TW200817054A

TW200817054A - Formulation of organic compounds

Info

Publication number: TW200817054A
Application number: TW096132781A
Authority: TW
Inventors: Dieter Becker; Barbara Luckel; Bruno Galli; Stefanie Siepe; Jorg Ogorka
Original assignee: Novartis Ag
Priority date: 2006-09-04
Filing date: 2007-09-03
Publication date: 2008-04-16
Also published as: AR062613A1; WO2008028885A2; CL2007002553A1; WO2008028885A3; PE20081364A1

Abstract

The present invention concerns pharmaceutical compositions comprising an acidic drug compound which is an angiotensin II receptor antagonist or a releasable form thereof, and a pH modifier.

Description

200817054 九、發明說明：【發明所屬之技術領域】本發明係關於包括具有pH-依賴性吸收特徵曲線之藥物化合物的固體醫藥組合物。具體而言，本發明係關於一種醫藥組合物，其包括一酸性藥物化合物（例如纈沙坦 • (valsartan))，該酸性藥物化合物可呈自由酸、前藥、醫藥 - 上可接受鹽、溶合物、多晶物或其組合之形式。該酸性藥物化合物可呈結晶、部分結晶、非晶形或液體狀態。 • 【先前技術】纈沙坦，亦即（S)-N-(l_羧基-2-甲基丙-1-基）-N-戊醯基-Ν-[2’-(1Η-四唾-5-基）聯苯基-4-基曱基]胺，係一種弱酸性藥物化合物。纈沙坦之結構、製備及調配物闡釋於（例如） US 5399578、US 6294197、WO 97/49394、WO 00/38676 及WO 01/97805中，該等專利案之内容以引用的方式併入本申請案中。纟頭沙坦係一種血管張力素II受體拮抗劑且對治療充血性心臟哀竭及降血壓有效並具有良好财受性。亦已知其與氫氯噻嗪（HCTZ)之組合可用於治療高血壓。目前，纟領沙坦以速釋錠劑調配物（Diovan®)市售，其含女 • 40毫克、80毫克、160毫克或320毫克纈沙坦。當以此種形 • 式投與時，纈沙坦展示較低之生物利用率（約30%)及相對較高之個體間及個體内之變化性。諸如纈沙坦之酸性藥物化合物沿胃腸（GI)道表現顯著的 pH-依賴滲透性。酸性藥物化合物之淨電荷隨pH而增加，其又可導致親脂性降低。結果係酸性藥物化合物穿透GI道 123701.doc 200817054 親脂膜之滲透性隨pH降低。由於沿GI道pH逐漸增加（pH植之大致範圍係··胃pH為1至2 ’·十二指腸pH為4至5，·空腸及回腸pH為5至8 ;且結腸pH為6至8)，因此酸性藥物化合物之滲透性隨化合物沿腸道行進而降低。此滲透性之下降限制化合物在GI道中酸性較低區域之吸收速率及生物利用率。酸性藥物化合物之另一性質係其在水中之溶解度隨pH 而升高。因此，化合物在GI道之酸性較低區域溶解度更大，此增加其排泄而非吸收之可能性。【發明内容】因此，本發明係關於一種提供長時間藥物持續釋放（例如’自投與長達24小時）之纈沙坦調配物。本發明亦係關於一種纈沙坦調配物，其可降低一個或更多個體間之變化性’降低個體内之變化性及提高生物利用率。本發明至少部分地基於一令人驚奇之發現：藉由將酸性藥物調配物之微環境pH改變至更強酸性條件下，可使通過 GI迢酸性較弱區域藥物分子之淨電荷減少。此又可增強該等酸性較弱區域中藥物分子之親脂性及滲透性。以此種方式調節pH亦可降低化合物在該等區域之水溶性，此可降低 $合物被排泄之可能性。具體而言，本發明係關於弱酸性樂物化合物（尤其係纈沙坦）和其他血管張力素^受體拮抗劑之調配物。因此在一態樣中，本發明提供一種包括以下之醫藥組合物： (i)至少一種係血管張力素II受體拮抗劑之酸性藥物化 123701.doc 200817054 合物或其可釋放形式； (Π)至少一種pH調節劑；及 (iii)至少一種醫藥上可接受之賦形劑。一在另-態樣中，本發明提供血管張力素„受體拮抗劑或其可釋放形式及pH調節劑之用途，其用於製備尤其藉由受體抑制治療患有與血管張力奸受體活性相關疾病：患：之藥劑。在另-態樣中’本發明提供-種經口投與酸性藥物化合物（其為血管張力素II受體拮抗劑或其可釋放形式）之= 法，該方法包括對需要治療之患者經σ投與本發明之醫藥組合物。該組合物可呈適宜於一天投與一次之形式。、另-態樣係-種適用於在腸道中產生局部酸性環境之經口的纈沙坦組合物。缬沙坦可呈游離化合物之形式或呈其可釋放纈沙坦之衍生物形式。 μ 另-態樣係關⑨-種醫藥上可接受酸用⑨製造包括為血管張力素II受體拮抗劑之酸性藥物化合物或其可釋放彤式之經口藥劑之用途，其中該醫藥上可接受酸可促進該酸：藥物化合物在腸道内之質子化。本發明進-步包括-種可增強為灰管張力㈣受體抬抗劑之酸性藥物化合物腸道吸收之方法，其包括聯合投與該酸性藥物化合物或其可釋放形式與一？11調節劑。 - 熟悉此項技術者藉由參考下列說明書及中請專利範圍將理解並暸解本發明之該等及其他特徵、優點及目的。而且，適當時，所用單數術語亦包括複數且反之亦然。 123701.doc 200817054 【實施方式】酸性藥物化合物本發明係關於為jk管張力素II受體拮抗劑酸性藥物化合物或其可釋放形式之用途。本文所用術語”酸性藥物化合物π意指包括一個或以上（例如一個或兩個）酸性基團（例如一個或以上選自由羧酸及四唑基之基團）之藥物化合物。該酸性藥物化合物可係弱酸性藥物化合物。具體而言，該術語意指弱酸，舉例而言，包括一個或更多具有超過2(例如2.1，例如3或更高，3.5或更高，且尤其為4或更高）pKa 之酸性基團之弱酸。其中尤指包括一個或更多酸性基團 (緩k基）之血|張力素II受體拮抗劑，例如顯沙坦、洛沙坦、依普羅沙坦、坎地沙坦、替米沙坦、厄貝沙坦、奥美沙坦及以下化合物：200817054 IX. