201141469 六、發明說明： 【發明所屬之技術領域】 本發明關於膠囊型之醫藥組成物，其包含懸浮在含有 多不飽和脂肪酸烷基酯（PUF A )之油中的聚合微膠囊懸 浮液，其中該微膠囊含有至少一種聚合物及一種活性藥用 成分’本發明亦關於該膠囊型醫藥組成物於治療及/或預 防心血管疾病之用途。 【先前技術】 最常用於治療心血管疾病，尤其是用於治療高血壓之 活性藥用成分中有血管收縮素轉化酶抑制劑（ACE抑制劑 )及血管收縮素Π受體阻斷劑（ARB，血管收縮素Π受體 拮抗劑）。ACE抑制劑及ARB係作用於腎素血管收縮素系 統。ACE抑制劑抑制血管收縮素轉化酶，防止血管收縮素 I轉化爲血管收縮素Π。其爲非常有效之抗高血壓藥物（ 其亦可用於治療心臟衰竭及心肌梗塞）。大部分投服之 ACE抑制劑在二乙酯形式中之二級胺基的α位置中帶有羧 基，雖然其酸類爲生物活性形式。 ARB經由阻斷動脈中之血管收縮素Π受體，防止其作 用來作用。因此，ARB亦爲高血壓之第一線治療劑’尤其 是在因ACE抑制劑而發展出咳嗽之患者的情況中。ARB亦 用於治療心臟衰竭及糖尿病腎病。 多不飽和脂肪酸（PUFA )亦具有己知之預防心血管 事件的有利作用且經常用於罹患某些類型之心血管發作之 -5- 201141469 患者的組合醫療中。有許多關於PUFA之抗高血壓、降低 血清膽固醇、抗高三酸甘油酯血症、抗心律不整、抗血小 板及抗發炎作用的硏究[Bucher H.C. et al. Am. J_ Med· 1 1 2:298-3 04(2002) ； Benatti P. et al. J. Am. Coll. Nutr. 23: 2 8 1 -3 02(2004) ； Lee J.H. et al. Mayo Clin. Proc. 83: 3 24-3 3 2(200 8) ； Heinz R. Adv. Ther. 26: 675 -690 (2009)] ° PUFA爲必需脂肪酸且應從個人之飲食中取得。其根 據第一個不飽和位置分爲ω -3和ω -6脂肪酸（分別稱爲n-3 及n-6 )。主要之ω -3脂肪酸係在魚油中找到，諸如二十碳 五烯酸（ΕΡΑ)及二十二碳六烯酸（DHA) «PUFA可以三 酸甘油酯或烷基酯的形式找到。市售之ω -3脂肪酸烷基酯 組成物中之脂肪酸的純度和含量各不相同且其表現通常與 ΕΡΑ和DHA中之含量有關。 任何形式之PUFA均很容易地被氧化，因而應該貯存 在惰性大氣下且需避光。市售之組成物中含有抗氧化劑以 減少其降解。 亦已知許多上述之藥用抗高血壓活性成分很不穩定， 尤其是ACE抑制劑。ACE抑制劑可能苦於三種類型之降解 :a )內環化形成二酮基六氫吡畊，b )側鏈之酯基水解產 生二酸，及c )氧化產生不要之有色產品。液態和固態均 會發生降解。201141469 6. Technical Field of the Invention: The present invention relates to a pharmaceutical composition of a capsule type comprising a suspension of a polymeric microcapsule suspended in an oil containing a polyunsaturated fatty acid alkyl ester (PUF A ), wherein The microcapsules contain at least one polymer and an active pharmaceutical ingredient. The invention also relates to the use of the capsule-type pharmaceutical composition for the treatment and/or prevention of cardiovascular diseases. [Prior Art] Most commonly used in the treatment of cardiovascular diseases, especially in the active pharmaceutical ingredients for the treatment of hypertension, angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin-receptor blockers (ARB) , angiotensin Π receptor antagonist). ACE inhibitors and ARBs act on the renin vasoconstrictor system. ACE inhibitors inhibit angiotensin converting enzyme and prevent the conversion of angiotensin I to angiotensin. It is a very effective antihypertensive drug (which can also be used to treat heart failure and myocardial infarction). Most of the administered ACE inhibitors carry a carboxyl group in the alpha position of the secondary amine group in the diethyl ester form, although the acid is in a biologically active form. ARB prevents its action by blocking the angiotensin receptor in the artery. Therefore, ARB is also the first line of treatment for hypertension', especially in patients who develop cough due to ACE inhibitors. ARB is also used to treat heart failure and diabetic nephropathy. Polyunsaturated fatty acids (PUFAs) also have a beneficial effect in preventing cardiovascular events and are often used in combination therapy for patients with certain types of cardiovascular attacks. There are many studies on the antihypertensive effect of PUFA, lowering serum cholesterol, anti-triglycerideemia, antiarrhythmia, antiplatelet and anti-inflammatory effects [Bucher HC et al. Am. J_ Med· 1 1 2:298 -3 04(2002) ; Benatti P. et al. J. Am. Coll. Nutr. 23: 2 8 1 -3 02 (2004) ; Lee JH et al. Mayo Clin. Proc. 83: 3 24-3 3 2 (200 8) ; Heinz R. Adv. Ther. 26: 675 -690 (2009)] ° PUFA is an essential fatty acid and should be obtained from an individual's diet. It is classified into ω-3 and ω-6 fatty acids (referred to as n-3 and n-6, respectively) according to the first unsaturated position. The main omega-3 fatty acids are found in fish oils such as eicosapentaenoic acid (ΕΡΑ) and docosahexaenoic acid (DHA). «PUFA can be found in the form of triglycerides or alkyl esters. The purity and content of fatty acids in commercially available ω-3 fatty acid alkyl ester compositions vary and their performance is usually related to the levels of guanidine and DHA. Any form of PUFA is easily oxidized and should be stored under an inert atmosphere and protected from light. Commercially available compositions contain antioxidants to reduce their degradation. Many of the above-described medicinal antihypertensive active ingredients are also known to be very unstable, especially ACE inhibitors. ACE inhibitors may suffer from three types of degradation: a) internal cyclization to form diketohexahydropyrazine, b) esterification of the side chain to produce diacids, and c) oxidation to produce undesirable colored products. Both liquid and solid state degradation.
根據 WO 2006/050533 A2、EP 03 1 7878 Bl、US 5442008 A、US 5 1 5 1 43 3 A、WO 2004/064809 Al 及 EP -6- ⑤ 201141469 1 429748 B1，已知之雷米普利（ramipril )調製劑的不穩 定係受不同因素影響，諸如機械應力（壓縮）、製造過程 、賦形劑、儲存條件、熱量及濕氣。因此，需要嚴格控制 雷米普利之配製條件以盡量將分解減至最少並避免形成上 述之降解產物（二酮基六氫吡哄和二酸）。根據WO 2008/000040 A1 及 WO 2008/00 1 1 84 A2 的，不同賦形劑之 選擇會影響雷米普利及其他ACE抑制劑（諸如喹那普利（ quinapril )、依那普利（enalapril )或史比拉普利（ spirapril))之穩定性，加速其降解；此外，分解的一個 重要原因是與製造過程有關之機械應力。 根據US 20072 8 1 000 A1，爲了改善對濕氣敏感之活性 藥用成分之穩定性，可在調製劑中納入水清道夫化合物， 諸如西拉普利（cilazapril )情況中之共聚維酮（ copovidone)。由於福辛普利（fosinopril)易受醋及磷酸 二酯基團中之水解降解影響，因此不穩定，群多普利（ trandolapril)醋基亦有同樣情形；EP 1906931 B1中係以 聚二甲矽烷（dimethicone)來穩定這兩種活性成分之組成 物，從而抑制環化、水解及/或氧化作用。 文獻中有許多確認不同ACE抑制劑在活性藥用成分配 製期間分解的實例，即使是在片劑之製備過程中亦是。此 問題企圖藉由，例如：加入酸穩定劑[E P 〇 2 6 4 8 8 8 B 1 ; EP 04 68929 Bl ; US 4830853 A1]，與葡甲胺（meglumine )[W02005/04 1 940 A1]形成依那普利鹽[WO 0 1 /3 2689] ，將ACE抑制劑與在醇中之金屬分散液混合[W〇 201141469 04/071526 A1]、透過使用鹼性碳酸鹽或鹼土金屬來抑制環 化或顏色改變，以及醣來抑制水解[US 4743 45 0 A] ’或以 氧化鎂作爲穩定劑來對抗環化及控制濕度之方式[EP 1 083 93 1 Bl ； WΟ2008/000040 A 1]。 穩定含有A C E抑制劑（其中未加入穩定賦形劑）之翳 藥組成物的方法爲那些使用聚合物塗層者，諸如聚結物之 聚合物塗層[US 5151433 A]或在最終固態調製劑中之雷米 普利的個別微粒之聚合物塗層[WO 2006/050533 A2]，或 以活性藥用成分本身塗覆惰性核心[US 200520208 1 A1]， 其可避免由壓縮之機械應力及活性藥用成分與可能不相容 之賦形劑接觸而引起降解。 —些ARB亦顯示配製問題，根據從文獻中描述之纈沙 坦（valsartan )調製劑所推導出者，避免水的存在是必要 的。 例如：由於該固體之物理特性，厄貝沙坦（ Irbesartan )、纈沙坦（包括大體積粉末）及坎地沙坦酯 (candesartan cilexetil )(黏的）都很難調製在片劑或膠 囊中[EP 0747050 Bl、EP 1 774967 Al、WO 2008/0 1 23 72 A1] » 諸如氯沙坦（losartan )鉀鹽之懸浮液的調製劑在光 之存在下會降解而使該咪唑環被破壞[Seburg R.A. et al. J. Pharm. Biomed. Anal. 42: 411-422(2006)]。此外，氯沙坦 鉀爲非結晶型時不穩定，且趨向變成較不可溶且較不具生 物活性之結晶型。