 and 4 grams, preferably between 0.1 and 2 grams. In a particular embodiment, the/5-blocking active ingredient is unrestrictedly selected from the group consisting of acebutolol, aprenolol, amosulalol, and arotinolol. , atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, cloth Bupranolol, carazolol, carteolol, carvedilol, celiprolol, esatenolol, esmolol (esmolol), indenolol, labetalol, landiolol, levobunolol, mepindolol, metoprolol (metipranolol), metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, D-inducing loll ( Pindolol), propranolol, sotalol, thallalol Tal inolol ), tertatolol, tililol (-10-201138862 Chuan-丨〇1), timolol (timol〇i), butoxamine, and/or A pharmaceutically acceptable salt. The polymer of the microcapsules of the pharmaceutical capsule of the present invention is not limitedly selected from the group consisting of 'protein, glycan' polyester, polyacrylate, polycyanoacrylate, polyethylene glycol and/or mixtures thereof. Preferably, the polymer of the microcapsule is selected from the group consisting of gelatin, albumin, alginate, staghorn gum, pectin, gum arabic, polyglucosamine, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl group Cellulose (ΗPMC), nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose Acid ester-butyrate, polyvinyl acetate phthalate, poly(caprolactone), poly(p-dioxanone), poly(<5-valerolactone), poly(call-hydroxybutyrate) ), poly(Θ-hydroxybutyrate) copolymer and 10,000-hydroxyvalerate copolymer 'poly(/3-hydroxypropionate), methacrylic acid copolymer (Eudragit® L and S), methacrylic acid Dimethylaminoethyl ester copolymer (Eudragit E), trimethyl methacrylate copolymer (( Eudragit® RL and RS)) 'Polymer and copolymer of lactic acid and glycolic acid, lactic acid and glycolic acid and poly Polymers and copolymers of ethylene glycol and/or mixtures thereof. More preferably, the polymer is a copolymer of methacrylic acid (E udragit ® L and S), a polymer and a copolymer of lactic acid and glycolic acid, and polymers and copolymers of lactic acid and glycolic acid and polyethylene glycol. / or a mixture of them. The polymer of the microcapsules of the pharmaceutical capsule of the invention selectively comprises a plasticizer additive. The plasticizer additive is unrestrictedly selected from the group consisting of citric acid esters (such as triethyl citrate, tributyl citrate, acetaminophen citrate)

S -11 - 201138862 酯和檸檬酸乙醯基三乙酯）、酞酸酯（如酞酸丁酯和酞酸 二乙酯）、甘油、山梨糖醇、甘露糖醇、丙二醇、聚乙二 醇、葡萄糖'蔗糖'羊毛脂、棕櫚酸、油酸、硬脂酸、脂 肪酸（如硬脂酸或棕櫚酸）的金屬鹽、硬脂酸鈉、硬脂酸 鉀、單硬脂酸丙二醇酯、乙醯化的單甘油酸酯（如單乙醯 化的甘油）和三醋酸甘油酯或甘油三乙酸酯、甘油卵磷酯 、甘油單硬脂酸酯、癸二酸烷酯（如癸二酸二丁酯或癸二 酸二乙酯）、反丁烯二酸烷酯、丁二酸烷酯、中等鏈三酸 甘油酯（MCT )、蓖麻油、氫化的植物油、蠟和/或混合 物。 選擇性地，摻入聚合物的其他專用添加劑以改良或有 助於包封法，如流化劑（如滑石、膠態二氧化矽、甘油、 聚乙二醇、單硬脂酸甘油酯和/或硬脂酸金屬鹽）。 選擇性地，本發明之醫藥膠囊包含至少一種抗氧化劑 ，如且不限於，丁基羥基甲苯（BHT ) 、丁基羥基茴香醚 (BHA )、三級丁基氫醌（TBHQ )、五倍子酸酯（如五 倍子酸丙酯）、生育酚（如維生素E乙酸酯）、抗壞血酸 酯（如棕櫚酸抗壞血酸酯和乙酸抗壞血酸酯）、肉鹼和/ 或彼等之混合物。較佳地，此抗壞血酸係維生素E乙酸酯 〇 特別的實施例中，微膠囊的量以本發明之醫藥組成物 總重計爲介於0.00 1重量％至80重量％之間，較佳以本發明 之醫藥組成物總重計爲介於0.01重量％至60重量％之間， 且更佳介於0.1重量％和5 0重量％之間。 -12- ⑧ 201138862 摻入這些微膠囊中之θ -阻斷活性醫藥成分的量以微 膠囊總重計爲介於1重量％和8 0重量％之間，較佳介於1重 量％和6 0重量％之間。本發明之醫藥組成物中含括之活性 醫藥成分的總量取決於建議每日用量。 另一特別的實施例中，本發明之用於口服施用的醫藥 組成物爲膠囊形式’較佳爲軟膠囊形式。此膠囊可爲明膠 膠囊或醫藥工業中之膠囊製備中之任何常用的聚合物，如 且不限於’羥丙基甲基纖維素（HPMC) '聚三葡萄糖、 經改質的澱粉、鹿角膠和/或彼等之混合物。選擇性地， 此膠囊具有腸衣。此膠囊的包衣含有其他添加劑，如塑化 劑、著色劑、顏料、不透明劑、防腐劑、潤濕劑、界面活 性劑、甜味劑和/或調味劑。此膠囊之製備係經由醫藥工 業中的一般程序進行，且可爲嫻於此技術者已知的任何形 式和尺寸。 微膠囊之製備可以依循文獻中所描述的任何程序進行 。作爲不具限制性的描述，用以得到微膠囊的不同程序可 歸類成下列者： A ) 簡單的凝聚程序 在適當溶劑中製備聚合物與其可能的添加劑之溶液。 待包封的活性醫藥成分懸浮於此聚合物溶液中，於其中添 加不溶解聚合物的溶劑，迫使聚合物沉積在活性成分的晶 體上。這些程序的例子可見於文獻，如ES 2009346 A6、 EP 0052510 A2和 EP 0346879 A1 。