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a solid pharmaceutical composition comprising a pharmaceutical compound having a pH-dependent absorption profile. In particular, the present invention relates to a pharmaceutical composition comprising an acidic pharmaceutical compound (e.g., valsartan) which is a free acid, a prodrug, a pharmaceutically acceptable salt, and a soluble In the form of a compound, a polymorph, or a combination thereof. The acidic drug compound may be in a crystalline, partially crystalline, amorphous or liquid state. • [Prior Art] Valsartan, ie (S)-N-(l-carboxy-2-methylpropan-1-yl)-N-pentamethylene-Ν-[2'-(1Η-four saliva -5-yl)biphenyl-4-ylindenyl]amine, a weakly acidic pharmaceutical compound. The structure, preparation and formulation of valsartan are illustrated in, for example, US Pat. No. 5,995, 978, US Pat. No. 6,294,197, WO 97/49,394, WO 00/38676, and WO 01/97805, the contents of each of which are incorporated herein by reference. In the application. Shantou Shatan is an angiotensin II receptor antagonist and is effective for treating congestive heart pain and lowering blood pressure and has good financial properties. It is also known to be useful in the treatment of hypertension in combination with hydrochlorothiazide (HCTZ). Currently, Satan is marketed as an immediate release tablet formulation (Diovan®) containing 40 mg, 80 mg, 160 mg or 320 mg valsartan. When administered in this form, valsartan exhibited lower bioavailability (approximately 30%) and relatively higher inter-individual and intra-individual variability. Acidic drug compounds such as valsartan exhibit significant pH-dependent permeability along the gastrointestinal (GI) tract. The net charge of the acidic drug compound increases with pH, which in turn can lead to a decrease in lipophilicity. As a result, the acidic drug compound penetrates the GI tract 123701.doc 200817054 The permeability of the lipophilic membrane decreases with pH. Due to the gradual increase in pH along the GI tract (the approximate range of pH planting is • gastric pH 1 to 2 '·duodenal pH 4 to 5, jejunum and ileum pH 5 to 8; and colon pH 6 to 8), Thus the permeability of the acidic drug compound decreases as the compound travels along the intestinal tract. This decrease in permeability limits the rate of absorption and bioavailability of the compound in the lower acidic regions of the GI tract. Another property of acidic pharmaceutical compounds is their solubility in water increases with pH. Thus, the compound is more soluble in the lower acidic regions of the GI tract, which increases its likelihood of excretion rather than absorption. SUMMARY OF THE INVENTION Accordingly, the present invention is directed to a valsartan formulation that