此非結晶型可經由在接下去調製成片劑 -8 - ⑧ 201141469Ramipril is known according to WO 2006/050533 A2, EP 03 1 7878 Bl, US 5442008 A, US 5 1 5 1 43 3 A, WO 2004/064809 Al and EP -6-5 201141469 1 429748 B1 The instability of the modulator is affected by various factors such as mechanical stress (compression), manufacturing process, excipients, storage conditions, heat and moisture. Therefore, it is necessary to strictly control the formulation conditions of ramipril to minimize decomposition and avoid the formation of the above degradation products (diketohexahydropyridinium and diacid). According to WO 2008/000040 A1 and WO 2008/00 1 1 84 A2, the choice of different excipients affects ramipril and other ACE inhibitors (such as quinapril, enalapril) Or the stability of spirapril, which accelerates its degradation; in addition, an important cause of decomposition is the mechanical stress associated with the manufacturing process. According to US 20072 8 1 000 A1, in order to improve the stability of moisture-sensitive active pharmaceutical ingredients, water scavenger compounds can be incorporated in the preparation, such as copovidone in the case of cilazapril ). Since fosinopril is susceptible to hydrolytic degradation in vinegar and phosphodiester groups, it is unstable, and the same applies to trandolapril vinegar; EP 1906931 B1 is polydimethylene. Dimethicone stabilizes the composition of the two active ingredients to inhibit cyclization, hydrolysis and/or oxidation. There are many examples in the literature that confirm the decomposition of different ACE inhibitors during the active pharmaceutical formulation, even during the preparation of tablets. This problem is attempted by, for example, the addition of an acid stabilizer [EP 〇 2 6 4 8 8 8 B 1 ; EP 04 68929 Bl ; US 4830853 A1], formed with meglumine [W02005/04 1 940 A1]. Enalapril salt [WO 0 1 /3 2689], the ACE inhibitor is mixed with a metal dispersion in an alcohol [W〇201141469 04/071526 A1], and the cyclization is inhibited by using an alkali carbonate or an alkaline earth metal. Or color change, and sugar to inhibit hydrolysis [US 4743 45 0 A] ' or use magnesium oxide as a stabilizer to combat cyclization and control humidity [EP 1 083 93 1 Bl ; WΟ 2008/000040 A 1]. Methods for stabilizing the anti-pigment composition containing ACE inhibitors, wherein no stabilizing excipients are added, are those which use polymer coatings, such as polymer coatings of agglomerates [US 5,151,433 A] or in the final solid state preparation a polymer coating of individual microparticles of ramipril [WO 2006/050533 A2], or an inert core coated with an active pharmaceutical ingredient itself [US 200520208 1 A1], which avoids mechanical stress and activity by compression The pharmaceutical ingredient is contacted with excipients that may be incompatible to cause degradation. Some ARBs also show formulation problems, and it is necessary to avoid the presence of water, based on the valsartan modulators described in the literature. For example, due to the physical properties of the solid, Irbesartan, valsartan (including bulk powder) and candesartan cilexetil (sticky) are difficult to prepare in tablets or capsules. [EP 0747050 Bl, EP 1 774967 Al, WO 2008/0 1 23 72 A1] » A preparation such as a suspension of losartan potassium salt degrades in the presence of light to destroy the imidazole ring [ Seburg RA et al. J. Pharm. Biomed. Anal. 42: 411-422 (2006)]. In addition, losartan potassium is unstable when it is amorphous, and tends to become less soluble and less biologically active. This amorphous form can be prepared into tablets by -8 - 8 201141469
時使用聚合物來使其穩定[wo 2004/064834 A1、US 2006 1 6087 1 A1]。此亦適用於纈沙坦之情況[US 2007166372 Al 、 US 2008152717 A1]。 當坎地沙坦酯被隔離時，其在溫度、濕氣及光之條件 下是穩定的，但當其與賦形劑一起調製在片劑中時其將隨 著時間的推移而分解。 降解之主要產物爲衍生物0-去乙基。此由造粒或高壓 成型過程中施用之壓力、磨損及熱造成之降解作用可透過 在壓縮前於調製劑中納入下列物質來減少：低熔點之油性 物質[EP 05463 5 8 B1]、脂質或磷脂[WO 2 005/07975 1 A2] 、不同之助溶劑[WO 2005/0703 98 A2]、用於形成活性成 分之吸附物的碳水化合物[EP 1952806 A1]、水溶性聚合物 [WO 2005/084648 A1]或具有非結晶型活性成分之甲基丙 烯酸聚合物[EP 1997479 A1]» 促進降解之壓縮力在製備片劑型固態口服調製劑時是 不可避免的。此類型之固態口服調製劑的替代品爲明膠囊 〇 明膠囊（無論是硬膠囊或軟膠囊）可容許活性藥用成 分被納入其內部，但當該物質在濕氣或氧化劑之存在下可 被降解或不穩定時，對該活性成分之此種保護是不能令人 滿意的。 傳統之明膠囊具有基本成分爲明膠之外層，一般而言 ，此膠囊可爲硬或軟，後者含有增塑劑。該傳統明膠囊之 塗層係由一包覆內含物之具有均勻厚度及組成的外層所組 201141469 成，該內含物中包含與合適之賦形劑混合的活性藥用成分 。該軟膠囊之內含物通常爲液體或半液體：油'極性液體 、微乳劑、懸浮液、蠟或膠體。在內部液體之水含量不能 超過20%，如此才不會將明膠層溶解。 膠囊之外層含有一定量之水作爲一種成分。然而，當 該欲調製之活性藥用成分或其鹽類爲水溶性、在濕氣之存 在下會降解或當與水接觸時呈現不穩定時，在傳統明膠囊 之塗層中出現水會構成嚴重的問題。事實上，使用一般成 分及技術來製造軟膠囊時，不論是在生產過程中或是在成 品膠囊之儲存過程中，由於該塗層之水有部分朝膠囊裡面 擴散或由於一部分活性成分與膠囊壁接觸，包含在膠囊中 之活性藥用成分是無法避免接觸到外層明膠片之濕氣。由 於膠囊之外塗層包含大量之習知添加劑（諸如增塑劑、著 色劑、遮光劑和防腐劑）以及水，因此亦很難令人滿意地 防止或控制外塗層與活性成分間任何可能之不相容性。這 些添加劑可促進氧化、降解或水解過程，造成調製之活性 成分的活性損失[EP 076993 8 B1]。另一個考量因素爲內含 物與膠囊之明膠間可能的化學交互作用，這可能有利於交 聯作用，從而減少膠囊在水性介質中的溶解度（延緩其崩 解的速度）。 因此，雖然軟膠囊被廣泛應用於製藥工業中，那些在 存有中等量之水的情況下不穩定的活性成分並不建議使用 軟膠囊。 爲了克服將易受水解影響之活性成分調製在軟膠囊中 -10- ⑤ 201141469 困難，EP 076993 8 B1中描述在明膠層下加入—或多層疏 水聚合物層’且在膠囊內加入矽樹脂。該活性成分（其可 爲A C E抑制劑或抗膽固醇劑，諸如ω _ 3脂肪酸二十碳五烯 酸（ΕΡΑ)或二十二碳六烯酸（DHA)，等）可在矽樹脂 內混合、溶解、懸浮或結合在矽樹脂上。然而，該常用之 過程及生產設備需要大量的修改。 亦已知’以脂質爲基底之調製劑可增加某些活性藥用 成分之生物可利用率。藉由使用PUFA來增加該活性成分 之生物可利用率的調製劑實例描述於文獻中，一般係經由 形成乳劑來達成。因此，US 5447729 Α中提出一種釋出系 統，其係由活性成分（其可爲ACE抑制劑，等）之微粒的 乳劑或分散液所組成，其中交替不同之疏水及親水層；該 乳劑可納入膠囊及片劑中且調製時可使用長鏈脂肪酸（諸 如亞麻油酸、亞油酸或花生四烯酸）。WO 2006/1 3 54 1 5 A2中描述包含活性藥用成分（諸如ACE抑制劑或ARB，等 )之由酸類（諸如二十碳五烯酸（EPA ))的奈米粒子形 成之微乳劑的製備方法。在所有這些情況中，活性藥用成 分無法避免與水或賦形劑接觸，而此爲許多活性成分降解 之原因。 除了上述具體瞄準將ACE抑制劑及ARB之降解減至最 少的調製劑實例外，文獻中還有其他具有相同目標之調製 劑實例且其亦可納入P U F A。 正如先前已經指出，W02005/07975 1 A2中係透過在組 成物中加入磷脂或脂質來穩定片劑中之坎地沙坦酯。該脂 -11 - 201141469 質可爲脂肪酸，諸如亞油酸及/或花生四烯酸，或其甘油 酯類。 WO 2007/103557 A2中提出具有二或多種活性藥用成 分之組成物的化學不相容性問題之解决方法，其係以一或 多層該膠囊之塗層將含有第一活性成分（諸如ω-3脂肪酸 )之硬或軟膠囊中的組成分物理隔離，其中至少一種膠囊 塗層係由聚合物合倂另一活性成分（諸如依那普利）組成 ，且該含有此活性成分之塗層係與膠囊隔離且選擇性地透 過另外之塗層與外部隔離。因爲明膠塗層之脆弱性和在水 中之溶解度，該製造過程複雜且在塗層期間需要嚴格控制 溫度及沈積速度。 WO 2006/08 1 5 1 8 Α2中，爲了達到修改多種活性成分 (抗高血壓劑，等）之釋出，製備活性成分與離子交換樹 脂之複合物，其可帶有或不帶有聚合物塗層且懸浮於非離 子性及非水性載劑（“ NINA ”載劑）（諸如醇、多元醇 、油、三酸甘油酯或蠟、ω-3，等）中。該活性藥用成分 必須包含酸性或鹼性官能基，以便能夠形成該複合物。此 外，於此文件之實例中，這些調製劑僅經由局部途徑施用 。樹脂酸鹽用於口服是有爭議的，因爲投服大量離子交換 樹脂或在慢性治療中長期使用離子交換樹脂可以改變胃腸 道液之離子力，造成電解質不平衡。 儘管許多所描述之參考資料代表解決與含有ACE抑制 劑及/或ARBs之醫藥組成物有關之不穩定性問題的企圖， 由該技術所產生之問題爲需要改進這些醫藥組成物之穩定 -12- 201141469 性’尤其是在濕氣存在時。本發明所提出之解決方案爲一 種藥用膠囊’其納入PUF A烷基酯及藉由聚合物隔離之所 需活性成分之微膠囊。 本發明之標的物爲膠囊型醫藥組成物，其對活性藥用 成分提供更多保護來對抗濕氣 '氧化劑及/或與外部塗層 之添加劑間可能之化學交互作用。本發明之藥用膠囊使那 些不穩定出名之活性藥用成分（諸如血管收縮素轉化酶抑 制劑（ACE抑制劑）及/或血管收縮素π受體拮抗劑（ARB ))較方便配製’透過由活性藥用成分之聚合物塗層與其 在PUFA之烷基酯中之懸浮液的組合所提供之隔離可避免 該活性藥用成分降解。 