S -11 - 201138862 Ester and ethyl citrate triethyl ester), phthalate esters (such as butyl phthalate and diethyl decanoate), glycerin, sorbitol, mannitol, propylene glycol, polyethylene glycol , metal salts of glucose 'sucrose' lanolin, palmitic acid, oleic acid, stearic acid, fatty acids (such as stearic acid or palmitic acid), sodium stearate, potassium stearate, propylene glycol monostearate, B Deuterated monoglycerides (such as monoethylated glycerol) and triacetin or triacetin, glyceryl lecithin, glyceryl monostearate, alkyl sebacate (such as azelaic acid) Dibutyl or diethyl sebacate), alkyl fumarate, alkyl succinate, medium chain triglyceride (MCT), castor oil, hydrogenated vegetable oil, wax and/or mixture. Optionally, other specific additives are incorporated into the polymer to modify or aid in encapsulation processes such as fluidizers (eg, talc, colloidal cerium oxide, glycerin, polyethylene glycol, glyceryl monostearate, and / or metal stearate). Optionally, the pharmaceutical capsule of the present invention comprises at least one antioxidant such as, but not limited to, butylhydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butyl hydroquinone (TBHQ), gallic acid ester (such as propyl gallate), tocopherol (such as vitamin E acetate), ascorbate (such as ascorbyl palmitate and ascorbyl acetate), carnitine and / or a mixture thereof. Preferably, in the particular embodiment of the ascorbic acid-based vitamin E acetate oxime, the amount of the microcapsules is between 0.001% and 80% by weight, based on the total weight of the pharmaceutical composition of the present invention, preferably The total weight of the pharmaceutical composition of the present invention is between 0.01% and 60% by weight, and more preferably between 0.1% and 50% by weight. -12- 8 201138862 The amount of the θ-blocking active pharmaceutical ingredient incorporated into these microcapsules is between 1% by weight and 80% by weight, preferably between 1% by weight and 60% by weight of the total microcapsules. Between weight%. The total amount of active pharmaceutical ingredients included in the pharmaceutical compositions of the present invention depends on the recommended daily usage. In another particular embodiment, the pharmaceutical composition of the present invention for oral administration is in the form of a capsule, preferably in the form of a soft capsule. The capsule may be gelatin capsules or any of the commonly used polymers in the preparation of capsules in the pharmaceutical industry, such as, but not limited to, 'hydroxypropyl methylcellulose (HPMC) 'polytriglucose, modified starch, staghorn gum and / or a mixture of them. Optionally, the capsule has a casing. The coating of the capsule contains other additives such as plasticizers, colorants, pigments, opacifiers, preservatives, wetting agents, surfactants, sweeteners and/or flavoring agents. The preparation of such capsules is carried out via general procedures in the pharmaceutical industry and can be of any form and size known to those skilled in the art. The preparation of the microcapsules can be carried out according to any of the procedures described in the literature. As a non-limiting description, the different procedures used to obtain the microcapsules can be categorized as follows: A) Simple coacervation procedure A solution of the polymer with its possible additives is prepared in a suitable solvent. The active pharmaceutical ingredient to be encapsulated is suspended in the polymer solution, to which a solvent which does not dissolve the polymer is added, forcing the polymer to deposit on the crystal of the active ingredient. Examples of such procedures can be found in the literature, such as ES 2009346 A6, EP 0052510 A2 and EP 0346879 A1.