provides sustained release of a drug over a prolonged period of time (e.g., 'self-administered for up to 24 hours). The invention is also directed to a valsartan formulation that reduces variability between one or more individuals' reduces variability within the individual and increases bioavailability. The present invention is based, at least in part, on the surprising discovery that by changing the microenvironmental pH of an acidic pharmaceutical formulation to more acidic conditions, the net charge of drug molecules passing through the weaker regions of the GI can be reduced. This in turn enhances the lipophilicity and permeability of the drug molecules in the less acidic regions. Adjusting the pH in this manner also reduces the water solubility of the compound in such areas, which reduces the likelihood of excretion of the compound. In particular, the present invention relates to formulations of weakly acidic music compounds (especially valsartan) and other angiotensin receptor antagonists. Thus in one aspect, the invention provides a pharmaceutical composition comprising: (i) at least one acidic pharmaceutical compound of an angiotensin II receptor antagonist 123701.doc 200817054 or a releasable form thereof; At least one pH adjusting agent; and (iii) at least one pharmaceutically acceptable excipient. In another aspect, the invention provides the use of an angiotensin receptor antagonist or a releasable form thereof, and a pH adjusting agent for the preparation of a vasopressor receptor, particularly by receptor inhibition therapy Activity-related disease: an agent: In another aspect, the invention provides a method of orally administering an acidic drug compound which is an angiotensin II receptor antagonist or a releasable form thereof, The method comprises administering to a patient in need of treatment a pharmaceutical composition of the invention via σ. The composition may be in a form suitable for administration once a day. The other-type strain is suitable for producing a local acidic environment in the intestine. Oral valsartan composition. Valsartan may be in the form of a free compound or in the form of a derivative thereof which can release valsartan. μ---------------------------------------- An acidic pharmaceutical compound of an angiotensin II receptor antagonist or a releaseable oral medicinal agent thereof, wherein the pharmaceutically acceptable acid promotes the acid: protonation of the pharmaceutical compound in the intestinal tract. -step includes - A method for enhancing intestinal absorption of an acidic pharmaceutical compound which is enhanced to a gray tube tension (IV) receptor antagonist, which comprises co-administering the acidic pharmaceutical compound or a releasable