【發明內容】 因此，本發明關於一種新醫藥組成物，當將其中之活 性藥用成分（諸如血管收縮素轉化酶抑制劑（ACE抑制劑 )及/或血管收縮素Π受體拮抗劑（ARB ))配製成供口服 之藥用膠囊時可避免這些活性藥用成分降解之問題。 於第一種觀點中’本發明關於一種包含聚合微膠囊懸 浮液之藥用膠囊，該聚合微膠囊包含至少一種聚合物及至 少一種選自如下群體之活性藥用成分：A C E抑制劑及A RB ’這些微膠囊係懸浮在含有多不飽和脂肪酸烷基酯之油中 。該微膠囊之聚合物構成其外在部分並提供膠囊中之活性 藥用成分完整的塗層。 於本發明之藥用膠囊中，該活性藥用成分係在聚合微 -13- 201141469 膠綴內懸浮液中之含有PUFA烷基酯的油中找到。該活性 藥用成分係透過聚合物與外在介質和PUFA烷基酯隔離， 而此聚合物在腸胃道介質中很容易崩解。本發明之藥用膠 囊可在組合療法中將活性藥用成分一起投服，並令該活性 藥用成分與濕氣和膠囊塗層添加劑，以及外在之濕氣和氧 氣隔離。該聚合物塗層提供活性藥用成分穩定性，避免在 製備藥用膠囊型之最終組成物的過程中，濕氣、壓縮及高 溫造成降解產物形成。 較佳地，該PUFA烷基酯的脂肪酸係屬於ω -3系列。較 佳地，該PUFA係選自（全順式）-5,8,11，14,17-二十碳五 烯酸或二十碳五烯酸（ΕΡΑ)或提諾東尼酸（timnodonic acid)或稱爲艾康酸（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 )或稱爲色浮尼可酸（cervonic acid)或稱爲達康 酸（doconexent) ( C22 : 6 n-3)及/或彼等之混合物，諸如 Omacor®、Lovaza®或Zodin®，等。於較佳之體系中，該 EPA: DHA之關係可在100:0至0:100之範圍內，較佳爲介 於4:1與1:4之間，而更佳爲介於1:2與2:1之間。該PUFA可 僅包含EPA或僅包含DHA。 較佳地，該PUFA烷基酯之烷基係選自具有1至8個碳 原子之短鏈烷基。較佳地，該烷基係選自乙基、甲基、丙 基、丁基及/或彼等之混合物。更佳地，該烷基爲乙基。 較佳地，該含有PUFA烷基酯之油爲富含PUFA烷基酯 之油，較佳地，該油含有超過50%之PUFA烷基酯，更佳 -14- ⑤ 201141469 地，含有超過60%之PUFA烷基酯，再更佳地，其含有超 過85%之PUFA烷基酯。 於一較佳之體系中，包含在本發明之藥用膠囊中的 PUFA烷基酯量係在〇.〇1至4克，較佳爲0.1至2克。 於一特殊之體系中，該活性藥用成分爲選自如下群體 之血管收縮素轉化酶抑制劑（但不限於此）：卡托普利（ captopril )、依那普利（enalapril)、依那普利拉（ enalaprilat )、雷米普利(ramipri 1 )、嗤那普利( quinapril )、培哚普利（perindopri 1 )、賴諾普利（ lisinopril)、苯那普利（benazepril)、福辛普利（ fosinopril ) '史比拉普利（spirapri 1 )、群多普利（ trandolapril)、莫西普利（moexipril)、西拉普利（ cilazapri 1 )、味達普利（imidapril)、藍提普利（ rentiapril)、替莫卡普利（temocapril)、艾拉塞普利（ alacepril )、迪拉普利（delapril )、莫維替普利（ moveltipril )、柔非諾普利（zofenopril )、潘托普利（ pentopril )、利本薩普利（libenzapril )、皮渥普利（ pivoPril)、塞若納普利（ceronapril)、印朵拉普利（ indolapril)、替普泰德（teprotide)、其藥學上可接受之 鹽類及其酸類。 於另一特殊之體系中，該活性藥物成分爲選自如下群 體之血管收縮素Π受體阻斷劑（但不限於此）：坎地沙坦 (candesartan)、依普羅沙坦（eprosartan)、厄貝沙坦 (irbesartan )、氯沙坦（losartan )、奧美沙坦（ -15- 201141469 olmesartan )、替米沙坦（telmisartan)、顯沙坦（ valsartan )、塔索沙坦（tasosartan)、普托沙坦（ pratosartan )、阿里沙坦（azilsartan)、沙若拉辛（ saralasin )、利皮沙坦（r i p i s a r t a η )、伊利沙坦（ elisartan )、米法沙坦（milfasartan)、因布沙坦（ embusartan )、方沙坦（f ο n s a r t a η )、沙普利沙坦（ saprisartan )、柔拉沙坦（zolasartan)、弗若沙坦（ forasartan)、波米沙坦（pomisartan)、艾比替沙坦（ abitesartan )、非馬沙坦（fimasartan ) 、N-节基-氯沙坦 (N-benzyl-losartan )、伊諾他索沙坦（enoltasosartan) 、甘氨醯氯沙坦（glycyl-losartan )、歐波米沙坦（ opomisartan )、三苯甲基-氯沙坦（trityl-losartan)、沙 美辛（sarmesin)、異替林（isoteolin)及其藥學上可接 受之鹽。 本發明藥用膠囊之微膠囊的聚合物係選自如下群體（ 但不限於此）：蛋白質、多醣、聚酯、聚丙烯酸酯、聚氰 基丙烯酸酯、聚乙二醇及/或彼等之混合物。較佳地，該 微膠囊之聚合物係選自如下群體：明膠、白蛋白、藻酸鹽 、卡拉膠、果膠、阿拉伯膠、殼聚醣、羧甲基纖維素、乙 基纖維素、羥丙基甲基纖維素（HPMC )、硝基纖維素、 纖維素醋酸丁酸酯、纖維素醋酸酞酸酯、羥丙基甲基纖維 素酞酸酯、羥丙基甲基纖維素醋酸琥珀酸酯、聚乙烯醋酸 酞酸酯、聚（ε·己內酯）、聚（對-二氧環己酮）、聚（δ-戊內酯）、聚（β-羥基丁酸酯）、聚（β-羥基丁酸酯）共 -16- ⑧ 201141469 聚物和β-羥基戊酸酯、聚（β-羥基丙酸酯）、甲基丙烯酸 共聚物（Eudragit®L及S)、甲基丙烯酸二甲胺基乙酯共 聚物（Eudragit®E )、甲基丙烯酸三甲銨乙酯共聚物（ Eudragit®RL及RS )、乳酸和甘醇酸之聚合物及共聚物、 乳酸和甘醇酸及聚乙二醇之聚合物和共聚物及/或彼等之 混合物。更佳地，該聚合物係由甲基丙烯酸共聚物（ Eudragit®L及S )、乳酸和甘醇酸之聚合物及共聚物、乳 酸和甘醇酸及聚乙二醇之聚合物和共聚物及/或彼等之混 合物形成。 可選擇地，本發明藥用膠囊之微膠囊的聚合物可包含 增塑劑添加劑。該增塑劑添加劑係選自如下群體（但不限 於此）：檸檬酸之烷基酯類（諸如檸檬酸三乙酯、檸檬酸 三丁酯、乙醯檸檬酸三丁酯及乙醯檸檬酸三乙酯）、酞酸 酯（諸如酞酸丁酯及酞酸二乙酯）、甘油、山梨醇、麥芽 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（諸如硬脂酸或棕櫚酸）之金 屬鹽（硬脂酸鈉、硬脂酸鉀）、丙二醇單硬脂酸、乙醯基 化之單甘油酯（諸如單乙醯基化之甘油）及三醋酸甘油酯 或三醋精、甘油卵磷脂、單硬脂酸甘油酯、癸二酸烷基酯 (諸如癸二酸二丁酯或癸二酸二乙酯）、富馬酸烷基酯' 琥珀酸烷基酯、中鏈三酸甘油酯（MCT )、蓖麻毒素油、 氫化之植物油、蠟及/或混合物。 可選擇地，其他可納入之用以改善或促進包囊過程之 聚合物的技術添加劑有，諸如流化劑，諸如滑石粉、膠狀 -17- 201141469 二氧化矽、甘油、聚乙二醇、甘油單硬脂酸及/或金屬硬 脂酸鹽。 可選擇地，本發明之藥用膠囊包含至少一種抗氧化劑 ，諸如，但不限於丁羥基甲苯（BHT) 、丁羥基茴香醚（ BHA )、第三丁基醌（TBHQ ) '沒食子酸酯（諸如沒食 子酸丙酯）、生育酚（諸如維生素E醋酸酯）、抗壞血酸 酯類（諸如棕櫚酸抗壞血酸酯及醋酸抗壞血酸酯）、肉鹼 及/或彼等之混合物。較佳地，該抗氧化劑爲維生素E醋酸 酯。 於一特殊之體系中’該微膠囊佔本發明藥用膠囊之總 重量的0.001 %至80% ’宜佔本發明藥用膠囊之總重量的 0.01%至60%，更宜爲佔0.1%至50%。 納入這些微膠囊之活性藥用成分的量佔該微膠囊之總 重量的1重量％至80重量％，宜佔該微膠囊之總重量的1重 量％至60重量％。包含在本發明之藥用膠囊中之活性藥用 成分的總量取決於該建議之每日劑量。 本發明之藥用膠囊可爲從明膠或製藥工業中製備膠囊 時任何常用之聚合物製成之硬或軟膠襄，諸如，但不限於 :羥丙基甲基纖維素（HPMC )、普魯藍多醣（pullulan ) 、經改質之澱粉、卡拉膠及/或彼等之混合物。較佳地， 其爲明膠囊。更佳地，此膠囊係由軟明膠製成。可選擇地 ’該膠漢具有腸溶衣。該膠囊塗層可含有其他添加劑，諸 如增塑劑、著色劑、染料、遮光劑、防腐劑、保濕劑、界 面活性劑、甜味劑及/或調味料。膠囊可由熟習本技藝之 -18- ⑤ 201141469 人士透過製藥工業中之一般程序製備，且可爲已知之任何 形式和尺寸。 微膠囊可經由依照文獻中所描述之任何程序來製備。 如所描述者（但不僅限於此），用於取得微膠囊之不同程 序可分爲以下部分： A) 單純凝聚程序 在適當之溶劑中製備聚合物與其可能之添加劑的溶液 。將欲包囊之活性藥用成分懸浮在此聚合物之溶液中並加 入一種該聚合物不會在其中溶解之溶劑，以迫使聚合物沉 積在該活性成分之晶體上。這些程序之實例可在諸如ES 2009346 A6、 EP0052510 A2及 EP 0346879 A1之文件中找 到。 B) 錯合凝聚程序 此係以二種帶有相反電荷之膠體交互作用產生不溶性 錯合物爲基礎，該不溶性錯合物沉積在該欲包囊之活性藥 用成分之顆粒上，形成將活性藥用成分隔離之膜。這些程 序之實例可在諸如GB 1393805 A之文件中找到。 C )雙乳劑程序 將欲包囊之活性藥用成分溶解在水中或另一種輔助佐 劑之溶液中且將其在合適溶劑（諸如二氯甲烷）中之聚合 物與添加劑的溶液中乳化。接著，將由此產生之乳劑在水 中或乳化劑（諸如聚乙烯醇）之水溶液中乳化。一旦進行 此第二次乳化，將該其中溶解了聚合物及增塑劑的溶劑藉 由蒸發或萃取排除。藉由過濾或蒸發來直接取得由此產生 -19- 201141469 之微膠囊。這些程序之實例可在諸如us 465 244 1之文件中 找到。 D) 單純乳劑程序 將欲包囊之活性藥用成分、聚合物及添加劑一起溶解 在合適之有機溶劑中。將此溶液在水中或乳化劑（諸如聚 乙烯醇）之溶液中乳化並藉由蒸發或萃取排除該有機溶劑 。藉由過濾或乾燥來回收由此產生之微膠囊。這些程序之 實例可在諸如US 5445832 A之文件中找到。 E) 溶劑蒸發程序 將欲包囊之活性藥用成分、聚合物及添加劑一起溶解 在合適之溶劑中。將此溶液蒸發並將由此產生之殘質微粒 化以取得合適之大小，或者藉由噴霧乾燥將其乾燥。此程 序之實例可在諸如GB 2209937 A之文件中找到。 本發明之另一觀點係關於用於治療和/或預防心血管 疾病之本發明的藥用膠囊。較佳地，該心血管疾病係選自 高血壓、心臟衰竭及心肌梗塞。 本發明之另一觀點係關於治療及/或預防心血管疾病 之方法，其包含投服本發明之藥用膠漢。較佳地，該心血 管疾病係選自高血壓、心臟衰竭及心肌梗塞。 此處提供以下具體實例子來說明本發明之性質。這些 實例僅供說明用途，不應被解釋爲用於限制此處所主張之 本發明的專利範圍》 【實施方式】 -20- ⑧ 201141469 實例ι·透過單純凝聚程序製備含有雷米普利微膠囊 與明膠之藥用膠囊。 製備在水中之1 %明膠溶液。 取100毫升此溶液並將1克雷米普利粉末分散在其中。 接著，加入3 0毫升在水中之飽和硫酸鈉溶液。將該混合物 攪拌1小時並加入〇 . 5毫升在水中之5 0 %戊二醛溶液。 收集藉由過濾形成之微膠囊，以水清洗之並在真空乾 燥箱中乾燥之。這些微膠囊中之雷米普利之含量爲35%。 將由此產生之微膠囊粉末直接分散在含有最少90 % PUFA乙酯類（其含有最少85%之EPA/DHAC比例爲1.2: 1 ))的油中（每1〇〇克油中加入719毫克所取得之微膠囊懸 浮液）。接著，將1 .〇〇克在油中之微膠囊分散液納入軟膠 囊中以取得在每一膠囊中含有2.5毫克雷米普利之劑量。 實例2.含有群多普利微膠囊與聚（乳酸-乙醇酸）（ PLGA)及維生素Ε之藥用膠囊的製備方法。藉由單純乳劑 法（水包油）製備微膠囊。 溶液A :製備固有黏度（I_V.)爲0.17且乳酸/甘醇酸 之比例爲1:1之在二氯甲烷（DCM)中的10% PLGA溶液。 溶液B:將5克群多普利與1克維生素E醋酸酯溶解在 1〇〇毫升之溶液A中。 溶液C:製備在水中之1%聚乙烯醇（PVA)溶液。 在激烈攪拌下將1 〇 〇毫升溶液B慢慢地加入1 0 0 0毫升溶 液C中，直到取得乳白色乳劑。在此攪拌期間’將氮流通 -21 - 201141469 過先前之乳劑兩小時，以排除大部分D C Μ。接著，將所產 生之懸浮液冷凍及凍乾。取得一種粉末並以大量水清洗之 ，以排除過量之PVA並於減‘壓下乾燥之。 所取得之微膠囊粉末含有31%之群多普利，將其直接 分散在含有最少60 % PUFA乙酯類（其含有最少40 %之 DH A )的油中。接著，將所得之在油中的微膠囊分散液納 入軟膠囊中。用於製備不同尺寸之膠褒及不同劑量之群多 普利的量顯不於表1中。 分散液： 克微膠束/100克油 分散液之重量/膠束 群多普利之劑量/膠束 0.65 克 0.50 克 1毫克 0.43 克 0.75 克 1毫克 1.31 克 0.50 克 2毫克 0.65 克 1.00 克 2毫克 表1 實例3 ·藉由三重乳劑法製備含有賴諾普利微膠囊與聚 (乳酸甘醇酸）（PLGA )之藥用膠囊。 溶液A :將5克固有黏度（I.V.)爲0.4分公升/克且乳 酸/甘醇酸之比例爲1:1之PLG A溶解在50毫升之二氯甲烷（ DCM )中。 溶液B :將1·〇8克賴諾普利二水合物溶解於10毫升水 中〇 溶液C:製備濃度爲0.5 p/v %之在水中的聚乙烯醇（ PVA )溶液。 -22- ⑧ 201141469 藉由Ultra Turrax均質機之協助將水相（溶液B )在 PLGA之溶液（溶液A )中乳化（W/0型乳劑）。 在激烈攪拌下將先前製備之W/0乳劑加入1升之PV A溶 液（溶液C )中。攪拌新形成之乳劑，同時將氮流以不低 於5 0升/分之流速通過反應器以蒸發D CM。經由通過孔徑 爲5微米之膜過濾來回收微膠囊’以大量水沖洗之以排除 過量之PVA並藉由凍乾法乾燥之。 所取得之微膠囊粉末中含有16%之賴諾普利，將其直 接分散在含有最少90% PUFA乙酯類（其含有最少85%之 EPA/DHA (比例爲1.2 : 1 ))的油中。（每1 0〇克油中加 入1 . 