S -13- 201138862 B ) 錯合物凝聚程序 基於具有相反電荷的兩種膠體之間的交互作用以生成 不溶的錯合物，該錯合物沉積在待包封的活性醫藥成分上 ，形成用於隔離彼的膜。這些程序的例子可見於文獻，如 GB 1 3 9 3 8 0 5 A。 C )雙重乳化程序 待包封的活性醫藥成分溶於水中或溶於另一佐藥的溶 液中並在聚合物和添加劑於適當溶劑（如二氯甲烷）中之 溶液中乳化。所得乳液再於水中或於乳化劑（如聚乙烯醇 )的水溶液中乳化。一旦進行此二次乳化，藉蒸發或萃取 去除聚合物和塑化劑溶解於其中的溶劑。所得微膠囊藉過 濾或蒸發直接得到。這些程序的例子可見於文獻，如U S 4652441 A 。 D ) 簡單的乳化程序 待包封的活性醫藥成分、聚合物和添加劑一起溶於適 當的有機溶劑中。此溶液在水中或在乳化劑（如聚乙烯醇 )的溶液中乳化，並藉蒸發或萃取去除有機溶劑。藉過濾 或乾燥回收所得的微膠囊。這些程序的例子可見於文獻如 US 5 44 5 8 3 2 Α。 E) 溶劑蒸發程序 201138862 待包封的活性醫藥成分' 聚合物和添加劑一起溶於適 當溶劑中。此溶液經蒸發且所得殘渣經微細化以得到適當 尺寸’或者其藉噴霧乾燥而乾燥。此程序的例子可見於文 獻如 GB 2209937 A。 本發明的另一方面係關於本發明之用於口服施用的醫 藥組成物於製備用以治療和/或預防心血管疾病的藥物之 用途。較佳地，這些心血管疾病選自心律不整、高血壓、 狹心症、心肌梗塞和心衰竭。 本發明的另一方面係關於本發明之用於口服施用的醫 藥組成物於製備用以治療和/或預防選自酒精戒斷症候群 、焦慮症、甲狀腺機能亢進、自發性震顫、偏頭痛、糖尿 病倂發症和/或與門脈高壓相關的靜脈曲張出血之失調和 /或病理的藥物之用途。 本發明的另一方面係關於治療和/或預防心血管疾病 之方法，其包含施用醫藥有效劑量的本發明之醫藥組成物 。較佳地，這些心血管疾病選自心律不整、高血壓、狹心 症、心肌梗塞和心衰竭。 本發明的另一方面係關於治療和/或預防選自酒精戒 斷症候群、焦慮症、甲狀腺機能亢進和自發性震顫，及偏 頭痛和糖尿病倂發症、與門脈高壓相關的靜脈曲張出血之 失調和/或病理之方法，其包含施用醫藥有效劑量的本發 明之醫藥組成物。 提出下列特定實例以說明本發明之本質。這些實例僅 含括用於說明之目的且不亦衍生作爲本發明所請之限制。S-13-201138862 B) The complex agglomeration procedure is based on the interaction between two colloids having opposite charges to form an insoluble complex which is deposited on the active pharmaceutical ingredient to be encapsulated for formation. To isolate the membrane. Examples of these procedures can be found in the literature, such as GB 1 3 9 3 8 0 5 A. C) Double emulsification procedure The active pharmaceutical ingredient to be encapsulated is dissolved in water or dissolved in a solution of another adjuvant and emulsified in a solution of the polymer and the additive in a suitable solvent such as dichloromethane. The resulting emulsion is then emulsified in water or in an aqueous solution of an emulsifier such as polyvinyl alcohol. Once this secondary emulsification is carried out, the solvent in which the polymer and the plasticizer are dissolved is removed by evaporation or extraction. The resulting microcapsules are obtained directly by filtration or evaporation. Examples of such procedures can be found in the literature, such as U S 4652441 A. D) Simple emulsification procedure The active pharmaceutical ingredients, polymers and additives to be encapsulated are dissolved together in a suitable organic solvent. This solution is emulsified in water or in a solution of an emulsifier such as polyvinyl alcohol, and the organic solvent is removed by evaporation or extraction. The resulting microcapsules are recovered by filtration or drying. Examples of such procedures can be found in the literature such as US 5 44 5 8 3 2 Α. E) Solvent evaporation procedure 201138862 Active pharmaceutical ingredients to be encapsulated 'Polymers and additives are dissolved together in a suitable solvent. This solution is evaporated and the resulting residue is refined to give an appropriate size' or it is dried by spray drying. An example of this procedure can be found in the literature such as GB 2209937 A. Another aspect of the invention relates to the use of a pharmaceutical composition for oral administration of the invention for the manufacture of a medicament for the treatment and/or