form thereof and a ?11 modulator. - Familiar with the technology These and other features, advantages and objects of the present invention will be understood and understood by reference <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Modes] Acidic Pharmaceutical Compounds The present invention relates to the use of an acidic pharmaceutical compound or a releasable form thereof, which is a jk vasopressin II receptor antagonist. The term "acidic drug compound π" as used herein is meant to include one or more (eg one or two) An acidic compound (for example, one or more selected from the group consisting of a carboxylic acid and a tetrazolyl group). The acidic drug compound can be a weakly acidic drug compound. In particular, the term means a weak acid, for example, comprising one or more acidic groups having a pKa of more than 2 (eg 2.1, such as 3 or higher, 3.5 or higher, and especially 4 or higher). Weak acid. Especially including blood containing one or more acidic groups (slow-k base) | tensin II receptor antagonists, such as salbuta, losartan, eprosartan, candesartan, telmisartan , irbesartan, olmesartan and the following compounds:

前藥、醫藥上可接受鹽、工4释狹形式，本文所用術語”可釋放以可控方式經口投與將酸性化合物釋放 _ $式。該酸性藥物化合物可呈游離酸、式。舉例而言，接文鹽、溶合物、多晶物或其組合之形〖生藥物化合物可作為鹼加成鹽投與，其 123701.doc 200817054 在腸道環境中會形成與其至少一種去質子形式平衡之游離酸藥物化合物，此導致特定時間依賴性釋放特性曲線。該藥物化合物可呈結晶、部分結晶、非晶形或液體狀態。較佳藥物化合物係纈沙坦或其可釋放形式（例如，醫藥上可接受之鹽或劑型形式）。其中尤其係纈沙坦游離酸或其鈣聲。纈沙坦之羧酸基之pKa約為39，而纈沙坦之四唑基之pKa約為4.7。該酸性藥物化合物可與一種或更多.其他治療劑組合使用。舉例而言，本發明之纈沙坦組合物可進一步包括一種或更多選自由利尿劑、鈣通道阻斷劑（CCB)、阻斷劑及 ACE抑制劑等組成之群之抗高血壓藥。利尿劑為（例如）選自由氯嗟嗪、氫氯噻嗪、甲氯噻嗪、及氣噻酮組成之群之噻嗪類衍生物。最佳為氫氯噻嗪。可用之CCB較佳係選自由胺氯地平（aml〇dipine)、非洛地平 (felodipine)、柳的平（ry0sidine)、伊拉地平（isradipine)、拉西地平（lacidipine)、尼卡地平（nicardipine)、硝苯地平 (nifedipine)、尼古地平（nigUidipine)、尼魯地平（niludipine)、尼莫地平（nimodipine)、尼索地平（nisoldipine)、尼群地平 (nitrendipine)、及尼伐地平（nivaldipine)組成之群之DHP代表物’及較佳選自由I桂利嘻（flunarizine)、普尼拉明 (prenylamine)、地爾硫卓（diltiazem)、芬地林（fendiline)、加洛帕米（gallopamil)、口米拉地爾（mibefradil)、阿尼帕米 (anipamil)、噻帕米（tiapamil)及維拉帕米（verapamil)、及在任一情形下其醫藥上可接受之鹽組成之群的非-DHP代 12370l.doc -10- 200817054 表物。 β-腎上腺素能受體阻斷劑包括艾司洛爾（esmolol)且尤其係其氫氯酸鹽、醋丁洛爾（acebutolol)、阿普洛爾（alprenolol)、胺石黃洛爾（amosulalol)、阿羅洛爾（arotinolol)、阿替洛爾 (atenolol)、苯 σ夫洛爾（befunolol)、倍他洛爾（betaxolol)、貝凡洛爾（bevantolol)、比索洛爾（bisoprolol)、波ϋ引洛爾 (bopindolol)、布庫洛爾（bucumolol)、布非洛爾 (bufetolol)、丁吱洛爾（bufuralol)、布尼洛爾（bunitrolol)、布拉洛爾（bupranolol)、butiridine hydrochloride、丁非洛爾（butofilolol)、卡拉洛爾（。狂1^2〇1〇1)、卡替洛爾（〇旺1^〇1〇1)、卡維地洛（carvedilol)、塞利洛爾（celipr〇l〇l)、塞他洛爾 (cetamolol)、氯拉洛爾（cloranolol)、地來洛爾（dilevalol)、依泮洛爾（epanolol)、茚諾洛爾（indenolol)、拉貝洛爾 (labetalol)、左布諾洛爾（levobunolol)、曱 °引洛爾（mepindolol)、美替洛爾（metipranolol)、美托洛爾（metopr〇l〇l)、甲氧苯 φ 心安（moprolol)、納多洛爾（nadolol)、萘肟洛爾（nadoxolol)、奈必洛爾（nebivolol)、尼普地洛（nipradil〇i)、氧烯洛爾 (oxprenolol)、噴布洛爾（perbutolol)、吲哚洛爾（pindolol)、 " 普拉洛爾（Practolol)、丙萘洛爾（pr〇nethal〇1)、普萘洛爾 k (Propranolol)、索他洛爾（sotai〇1)、硫氧洛爾（sulfinal〇1)、他林洛爾（talinolol)、特他洛爾（把伽〇1〇1)、替利洛爾（仙8〇1〇1)、噻嗎洛爾（timolol)、托利洛爾（toliprolol)、及希苯洛爾 (xibenolol)，或在任一情形下其醫藥上可接受之鹽。 