5 9克所取得之微膠囊懸浮液）。接著，將1 · 〇〇克在油 中之微膠囊分散液納入軟膠囊中’以取得在每一膠囊中含 有2.5毫克賴諾普利之劑量。 實例4.藉由錯合凝聚程序製備含有坎地沙坦酯微膠囊 與明膠及羧甲基纖維素之藥用膠囊。 溶液A :製備在水中之1 %明膠溶液並將pH値調整至7 或高於7。 溶液B:製備另一在水中之1%羧甲基纖維素鈉溶液並 將pH値調整至7或高於7。 將250毫升溶液A與250毫升溶液B混合，並加熱至40 t 。將4克粉末狀坎地沙坦酯分散在該混合物中。當所有粉 末均分散且無團塊時，經由加入醋酸將pH値調整到4-4.5 。將混合物在4 0 °C攪拌1小時’然後將溶液冷卻至1 0 °C， -23- 201141469 再將此溫度保持1小時。加入2毫升在水中之50%戊二醛溶 液。 藉由噴霧乾燥法將由此產生之懸浮液乾燥’以取得含 有4 0%坎地沙坦酯之微膠囊粉末。 將此微膠囊粉末直接分散在含有最少90%PUFA乙酯 類（其含有最少85%之EPA/DHA (比例爲1.2 : 1 ))的油 中。接著，將所得之在油中之微膠囊分散液納入軟膠囊中 。用於製備不同尺寸之膠囊及不同劑量之坎地沙坦酯的量 顯示於表2中。 分散液： 克微膠束/100克油 分散液之重量/膠束 坎地沙坦酯之劑量/膠束 2.04 克 1.00 克 8毫克 1.35 克 1.50 克 8毫克 4.17 克 1.00 克 16毫克 2.74 克 1.50 克 16毫克 表2 實例5.含有纈沙坦及甲基丙烯酸共聚物之藥用膠囊 的製備方法。 將10克纈沙坦懸浮在1〇〇毫升之Eudragit FS 30D® (在 具有30%甲基丙烯酸' 甲基丙烯酸甲酯及丙烯酸甲酯共聚 物之水中的懸浮液）中直到取得細懸浮液。將檸檬酸三乙 酯加至此懸浮液（聚合物增塑劑）中，直至濃度爲5%。 藉由噴霧乾燥將所產生之懸浮液乾燥，以產生含有22 %纈沙坦之微膠囊粉末。 -24- ⑧ 201141469 將由此產生之微膠囊粉末直接分散在含有至少65% PUFA乙酯類（其含有最少45%之EPA/DHA (比例爲1.2: 1 ))的油中。（每100克油中加入25.0克所取得之微膠囊 懸浮液）°接著，將1 . 0 0克在油中之微膠囊分散液納入軟 膠囊中以取得在每一膠囊中含有40毫克纈沙坦之劑量。 實例6.含有在油（其包含PUFA烷基酯類）中之雷米 普利、群多普利、賴諾普利、坎地沙坦酯及纈沙坦微膠囊 懸浮液之軟膠囊的穩定性之硏究。 對含有在油（其包含PUFA之烷基酯）中之活性藥用 成分懸浮液之軟膠囊進行經加速之穩定性（40±2°C，75 土 5 %相對濕度）的硏究，其中： a )該活性藥用成分不具有聚合物塗層（對照組成物 )° b)該活性藥用成分係在根據先前實例製備之微膠囊 (本發明之組成物）中。 在琥珀色玻璃容器中儲存1個月、2個月、3個月和4個 月後透過HPLC測定膠囊中之活性藥用成分的百分比。該 活性藥用成分之百分比顯示於表3中。 亦透過氣相色層分析硏究PUFA之穩定性（EPA及DHA 烷基酯之濃度，以及EPA/DHA之比例）’但在該組成物中 未觀察到變化。 -25- 201141469 活性成分 穩定性 (40±2 °C, 75±5 % RH) (%) 初始 1個月 2個月 3個月 4個月 雷米普利（實例1) a 99.2 96.3 91.7 87.0 81.1 b 98.9 99.0 _ 98.8 98.9 群多普利（實例2 ;劑量2毫克，膠束1克） a 99.1 97.0 93.2 88.6 84.5 b 99.2 99.0 _ 99.1 99.0 賴諾普利（實例3 ;劑量2.5毫克，膠束1 g) a 99.0 96.2 91.3 85.6 79.2 b 99.1 98.9 - 98.9 98.8 坎地沙坦酯 實例4 ;劑量16毫克，膠束1 g) a 98.8 97.5 94.8 91.9 87.9 b 98.7 98.8 _ 98.6 98.4 纈沙坦（實例 5) a 98.4 97.1 94.5 92.1 89.4 b 98.5 98.4 - 98.2 98.1 表3The polymer is used to stabilize it [wo 2004/064834 A1, US 2006 1 6087 1 A1]. This also applies to the case of valsartan [US 2007166372 Al, US 2008152717 A1]. When candesartan cilexetil is isolated, it is stable under conditions of temperature, moisture and light, but it will decompose over time as it is formulated with the excipients in the tablet. The main product of degradation is the derivative 0-deethyl. The degradation caused by pressure, abrasion and heat applied during granulation or high pressure molding can be reduced by incorporating the following substances into the preparation before compression: low melting oily substances [EP 05463 5 8 B1], lipids or Phospholipids [WO 2 005/07975 1 A2], different cosolvents [WO 2005/0703 98 A2], carbohydrates for forming adsorbates of active ingredients [EP 1952806 A1], water-soluble polymers [WO 2005/084648] A1] or a methacrylic polymer having an amorphous active ingredient [EP 1997479 A1]» The compressive force for promoting degradation is unavoidable in the preparation of a tablet-type solid oral preparation. An alternative to this type of solid oral preparation is Capsule Capsule (whether hard or soft) which allows the active pharmaceutical ingredient to be incorporated into the interior, but when the substance is present in the presence of moisture or oxidizing agents Such protection of the active ingredient is unsatisfactory when degraded or unstable. The traditional capsule has an outer layer of gelatin, and in general, the capsule may be hard or soft, and the latter contains a plasticizer. The coating of the conventional gelatin capsule is made up of an outer layer of a coating having a uniform thickness and composition, and the inclusion comprises an active pharmaceutical ingredient mixed with a suitable excipient. The contents of the soft capsule are typically liquid or semi-liquid: oil 'polar liquids, microemulsions, suspensions, waxes or gels. The water content of the internal liquid should not exceed 20% so that the gelatin layer is not dissolved. The outer layer of the capsule contains a certain amount of water as an ingredient. However, when the active pharmaceutical ingredient to be prepared or a salt thereof is water-soluble, degrades in the presence of moisture or is unstable when contacted with water, the presence of water in the coating of the conventional gel capsule constitutes serious problem. In fact, when using ordinary ingredients and techniques to make soft capsules, either during production or during storage of finished capsules, the water of the coating partially diffuses into the capsule or due to a portion of the active ingredient and the capsule wall. Contact, the active pharmaceutical ingredient contained in the capsule is moisture that is inaccessible to the outer film. Since the coating other than the capsule contains a large amount of conventional additives such as plasticizers, colorants, opacifiers and preservatives, as well as water, it is also difficult to satisfactorily prevent or control any possibility between the outer coating and the active ingredient. Incompatibility. These additives promote oxidation, degradation or hydrolysis processes, resulting in loss of activity of the prepared active ingredient [EP 076993 8 B1]. Another consideration is the possible chemical interaction between the inclusions and the gelatin of the capsule, which may facilitate cross-linking, thereby reducing the solubility of the capsule in the aqueous medium (delaying the rate of disintegration). Therefore, although soft capsules are widely used in the pharmaceutical industry, soft capsules are not recommended for active ingredients which are unstable in the presence of moderate amounts of water. In order to overcome the difficulty of modulating the active ingredient which is susceptible to hydrolysis in soft capsules -10- 5 201141469 Difficulty, EP 076993 8 B1 describes the addition of a layer or layers of hydrophobic polymer layer under the gelatin layer and the addition of a resin in the capsule. The active ingredient (which may be an ACE inhibitor or an anti-cholesterol agent such as ω 3 fatty acid eicosapentaenoic acid (ΕΡΑ) or docosahexaenoic acid (DHA), etc.) may be mixed in the oxime resin, Dissolve, suspend or bind to the resin. However, this common process and production equipment requires a lot of modifications. It is also known that lipid-based modulators increase the bioavailability of certain active pharmaceutical