prevention of cardiovascular diseases. Preferably, these cardiovascular diseases are selected from the group consisting of arrhythmia, hypertension, angina, myocardial infarction, and heart failure. Another aspect of the invention relates to a pharmaceutical composition for oral administration according to the invention for use in the treatment and/or prevention of a drug selected from the group consisting of alcohol withdrawal syndrome, anxiety, hyperthyroidism, spontaneous tremor, migraine, diabetes Use of a disorder and/or pathological drug for stenosis and/or variceal bleeding associated with portal hypertension. Another aspect of the invention relates to a method of treating and/or preventing a cardiovascular disease comprising administering a pharmaceutically effective amount of a pharmaceutical composition of the invention. Preferably, these cardiovascular diseases are selected from the group consisting of arrhythmia, hypertension, schizophrenia, myocardial infarction and heart failure. Another aspect of the invention relates to the treatment and/or prevention of variceal bleeding selected from the group consisting of alcohol withdrawal syndrome, anxiety disorder, hyperthyroidism and spontaneous tremor, and migraine and diabetes mellitus associated with portal hypertension A method of dysregulation and/or pathology comprising administering a pharmaceutically effective amount of a pharmaceutical composition of the invention. The following specific examples are set forth to illustrate the nature of the invention. These examples are for illustrative purposes only and are not to be construed as limiting the invention.

S -15- 201138862 實例 實例1. 經由簡單的凝聚程序，含有卡維地洛（ carvedi丨〇1)微膠囊和明膠的醫藥膠囊之製備 製備1 %明膠於水中之溶液。 取得1〇〇毫升的此溶液且1克的卡維地洛粉末分散於其 中。然後，添加3 〇毫升硫酸鈉飽和水溶液。此混合物攪拌 1小時並添加0.5毫升50%戊二醛水溶液。 藉過濾收集所形成的微膠囊，它們經水清洗並在真空 乾燥爐中乾燥。這些微膠囊中的卡維地洛含量是3 9%。 所得微膠囊粉末直接分散於最少含有90%PUFA乙酯（ 最低EPA/DHA含量爲85%，其比例爲1 .2 : 1 )的油中，每 1 〇 〇克油得到1 _ 6 3克微膠囊懸浮液。之後，1 · 0 0克微膠囊 在油中之分散液摻至軟明膠膠囊，以得到每個膠囊的卡維 地洛劑量爲6.25毫克。 實例2. 含有阿替洛爾（atenolol )微膠囊和聚乙二 醇的醫藥膠囊之製備 製備分子量爲3 5 000 (PEG- 3 5 00 0 )的聚乙二醇於水 中之10%溶液。 藉劇烈攪拌，5克阿替洛爾分散於1 〇〇毫升的此溶液中 。一旦無團塊，得到良好分散液且此溶液藉噴霧乾燥而乾 燥。 所得的微膠囊粉末的阿替洛爾濃度爲3 3 %，其直接分 -16- 201138862 散在最少含有65%PUFA乙酯（最低EPA/DHA含量爲45%， 比例爲1.2 : 1 )的油中，每1〇〇克油得到17.9克微膠囊懸 浮液。之後，1.00克微膠囊在油中之分散液摻至軟明膠膠 囊’以得到每個膠囊的阿替洛爾劑量爲5 〇毫克。 實例3. 含有普萘洛爾（propranolol)微膠囊和聚 (乳酸-共-羥基乙酸）（PLGA )和維生素E的醫藥膠囊之 製備 溶液A:製備100毫升PLGA (其固有黏度（I.V·)爲 〇. 1 7 )於乳酸/羥基乙酸比爲1 : 1 )於二氯甲烷中之]〇% 溶液。 溶液B : 4克普萘洛爾氯化氫和1克維生素E乙酸酯溶 於200毫升乙醇中。 溶液A和B在連續攪拌下混合。此攪拌期間內，氮流 通過之前的溶液2小時以消除大部分的二氯甲烷和乙醇。 然後，所得懸浮液經冷凍並凍乾。所得粉末經大量水清洗 以消除過量乙醇並於低壓下乾燥以得到粉末。 所得微膠囊粉末含有26%普萘洛爾，並直接分散於含 有至少90%PUFA乙酯（最低EPA/DHA含量爲85%，比例爲 1 .2 : 1 )的油中。之後，所得微膠囊於油中之分散液摻至 軟明膠膠囊。用於製備不同尺寸和劑量的普萘洛爾膠囊的 量示於表1。 -17- 201138862 表1 分散液：克微膠囊/10克油 分散液/膠囊的重量 普萘洛爾劑畫— 0.8 3 3 克 0·50 克 1 0毫克 0.400 克 1 .00 克 1 0毫克 1 .818克 1 .00 克 40毫克 1.143克 1 .50 克 40毫克__— 實例4. 卡維地洛、阿替洛爾和普萘洛爾微膠囊$ 含有PUF A烷酯的油中之安定性之硏究 進行Θ -阻斷活性成分在含有PUFA烷酯的油中之加速 安定性（40±2°C，75±5°/〇 RH )之硏究，其中： a) 活性醫藥成分不具有聚合性包衣，並’ @ $ 與PUFA烷酯接觸（對照用組成物）。 b) 活性醫藥成分在根據以前實例製備的微Φ ( 本發明之組成物）。 微膠囊懸浮液在褐色玻璃容器中儲存1個月、2個月' 3個月和4個月之後，藉HP LC測定活性醫藥成分的百分比 。活性醫藥成分的百分比示於表2。 