ACE抑制劑係選自由以下組成之群：阿拉普利 123701.doc 200817054 (alacepril)、貝那普利（benazepril)、貝那普利拉（benazeprilat)、卡托普利（captopril)、西羅普利（ceronapdl)、西拉普利 (cilazapril)、地拉普利（delapril)、依那普利（enalapril)、 enaprilat、福辛普利（fosinopril)、17米達普利（imidapril)、賴諾普利（lisinopril)、莫維普利（moveltopril)、培口朵普利 (perindopril)、喧那普利（quinapril)、雷米普利（ramipril)、螺普利（spirapril)、替莫普利（temocapril)、及群多普利 (trandolapril)，或在任一情形下其醫藥上可接受之鹽。本發明之組合物（尤其包括纈沙坦或其可釋放形式之彼等）尤其可藉由受體抑制用於與血管張力素II受體活性相關之病症與疾病之療法（亦即治療、預防或延遲發展）。例示性疾病及病症包含高血壓、充血性心臟衰竭及心肌梗塞。 pH調節劑本文所用術語pH調節劑一般係指醫藥上可接受的可釋放氫離子（酸）之有機或無機化學材料，例如有機或無機酸、酸性聚合物（例如卡波姆（carbomer))或潛在性酸。本發明用pH調節劑來將在腸道酸性較弱部分之酸性藥物調配物之微環境pH改變成酸性更強之狀況。本文所用術語”微環境 pH"意指在藥物調配物範圍内及附近之pH值。本文所用術語"腸道"意指小腸（包含十二指腸、空腸及回腸)及大腸（例如結腸）。組合物可能包括一種或更多pH調節劑。 pH調節劑可係pKa為自約1至約7之酸，具體而言自約2 至約6.5，更具體而言自約3至約6.5。其中尤指具有3.5或更低pKa之pH調節劑，例如，低於3.1，例如約3或更低； 123701.doc -12- 200817054 該等值在纈沙坦之情形下尤其較佳，其最低pKa為3·9。當本文提及pKa值時，通常認為係在25 °C溫度下於水中所測定之彼等。在某些情況下，pH調節劑之酸強度至少與酸性藥物化合物之酸強度相等，亦即其pKa應低於或等於（尤其低於）酸性藥物化合物之pKa，若有兩種或更多酸性基團，其pKa應低於酸性最強之pKa(本文稱為"pKal”）。該pH調節劑可為酸，具體而言可為潛在性酸，或其醫藥 0 上可接受之鹽。潛在性酸係在水存在下可水解為游離酸之化合物，例如葡萄糠酸-δ-内酯。使用固體酸或其醫藥上可接受之鹽作為pH調節劑對於製備本發明之組合物尤其適宜。在本發明之一較佳實施例中，該pH調節劑係有機酸或其醫藥上可接受之鹽。適宜有機酸包含一個或更多酸性基團，尤其包含選自叛酸及磺酸基團之酸性基團之化合物，尤其彼等在環境溫度下為固態且具有2個或更多酸性基團 _ 者。此外’可存在能調節（例如加強或減弱）酸性官能團之酸性的官能團，例如經基或胺基。在另一實施例中，pH調節劑為水溶性有機酸。適宜水溶 - 性有機酸包括但不限於選自單、二-或多元羧酸及單、二 . 或三磺酸之水溶性或水溶性較差之有機酸，較佳係彼等在環境溫度下為固態者。特定固態水溶性羧酸包括(例如)脂肪私單或來羧酸’例如彼等包含i至2〇個碳原子、具體而言2至6個碳原子、更具體而言包含4至6個且尤其4個碳原子之所有竣酸或：T錄赌甘士夂飞一羧I，其中任一酸可係飽和或不飽和或 123701.doc -13- 200817054 具有支鏈或非支鏈碳原子鏈。適宜固態水溶性脂肪族單羧酸之實例包括山梨酸（2,4-己二烯酸）。適宜固態水溶性脂肪族二緩酸之實例包括己二酸、丙二酸、號珀酸、戊二酸、馬來酸（maleic acid)或富馬酸（fumaric acid)。該脂肪族叛酸視情況可由相同或不同且選自（例如）羧基、胺基或备基之一個或更多基團（例如1、2或3個）取代。適宜經取代固悲水溶性脂肪族羧酸包括（例如）經羥基取代之脂肪族單羧酸（例如葡萄糖酸、乳酸之固態形式、乙醇酸或抗壞血酉文）’經Μ基取代之脂肪族二魏酸（例如蘋果酸、酒石酸、丙醇二酸（羥基丙二酸）或半乳糖二酸（黏酸））；經羥基2-取代之脂肪族三羧酸（例如擰檬酸）；或帶有酸性側鏈之胺基酸’例如麵胺酸或天冬胺酸。在另一實施例中，pH調節劑為芳族羧酸。適宜芳族羧酸包括含有至多20個碳原子之水溶性芳基羧酸。適宜芳基羧酸$含帶有一或多個羧基（例如1、2或3個羧基）之芳基（例如苯基或奈基）。該芳基視情況可經相同或不同且選自羥基、（1-4C)烷氧基（例如甲氧基）及磺醯基的一或更多基^ (例如1、2或3個）取代。芳聽酸之適宜實例包括（例如）苯甲暖、鄰苯，甲酸、間苯二甲酸、對笨二甲酸或偏苯三甲酸（1，2,4-苯三羧酸）。糊節劑可包括聚合有機酸或其醫藥上可接受之鹽。該聚合物可料性或具有支鏈或其組合。該聚合物可藉由一 ^或更多交聯劑交聯。適宜聚合酸包含具有酸性基^之線 ’主鏈、包含具有酸性基團之支鏈主鏈的聚合物或i混合 123701 ,(ΐ〇ς -14· 200817054 物。其中尤其係可能交聯的合成高分子量丙稀酸聚合物 (例如Carb— 71G)或與（例如）二乙歸基苯）交聯之甲基丙稀酸聚合帅物，AmbermeIRP_64)。亦可提及者係海蕩酸。 pH調節劑可包括水溶性無機酸，例如具有在上文定義 pH調節劑範圍内之_的水溶性或水溶性較差之無機酸。該等無機酸之實例係包含所有水合物（例如二水合物或單水合物）在内之磷酸二氫鈉及磷酸氫二鈉。較佳地，PH調節劑係選自有機酸、酸性聚合物及潛在性酸。