ingredients. Examples of modulators that increase the bioavailability of the active ingredient by using PUFAs are described in the literature, typically by forming an emulsion. Thus, US 5,447,729 discloses a release system consisting of an emulsion or dispersion of microparticles of an active ingredient (which may be an ACE inhibitor, etc.) in which different hydrophobic and hydrophilic layers are alternated; the emulsion may be incorporated Long-chain fatty acids (such as linoleic acid, linoleic acid or arachidonic acid) can be used in capsules and tablets and prepared. WO 2006/1 3 54 1 5 A2 describes a microemulsion formed from nanoparticles of an acid such as eicosapentaenoic acid (EPA) comprising an active pharmaceutical ingredient such as an ACE inhibitor or ARB, etc. Preparation. In all of these cases, the active pharmaceutical ingredient is incapable of avoiding contact with water or excipients, which is responsible for the degradation of many active ingredients. In addition to the above specific examples of modulators that minimize the degradation of ACE inhibitors and ARBs, there are other examples of modulators with the same objectives in the literature and which may also incorporate P U F A . As previously indicated, W02005/07975 1 A2 stabilizes candesartan cilexetil in a tablet by the addition of phospholipids or lipids to the composition. The lipid -11 - 201141469 may be a fatty acid such as linoleic acid and/or arachidonic acid, or a glyceride thereof. A solution to the problem of chemical incompatibility of a composition of two or more active pharmaceutical ingredients is proposed in WO 2007/103557 A2, in which one or more layers of the coating of the capsule will contain a first active ingredient (such as ω- The composition of the hard or soft capsule of 3 fatty acids is physically separated, wherein at least one of the capsule coatings is composed of a polymer compounded with another active ingredient such as enalapril, and the coating system containing the active ingredient It is isolated from the capsule and selectively isolated from the exterior by an additional coating. Because of the fragility of the gelatin coating and its solubility in water, the manufacturing process is complex and requires tight temperature and deposition rates during coating. WO 2006/08 1 5 1 8 In order to achieve the modification of the release of various active ingredients (antihypertensive agents, etc.), a composite of the active ingredient and the ion exchange resin can be prepared with or without a polymer. The coating is suspended in a nonionic and non-aqueous carrier ("NINA" carrier) such as an alcohol, polyol, oil, triglyceride or wax, omega-3, and the like. The active pharmaceutical ingredient must contain acidic or basic functional groups to enable formation of the complex. Moreover, in the examples of this document, these modulators are administered only via a topical route. The use of resinate for oral administration is controversial because the administration of large amounts of ion exchange resins or the long-term use of ion exchange resins in chronic treatment can alter the ionic forces of the gastrointestinal fluid, causing electrolyte imbalance. Although many of the references described represent an attempt to address the problem of instability associated with pharmaceutical compositions containing ACE inhibitors and/or ARBs, the problem arises from the need to improve the stability of these pharmaceutical compositions. 201141469 Sex 'especially in the presence of moisture. The solution proposed by the present invention is a pharmaceutical capsule which incorporates a PUF A alkyl ester and microcapsules which are required to separate the active ingredient by a polymer. The subject matter of the present invention is a capsule pharmaceutical composition that provides more protection to the active pharmaceutical ingredient against possible chemical interactions between the moisture 'oxidant and/or additives to the outer coating. The pharmaceutical capsules of the present invention make it easier to formulate active medicinal ingredients (such as angiotensin converting enzyme inhibitors (ACE inhibitors) and/or angiotensin π receptor antagonists (ARBs)) which are not well known. Isolation of the active pharmaceutical ingredient from the combination of the polymeric coating of the active pharmaceutical ingredient with its suspension in the alkyl ester of PUFA avoids degradation of the active pharmaceutical ingredient. SUMMARY OF THE INVENTION Accordingly, the present invention is directed to a novel pharmaceutical composition wherein an active pharmaceutical ingredient such as an angiotensin converting enzyme inhibitor (ACE inhibitor) and/or an angiotensin receptor antagonist (ARB) )) The problem of degradation of these active pharmaceutical ingredients can be avoided when formulated into a pharmaceutical capsule for oral administration. In a first aspect, the invention relates to a pharmaceutical capsule comprising a polymeric microcapsule suspension comprising at least one polymer and at least one active pharmaceutical ingredient selected from the group consisting of ACE inhibitors and A RB '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 of the active pharmaceutical ingredient in the capsule. In the pharmaceutical capsules of the present invention, the active pharmaceutical ingredient is found in an oil containing a PUFA alkyl ester in a suspension of the polymer micro-13-201141469. The active pharmaceutical ingredient is isolated from the external medium and the PUFA alkyl ester by a polymer which is readily disintegrable in the gastrointestinal tract. The medicinal capsule of the present invention can be administered together with the active pharmaceutical ingredient in combination therapy, and the active pharmaceutical ingredient is isolated from the moisture and capsule coating additives, as well as the external moisture and oxygen. The polymeric coating provides stability to the active pharmaceutical ingredient and prevents the formation of degradation products due to moisture, compression and elevated temperatures during the preparation of the final composition of the pharmaceutical capsule