雖然未觀察到組成物改變，亦藉氣相層析法研1究 PUFA的安定性（EPA和DHA的烷酯濃度，及EPA/DHA比 -18- ⑧ 201138862 表2 活性成分 安定性（40± 2°C，75± 5% RH ) (%) 初時 1個月 2個月 3個月 4個月 卡維地洛（養 W ) a 98.7 96.6 93.3 89.6 84.1 b 98.9 99.0 _ - 99.1 99.0 阿替洛爾（養 :例2) a 98.5 97.2 92.5 90.3 86.6 b 98.6 98.5 _ 98.3 98.2 普萘洛爾（賨 :例3 ;劑量40毫克，膠囊1克） a 97.6 95.4 92.2 88.3 82.7 b 98.1 98.0 97.8 97.9S -15- 201138862 EXAMPLES Example 1. Preparation of a pharmaceutical capsule containing carvedilol microcapsules and gelatin via a simple coacervation procedure A solution of 1% gelatin in water was prepared. One milliliter of this solution was taken and one gram of carvedilol powder was dispersed therein. Then, a saturated solution of 3 ml of sodium sulfate was added. This mixture was stirred for 1 hour and 0.5 ml of a 50% aqueous solution of glutaraldehyde was added. The formed microcapsules were collected by filtration, which were washed with water and dried in a vacuum drying oven. The carvedilol content in these microcapsules was 3 9%. The obtained microcapsule powder is directly dispersed in an oil containing at least 90% PUFA ethyl ester (the lowest EPA/DHA content is 85%, the ratio is 1.2:1), and 1 _ 6 3 g per 1 gram of oil is obtained. Capsule suspension. Thereafter, the dispersion of 1 00 g of the microcapsules in the oil was incorporated into a soft gelatin capsule to obtain a dose of 6.25 mg of carvedilol per capsule. Example 2. Preparation of a pharmaceutical capsule containing atenolol microcapsules and polyethylene glycol A 10% solution of polyethylene glycol having a molecular weight of 35,000 (PEG-3500) in water was prepared. With vigorous stirring, 5 g of atenolol was dispersed in 1 ml of this solution. Once there is no agglomerate, a good dispersion is obtained and the solution is dried by spray drying. The obtained microcapsule powder has an atenolol concentration of 33%, which is directly distributed in the oil of -16,888,862,862 in a minimum of 65% PUFA ethyl ester (the lowest EPA/DHA content is 45%, the ratio is 1.2:1). 17.9 g of a microcapsule suspension was obtained per 1 gram of oil. Thereafter, a dispersion of 1.00 g of the microcapsules in the oil was incorporated into the soft gelatin capsules to obtain an atenolol dose of 5 mg per capsule. Example 3. Preparation of a pharmaceutical capsule containing propranolol microcapsules and poly(lactic-co-glycolic acid) (PLGA) and vitamin E A: Preparation of 100 ml of PLGA (inherent viscosity (IV·) is 1. 1 7) The lactic acid/glycolic acid ratio is 1:1% in dichloromethane. Solution B: 4 g of propranolol hydrogen chloride and 1 g of vitamin E acetate were dissolved in 200 ml of ethanol. Solutions A and B were mixed with continuous stirring. During this stirring period, the nitrogen stream was passed through the previous solution for 2 hours to remove most of the dichloromethane and ethanol. The resulting suspension was then frozen and lyophilized. The resulting powder was washed with a large amount of water to eliminate excess ethanol and dried at a low pressure to obtain a powder. The resulting microcapsule powder contained 26% propranolol and was directly dispersed in an oil containing at least 90% PUFA ethyl ester (minimum EPA/DHA content of 85%, ratio of 1.2:1). Thereafter, the dispersion of the obtained microcapsules in oil is incorporated into a soft gelatin capsule. The amounts of propranolol capsules used to prepare different sizes and doses are shown in Table 1. -17- 201138862 Table 1 Dispersion: gram microcapsules / 10 grams of oil dispersion / capsule weight of propranolol - 0.8 3 3 grams 0 · 50 grams 1 0 mg 0.400 grams 1 .00 grams 1 0 mg 1 .818 g 1 .00 g 40 mg 1.143 g 1.50 g 40 mg __- Example 4. Carvedilol, atenolol and propranolol microcapsules $ Stability in oils containing PUF A alkyl esters Study on the nature of Θ - Blocking the accelerated stability of the active ingredient in oils containing PUFA alkyl esters (40 ± 2 ° C, 75 ± 5 ° / 〇 RH), where: a) active pharmaceutical ingredients are not It has a polymeric coating and '@$ is contacted with a PUFA alkyl ester (comparative composition). b) The active pharmaceutical ingredient is microΦ (composition of the present invention) prepared according to the previous examples. The microcapsule suspension was stored in a brown glass container for 1 month, 2 months '3 months and 4 months, and the percentage of active pharmaceutical ingredients was determined by HP LC. The percentage of active pharmaceutical ingredients is shown in Table 2. Although no change in composition was observed, the stability of PUFA was studied by gas chromatography (the alkyl ester concentration of EPA and DHA, and the EPA/DHA ratio -18-8 201138862 Table 2 Active ingredient stability (40 ± 2) °C, 75± 5% RH) (%) Initial 1 month 2 months 3 months 4 months Carvedilol ( raise W ) a 98.7 96.6 93.3 89.6 84.1 b 98.9 99.0 _ - 99.1 99.0 Atilol (Nut: 2) a 98.5 97.2 92.5 90.3 86.6 b 98.6 98.5 _ 98.3 98.2 Propranolol (賨: Example 3; dose 40 mg, capsule 1 g) a 97.6 95.4 92.2 88.3 82.7 b 98.1 98.0 97.8 97.9

S -19-S -19-

Claims (1)

201138862 七、申請專利範圍： 1 ·—種用於口服施用的醫藥組成物，其包含聚合性微 膠囊之懸浮液，該微膠囊包含至少一種聚合物和々-阻斷 活性成分’這些微膠囊懸浮於含有多不飽和脂肪酸烷酯的 油中。 2 .如申請專利範圍第1項之醫藥組成物，其中這些院 酯的多不飽和脂肪酸屬於ω - 3系列。 3 ·如申請專利範圍第2項之醫藥組成物，其中這些垸 醋的多不飽和脂肪酸選自二十碳五稀酸 （ eicosapentaenoic acid ) 、 二十 二碳六 條酸 （ docosahexaenoic acid)和/或彼等之混合物。 4 ·如申請專利範圍第1項之醫藥組成物，其中這些院 酯的烷基選自1至8個碳原子的短鏈烷基》 5 .如申請專利範圍第4項之醫藥組成物，其中這些院 酯的烷基選自乙基、甲基、丙基、丁基和/或彼等之混合 物。 6.如申請專利範圍第1項之醫藥組成物，其中此油含 有超過5 0 %多不飽和脂肪酸烷酯。 7 .如申請專利範圍第1項之醫藥組成物，其中此石-阻 斷活性成分選自醋丁洛爾（acebuto101)、阿普洛爾（ alprenolol)、氣擴洛爾（amosulalol)、阿羅洛爾（ arotinolol )、阿替洛爾（atenolol)、倍他洛爾 （ betaxolol ) '貝凡洛爾（be van to 1 ο 1 )、比索洛爾（ bisoprolol)、波卩引洛爾（bopindolol)、布新洛爾（ -20- 201138862 bucindolol ) 、布拉洛爾（bupranolol)、 卡 拉 洛 爾 carazo1〇1 ) 、 卡替洛爾（carteolol )' 卡 維 地 洛 carvedilol ) 、塞利洛爾 （c e 1 i p r o 1 o 1 )' 塞 坦 洛 爾 esatenolol ) 、艾司洛爾（esmolol )' 1 1 » 印 諾 洛 爾 indenolol ) 、 拉貝洛爾 （labetalol )' 蘭 地 洛 爾 1 an d i o1o 1 ) 、 左布諾洛爾（levobunolol) 、甲Π引 洛 爾 mepindolol ) 、美替洛爾（metipranol 〇1 ) 、美托 洛 爾 m eto pro 1o1 ) 、納多洛爾 （n a d ο 1 ο 1 )' 奈 必 洛 爾 n eb i vo1o1 ) 、 氧燃洛爾（oxprenolol )' 噴 布 洛 爾 penbutolol ) 、呵哄洛爾（p i n d ο 1 ο 1 )' 普 萘 洛 爾 propranolol ) 、索他洛爾（sotalol )' 他 林 洛 爾 t a 1 i η o 1 o 1 ) 、 特他洛爾（tertatolol )' 替 利 洛 爾 t i 1 i s ο 1 ο 1 )、噻嗎洛爾 （t i m ο 1 ο 1 )、布他沙明 （ butoxamine)、和/或它們於醫藥上可接受的鹽類。 