form. Preferably, the fatty acid of the PUFA alkyl ester belongs to the ω-3 series. Preferably, the PUFA is selected from (transcis)-5,8,11,14,17-eicosapentaenoic acid or eicosapentaenoic acid (ΕΡΑ) or timnodonic acid (timnodonic acid) ) or known as icosapent (C20: 5 n-3), (trans-cis)-4,7, 10,13, 16,19-docosahexaenoic acid or twenty-two carbon six Oleic acid (DHA) or cervonic acid or doconexent (C22: 6 n-3) and/or mixtures thereof such as Omacor®, Lovaza® or Zodin ®, etc. In a preferred system, the EPA: DHA relationship may range from 100:0 to 0:100, preferably between 4:1 and 1:4, and more preferably between 1:2 and Between 2:1. The PUFA may contain only EPA or only DHA. Preferably, the alkyl group of the PUFA alkyl ester is selected from short chain 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 -14 to 5 201141469, containing more than 60 More preferably, the PUFA alkyl ester contains more than 85% of the PUFA alkyl ester. In a preferred system, the amount of the PUFA alkyl ester contained in the pharmaceutical capsule of the present invention is from 1 to 4 g, preferably from 0.1 to 2 g. In a particular system, the active pharmaceutical ingredient is an angiotensin converting enzyme inhibitor selected from the group consisting of, but not limited to: captopril, enalapril, enalapril Enalaprilat, ramipri 1 , quinapril, perindopri 1 , lisinopril, benazepril, blessing Fosinopril 'spirapri 1 , trandolapril , moexipril , cilazapri 1 , imidapril , Rentiapril, temocapril, alacepril, deLapril, moveltipril, zofenopril ), pentopril, libenzapril, pivoPril, ceropanril, indolapril, and tepted ( Teprotide), its pharmaceutically acceptable salts and its acids. In another particular system, the active pharmaceutical ingredient is (but is not limited to) an angiotensin receptor receptor blocker selected from the group consisting of: candesartan, eprosartan, Irbesartan, losartan, olmesartan (-15-201141469 olmesartan), telmisartan, valsartan, tasosartan, pussartan Pratosartan, azilsartan, saralasin, ripisarta η, elisartan, milfasartan, embusartan ), essartan (f ο nsarta η ), saprisartan (sprisartan), zolasartan, forosaartan, pomisartan, ipacetartan ( Abitesartan ), non-marsartan, N-benzyl-losartan, enenotasolartan, glycyl-losartan, European Pomisartan (opomisartan), trityl-chloro Trityl-losartan, sarmesin, isoteolin, and pharmaceutically acceptable salts thereof. The polymer of the microcapsules of the pharmaceutical capsule of the present invention is selected from the group consisting of, but not limited to, proteins, polysaccharides, polyesters, polyacrylates, polycyanoacrylates, polyethylene glycols, and/or the like. mixture. Preferably, the polymer of the microcapsules is selected from the group consisting of gelatin, albumin, alginate, carrageenan, pectin, acacia, chitosan, carboxymethylcellulose, ethylcellulose, hydroxy Propylmethylcellulose (HPMC), nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinic acid Ester, polyethylene acetate phthalate, poly(ε·caprolactone), poly(p-dioxanone), poly(δ-valerolactone), poly(β-hydroxybutyrate), poly( Β-hydroxybutyrate)-16- 8 201141469 Polymer and β-hydroxyvalerate, poly(β-hydroxypropionate), methacrylic acid copolymer (Eudragit® L and S), methacrylic acid II Methylaminoethyl ester copolymer (Eudragit® E), trimethylammonium ethyl methacrylate copolymer (Eudragit® RL and RS), polymers and copolymers of lactic acid and glycolic acid, lactic acid and glycolic acid, and polyethylene Polymers and copolymers of diols and/or mixtures thereof. More preferably, the polymer is a polymer and copolymer of methacrylic acid copolymer (Eudragit® L and S), lactic acid and glycolic acid, polymers and copolymers of lactic acid and glycolic acid and polyethylene glycol. And/or a mixture of them is formed. Alternatively, the polymer of the microcapsules of the pharmaceutical capsule of the present invention may comprise a plasticizer additive. The plasticizer additive is selected from the group consisting of, but not limited to, the following: an alkyl ester of citric acid (such as triethyl citrate, tributyl citrate, tributyl citrate, and acetonitrile citrate). Triethyl ester), phthalate esters (such as butyl phthalate and diethyl phthalate), glycerin, sorbitol, maltitol, propylene glycol, polyethylene glycol, glucose, sucrose, lanolin, palmitic acid, oleic acid, a metal salt of stearic acid, a fatty acid such as stearic acid or palmitic acid (sodium stearate, potassium stearate), propylene glycol monostearate, an ethoxylated monoglyceride (such as monoethylation) Glycerol) and triacetin or triacetin, glycerol lecithin, glyceryl monostearate, alkyl sebacate (such as dibutyl sebacate or diethyl sebacate), fumaric acid Alkyl esters 'alkyl succinates, medium chain triglycerides (MCT), ricinoleic oils, hydrogenated vegetable oils, waxes and/or mixtures. Alternatively, other technical additives that may be incorporated into the polymer to improve or promote the encapsulation process are, for example, fluidizing agents such as talc, colloidal -17-201141469 cerium oxide, glycerin, polyethylene glycol, Glycerol monostearate and/or metal stearate. Alternatively, the pharmaceutical capsules of the present invention comprise at least one antioxidant such as, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and tert-butyl fluorene (TBHQ) 'gallate. (such as propyl gallate), tocopherol (such as vitamin E acetate), ascorbate (such as ascorbyl palmitate and ascorbyl acetate), carnitine and/or mixtures thereof. Preferably, the antioxidant is vitamin E acetate. In a special system, the microcapsule occupies 0.001% to 80% of the total weight of the pharmaceutical capsule of the present invention, and preferably accounts for 0.01% to 60%, more preferably 0.1%, of the total weight of the pharmaceutical capsule of the present invention. 50%. The amount of the active pharmaceutical ingredient to be incorporated into these microcapsules is from 1% by weight to 80% by weight based on the total weight of the microcapsules, preferably from 1% by weight to 60% by weight based on the total weight of the microcapsules. The total amount of active pharmaceutical ingredient contained in the pharmaceutical capsule of the present invention depends on the recommended daily dose. The pharmaceutical capsule of the present invention may be a hard or soft capsule made of any of the commonly used polymers when preparing capsules from gelatin or the pharmaceutical industry, such as, but not limited to, hydroxypropyl methylcellulose (HPMC), Pru A mixture of pullulan, modified starch, carrageenan and/or the like. Preferably, it is a gelatin capsule. More preferably, the capsule is made of soft gelatin. Alternatively, the gum has an enteric coating. The capsule coating may contain other additives such as plasticizers, colorants, dyes, opacifiers, preservatives, humectants, surfactants, sweeteners and/or flavorings. Capsules can be prepared by a person skilled in the art from the general procedures of the pharmaceutical industry, and can be of any form and size known. Microcapsules can be prepared via any of the procedures described in the literature. As described (but not limited to), the different procedures for obtaining microcapsules can be divided into the following sections: A) Simple coacervation procedure A solution of the polymer and its possible additives is prepared in a suitable solvent. The active pharmaceutical ingredient to be encapsulated is suspended in a solution of the polymer and a solvent in which the polymer is not dissolved is added to force the polymer to deposit on the crystal of the active ingredient. Examples of such programs can be found in documents such as ES 2009346 A6, EP0052510 A2 and EP 0346879 A1. B) Miscellaneous agglomeration procedure This is based on the formation of an insoluble complex by two oppositely charged colloidal interactions deposited on the particles of the active pharmaceutical ingredient to be encapsulated to form an active A film of medicinal ingredients isolated. Examples of such programs can be found in documents such as GB 1393805 A. C) Double emulsion procedure The active pharmaceutical ingredient to be encapsulated is dissolved in water or a solution of another auxiliary adjuvant and emulsified in a solution of the polymer and the additive in a suitable solvent such as dichloromethane. Next, the emulsion thus produced is emulsified in water or an aqueous solution of an emulsifier such as polyvinyl alcohol. Once this second emulsification is carried out, the solvent in which the polymer and the plasticizer are dissolved is removed by evaporation or extraction. The resulting microcapsules of -19-201141469 are directly obtained by filtration or evaporation. Examples of these programs can be found in documents such as us 465 244 1 . D) Simple emulsion procedure Dissolve the active pharmaceutical ingredients, polymers and additives to be encapsulated in a suitable organic solvent. This solution is emulsified in water or a solution of an emulsifier such as polyvinyl alcohol and the organic solvent is removed by evaporation or extraction. The microcapsules thus produced are recovered by filtration or drying. Examples of such procedures can be found in documents such as US 5,445,832 A. E) Solvent evaporation procedure Dissolve the active pharmaceutical ingredient, polymer and additives to be encapsulated in a suitable solvent. The solution is evaporated and the resulting residue is micronized to obtain a suitable size or dried by spray drying. An example of this procedure can be found in a document such as GB 2209937 A. Another aspect of the present invention relates to a pharmaceutical capsule of the present invention for use in the treatment and/or prevention of cardiovascular diseases. Preferably, the cardiovascular disease is selected from the group consisting of hypertension, heart failure, and myocardial infarction. Another aspect of the present invention relates to a method of treating and/or preventing a cardiovascular disease comprising administering a pharmaceutical gum of the present invention. Preferably, the cardiovascular disease is selected from the group consisting of hypertension, heart failure, and myocardial infarction. The following specific examples are provided herein to illustrate the nature of the invention. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention as claimed herein. [Embodiment] -20- 8 201141469 Example ι. Preparation of ramipril-containing microcapsules by a simple coacervation procedure Medicinal capsules of gelatin. A 1% gelatin solution in water was prepared. 100 ml of this solution was taken and 1 g of ramipril powder was dispersed therein. Next, 30 ml of a saturated sodium sulfate solution in water was added. The mixture was stirred for 1 hour and 〇. 5 ml of a 50% glutaraldehyde solution in water was added. The microcapsules formed by filtration were collected, washed with water and dried in a vacuum drying oven. The content of ramipril in these microcapsules was 35%. The resulting microcapsule powder was directly dispersed in an oil containing at least 90% of PUFA ethyl esters (which contained a minimum of 85% EPA/DHAC ratio of 1.2:1)) (719 mg per 1 gram of oil added) Obtained microcapsule suspension). Next, a microcapsule dispersion of 1. g of oil in oil was placed in a soft capsule to obtain a dose of 2.5 mg of ramipril in each capsule. Example 2. Preparation of a pharmaceutical capsule containing a group of Doppler microcapsules and poly(lactic-glycolic acid) (PLGA) and vitamin bismuth. The microcapsules were prepared by a simple emulsion method (oil-in-water). Solution A: A 10% PLGA solution having an intrinsic viscosity (I_V.) of 0.17 and a ratio of lactic acid/glycolic acid of 1:1 in dichloromethane (DCM) was prepared. Solution B: 5 g of group doppler and 1 g of vitamin E acetate were dissolved in 1 ml of solution A. Solution C: A 1% polyvinyl alcohol (PVA) solution in water was prepared. 