8 ·如申請專利範圍第1項之醫藥組成物，其中這些微 膠囊的聚合物選自蛋白質、聚酯、聚丙烯酸酯、聚氰基丙 烯酸酯 '聚醣、聚乙二醇和/或彼等之混合物。 9.如申請專利範圍第8項之醫藥組成物，其中這些微 膠囊的聚合物選自明膠、白蛋白、藻酸鹽、鹿角膠、果膠 、阿拉伯膠 '聚葡萄胺糖 '羧甲基纖維素、乙基纖維素、 經丙基甲基纖維素、硝基纖維素、纖維素乙酸醋丁酸醋、 纖維素乙酸酯酞酸酯、羥丙基甲基纖維素酞酸酯、羥丙基 甲基纖維素乙酸酯—丁酸酯、聚乙酸乙烯酯酞酸酯、聚（ ε -己內醋）、聚（對_二噁酮）、聚（占—戊內醋）、聚 S -21 - 201138862 (召-羥基丁酸酯）、聚（羥基丁酸酯）和羥基戊 酸酯共聚物、聚（^_羥基丙酸酯）、甲基丙烯酸共聚物 、甲基丙烯酸二甲胺基乙酯共聚物、甲基丙烯酸三甲銨乙 酯聚合物、乳酸和羥乙酸的聚合物和共聚物、乳酸和羥乙 酸和聚乙二醇的聚合物和共聚物和/或彼等之混合物。 1 〇 ·如申請專利範圍第1項之醫藥組成物，其中這些微 膠囊構成組成物總重計之〇 · 〇 〇 1 %和8 0 %之間。 1 1.如申請專利範圍第1項之醫藥組成物，其中摻入這 些微膨囊之活性醫藥成分的量介於1重量％和8 0重量％之間 〇 1 2 .如申請專利範圍第1項之醫藥組成物，其中這些微 膠囊的聚合物至少含有塑化劑、流化劑和/或抗氧化劑。 1 3 .如申請專利範圍第1項之醫藥組成物，其以膠囊形 式存在。 1 4 .如申請專利範圍第1 3項之醫藥組成物，其中此膠 囊係軟膠囊。 1 5 .如申請專利範圍第1 3項之醫藥組成物，其中此膠 囊的包衣之組成選自明膠、羥丙基甲基纖維素、聚三葡萄 糖、經改質的澱粉、鹿角膠和/或彼等之混合物。 1 6 .如申請專利範圍第1 3項之醫藥組成物，其中此膠 囊包含腸衣® 1 7. —種如申請專利範圍第1項之醫藥組成物於製造用 以治療和/或預防心血管疾病的藥物之用途。 1 8.—種如申請專利範圍第1項之醫藥組成物於製造用 -22- 201138862 以治療和/或預防選自酒精戒斷症候群、焦慮症' 甲狀腺 機能亢進、自發性震顫、偏頭痛、糖尿病倂發症和/或與 門脈高壓相關的靜脈曲張出血之失調和/或病理的藥物之 用途。 S -23- 201138862 四 指定代表圖： (一） 本案指定代表圖為：無 (二） 本代表圖之元件符號簡單說明：無 201138862 五、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：無201138862 VII. Patent application scope: 1 - A pharmaceutical composition for oral administration comprising a suspension of polymerizable microcapsules comprising at least one polymer and a ruthenium-blocking active ingredient' In oils containing polyunsaturated fatty acid alkyl esters. 2. The pharmaceutical composition of claim 1, wherein the polyunsaturated fatty acid of the hospital ester belongs to the omega-3 series. 3. The pharmaceutical composition of claim 2, wherein the polyunsaturated fatty acids of the vinegar are selected from the group consisting of eicosapentaenoic acid, docosahexaenoic acid and/or a mixture of them. 4. The pharmaceutical composition of claim 1, wherein the alkyl group of the compound is selected from the group consisting of short-chain alkyl groups of 1 to 8 carbon atoms. 5. The pharmaceutical composition of claim 4, wherein The alkyl groups of these esters are selected from the group consisting of ethyl, methyl, propyl, butyl and/or mixtures thereof. 6. The pharmaceutical composition of claim 1, wherein the oil contains more than 50% polyunsaturated fatty acid alkyl ester. 7. The pharmaceutical composition of claim 1, wherein the stone-blocking active ingredient is selected from the group consisting of acebuto 101, alprenolol, amosulalol, and arro Arotinolol, atenolol, betaxolol 'be van to 1 ο 1 , bisoprolol, bopindolol , Buxolol (-20- 201138862 bucindolol ), brarolol (bupranolol, carrollol carazo1〇1), carteolol (carteolol) carvedilol (carvedilol), celliol (ce 1 ipro 1 o 1 ) 'Settanol estarnolol ), esmolol ' 1 1 » enomol (indenolol ) , labetalol ' landiolol 1 an di o1o 1 ) , levobunolol, hyperthyroidism mepindolol, metoprolol 、1, metoprol 1 e1 ), nadol ο 1 ο 1 ' Nebolo n eb i vo1o1 ) , oxynolol (oxprenolol )' spray bulol Penbutolol ), 哄 哄 洛 (pind ο 1 ο 1 ) 'propranolol propranolol ) , sotalol ' hetalol ta 1 i η o 1 o 1 ) , betatalol (tertatolol ) 'Tilillo ti 1 is ο 1 ο 1 ), timolol (tim ο 1 ο 1 ), butoxamine, and/or their pharmaceutically acceptable salts. 8. The pharmaceutical composition of claim 1, wherein the polymer of the microcapsules is selected from the group consisting of proteins, polyesters, polyacrylates, polycyanoacrylates, polyethylene glycols, and/or the like. mixture. 9. The pharmaceutical composition according to claim 8 wherein the polymer of the microcapsules is selected from the group consisting of gelatin, albumin, alginate, staghorn gum, pectin, and gum arabic 'polyglucamine carboxymethyl fiber , ethyl cellulose, propyl methyl cellulose, nitrocellulose, cellulose acetate vinegar butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl Methyl cellulose acetate-butyrate, polyvinyl acetate phthalate, poly(ε-caprolactone), poly(p-dioxanone), poly(octa-valerene), poly S -21 - 201138862 (call-hydroxybutyrate), poly(hydroxybutyrate) and hydroxyvalerate copolymer, poly(^-hydroxypropionate), methacrylic acid copolymer, dimethylamine methacrylate A base ethyl ester copolymer, a trimethylammonium ethyl methacrylate polymer, a polymer and a copolymer of lactic acid and glycolic acid, a polymer and a copolymer of lactic acid and glycolic acid and polyethylene glycol, and/or a mixture thereof. 1 〇 · The pharmaceutical composition of claim 1 of the patent scope, wherein the microcapsules constitute the total weight of the composition 〇 〇 〇 between 1% and 80%. 1 1. The pharmaceutical composition according to claim 1, wherein the amount of the active pharmaceutical ingredient incorporated into the micro-expansion sac is between 1% by weight and 80% by weight 〇1 2 . A pharmaceutical composition of the invention, wherein the polymer of the microcapsules contains at least a plasticizer, a fluidizing agent and/or an antioxidant. 1 3. The pharmaceutical composition of claim 1 of the patent application, which is in the form of a capsule. 1 4 . The pharmaceutical composition of claim 13 wherein the capsule is a soft capsule. 1 5. The pharmaceutical composition of claim 13 wherein the composition of the capsule is selected from the group consisting of gelatin, hydroxypropyl methylcellulose, polytriglucose, modified starch, staghorn gum and/or Or a mixture of them. 16. The pharmaceutical composition of claim 13 wherein the capsule comprises a casing® 1 7. A pharmaceutical composition as claimed in claim 1 for the manufacture and/or prevention of cardiovascular disease Use of the drug. 1 8. A pharmaceutical composition as claimed in claim 1 in the manufacture of -22-201138862 for treatment and / or prevention selected from alcohol withdrawal syndrome, anxiety "hyperthyroidism, spontaneous tremor, migraine, Use of a drug that is dysregulated by diabetes mellitus and/or variceal bleeding associated with portal hypertension and/or pathology. S -23- 201138862 Four designated representative maps: (1) The representative representative of the case is: No (2) The symbol of the representative figure is a simple description: No 201138862 V. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: none
TW099139982A 2009-11-20 2010-11-19 Beta-blocking active ingredient capsules and polyunsaturated fatty acid esters TW201138862A (en)

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