1 〇 ml of solution B was slowly added to 100 ml of solution C under vigorous stirring until a milky white emulsion was obtained. During this agitation, the nitrogen was circulated -21 - 201141469 over the previous emulsion for two hours to exclude most of the D C Μ. Next, the resulting suspension was frozen and lyophilized. A powder is obtained and washed with a large amount of water to remove excess PVA and dry under reduced pressure. The microcapsule powder obtained contained 31% of the group of doppler and was directly dispersed in an oil containing a minimum of 60% of PUFA ethyl esters (which contained a minimum of 40% of DH A ). Next, the obtained microcapsule dispersion in oil was placed in a soft capsule. The amounts used to prepare capsules of different sizes and different doses of group Doppler are not shown in Table 1. Dispersion: gram of micromicelle / 100g of oil dispersion weight / micelle group Dopply dose / micelle 0.65 g 0.50 g 1 mg 0.43 g 0.75 g 1 mg 1.31 g 0.50 g 2 mg 0.65 g 1.00 g 2 mg Table 1 Example 3 - A pharmaceutical capsule containing lisinopril microcapsules and poly(lactic acid glycolic acid) (PLGA) was prepared by a triple emulsion method. Solution A: 5 g of PLG A having an intrinsic viscosity (I.V.) of 0.4 liter/g and a ratio of lactic acid/glycolic acid of 1:1 was dissolved in 50 ml of dichloromethane (DCM). Solution B: 1·〇8 g of lisinopril dihydrate was dissolved in 10 ml of water. Solution C: A polyvinyl alcohol (PVA) solution in water at a concentration of 0.5 p/v % was prepared. -22- 8 201141469 The aqueous phase (solution B) was emulsified in a PLGA solution (solution A) with the aid of an Ultra Turrax homogenizer (W/0 emulsion). The previously prepared W/0 emulsion was added to 1 liter of PV A solution (solution C) under vigorous stirring. The newly formed emulsion was stirred while the nitrogen stream was passed through the reactor at a flow rate of not less than 50 liters/min to evaporate D CM. The microcapsules were recovered by filtration through a membrane having a pore size of 5 μm, washed with a large amount of water to exclude excess PVA and dried by lyophilization. The obtained microcapsule powder contained 16% lisinopril, which was directly dispersed in oil containing at least 90% of PUFA ethyl esters (which contained a minimum of 85% EPA/DHA (ratio: 1.2:1)). . (1.59 g of the obtained microcapsule suspension was added to each 10 g of oil). Next, 1 g of the microcapsule dispersion in oil was placed in a soft capsule to obtain a dose of 2.5 mg of lisinopril in each capsule. Example 4. A pharmaceutical capsule containing candesartan cilexetil microcapsules and gelatin and carboxymethylcellulose was prepared by a miscible coacervation procedure. Solution A: Prepare a 1% gelatin solution in water and adjust the pH to 7 or above 7. Solution B: Another 1% sodium carboxymethylcellulose solution in water was prepared and the pH was adjusted to 7 or higher. 250 ml of solution A was mixed with 250 ml of solution B and heated to 40 t. 4 g of powdered candesartan cilexetil was dispersed in the mixture. When all the powders were dispersed and there was no agglomeration, the pH was adjusted to 4-4.5 via the addition of acetic acid. The mixture was stirred at 40 ° C for 1 hour' and then the solution was cooled to 10 ° C, -23-201141469 and this temperature was maintained for an additional 1 hour. Add 2 ml of a 50% glutaraldehyde solution in water. The resulting suspension was dried by spray drying to obtain a microcapsule powder containing 40% candesartan cilexetil. This microcapsule powder was directly dispersed in an oil containing a minimum of 90% PUFA ethyl esters which contained a minimum of 85% EPA/DHA (1.2:1 ratio). Next, the obtained microcapsule dispersion in oil is incorporated into a soft capsule. The amounts used to prepare capsules of different sizes and different doses of candesartan cilexetil are shown in Table 2. Dispersion: gram of micromicelle / 100 g of oil dispersion weight / micelle candesartan cilate dosage / micelle 2.04 g 1.00 g 8 mg 1.35 g 1.50 g 8 mg 4.17 g 1.00 g 16 mg 2.74 g 1.50 g 16 mg Table 2 Example 5. Preparation of a pharmaceutical capsule containing valsartan and a methacrylic acid copolymer. Ten grams of valsartan was suspended in 1 ml of Eudragit FS 30D® (suspension in water with 30% methacrylic acid 'methyl methacrylate and methyl acrylate copolymer) until a fine suspension was obtained. Triethyl citrate was added to this suspension (polymer plasticizer) until the concentration was 5%. The resulting suspension was dried by spray drying to produce a microcapsule powder containing 22% valsartan. -24- 8 201141469 The resulting microcapsule powder was directly dispersed in an oil containing at least 65% PUFA ethyl esters containing a minimum of 45% EPA/DHA (1.2:1 ratio). (25.0 g of the obtained microcapsule suspension was added per 100 g of oil). Next, 1.0 g of the microcapsule dispersion in oil was placed in a soft capsule to obtain 40 mg of laksa in each capsule. The dosage of Tan. Example 6. Stabilization of soft capsules containing ramipril, tranopril, lisinopril, candesartan cilexetil and valsartan microcapsule suspensions in oils containing PUFA alkyl esters Sexuality. An accelerated stability (40 ± 2 ° C, 75 ± 5 % relative humidity) of a soft capsule containing a suspension of the active pharmaceutical ingredient in an oil comprising an alkyl ester of PUFA, wherein: a) The active pharmaceutical ingredient does not have a polymer coating (control composition). b) The active pharmaceutical ingredient is in a microcapsule (composition of the present invention) prepared according to the previous examples. The percentage of active pharmaceutical ingredient in the capsule was determined by HPLC after storage for 1 month, 2 months, 3 months, and 4 months in an amber glass container. The percentage of the active pharmaceutical ingredient is shown in Table 3. The stability of PUFA (concentration of EPA and DHA alkyl esters, and EPA/DHA ratio) was also investigated by gas chromatography. However, no change was observed in the composition. -25- 201141469 Stability of active ingredients (40±2 °C, 75±5 % RH) (%) Initial 1 month 2 months 3 months 4 months Ramipril (Example 1) a 99.2 96.3 91.7 87.0 81.1 b 98.9 99.0 _ 98.8 98.9 Group Dopply (Example 2; dose 2 mg, micelle 1 g) a 99.1 97.0 93.2 88.6 84.5 b 99.2 99.0 _ 99.1 99.0 Lisinopril (Example 3; dose 2.5 mg, micelles) 1 g) a 99.0 96.2 91.3 85.6 79.2 b 99.1 98.9 - 98.9 98.8 Candesartan ester example 4; dose 16 mg, micelle 1 g) a 98.8 97.5 94.8 91.9 87.9 b 98.7 98.8 _ 98.6 98.4 valsartan (example 5 a 98.4 97.1 94.5 92.1 89.4 b 98.5 98.4 - 98.2 98.1 Table 3