The prodrug, the pharmaceutically acceptable salt, and the pharmaceutically acceptable salt, the term "releaseable" can be administered orally in a controlled manner to release the acidic compound. The acidic pharmaceutical compound can be in the form of a free acid. In the form of a salt, a lysate, a polymorph or a combination thereof, the biopharmaceutical compound can be administered as a base addition salt, and 123701.doc 200817054 forms a balance with at least one deprotonated form in the intestinal environment. a free acid drug compound which results in a specific time-dependent release profile. The drug compound may be in a crystalline, partially crystalline, amorphous or liquid state. Preferred pharmaceutical compounds are valsartan or a releasable form thereof (for example, in medicine) An acceptable salt or dosage form), especially valsartan free acid or its calcium sound. The carboxylic acid group of valsartan has a pKa of about 39, and the tetrazole of valsartan has a pKa of about 4.7. The acidic pharmaceutical compound may be used in combination with one or more other therapeutic agents. For example, the valsartan composition of the present invention may further comprise one or more selected from the group consisting of a diuretic, a calcium channel. An antihypertensive agent consisting of a group of (CCB), a blocker, and an ACE inhibitor. The diuretic is, for example, a thiazide selected from the group consisting of chloropyridazine, hydrochlorothiazide, methylchlorothiazide, and ketone. a derivative, preferably hydrochlorothiazide. The preferred CCB is selected from the group consisting of amlodipine, felodipine, ry0sidine, isradipine, and lacidipine. (lacidipine), nicardipine, nifedipine, nigdiidipine, niludipine, nimodipine, nisoldipine, nitrendipine ( DHP representative of nitrendipine) and nivaldipine ' and preferably selected from flunarizine, prenylamine, diltiazem, fendiline , gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in any case medicinally Non-D of the group of salt accepted HP generation 12370l.doc -10- 200817054 Table of contents. Beta-adrenergic receptor blockers include esmolol and especially its hydrochloride, acebutolol, apollo Alprenolol, amosilolol, arotinolol, atenolol, befunolol, betaxolol, befolo (bevantolol), bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunyrolol Bunitrolol), bupranolol, butiridine hydrochloride, butofilolol, carrollol. Mad 1^2〇1〇1), carteolol (〇旺1^〇1〇1), carvedilol, celiprol (llipr〇l〇l), cetalol ( Cetamolol), clolomolol, dilevalol, epanolol, indenolol, labetalol, levobunolol ), 曱° mepindolol, metipranolol, metopr〇l〇l, methoxybenzene, moprolol, nadolol, naphthoquinone Nadoxolol, nebivolol, nipradil〇i, oxprenolol, perbutolol, pindolol, " Practolol, propranolol (pr〇nethal〇1), propranolol (Propranolol), sotalol (sotai〇1), thiolatol (sulfinal〇1), he Talinolol, betatalol (Gaya 1〇1), tililol (xian 8〇1〇1), timolol, toliprolol, and Xibenolol, or in any situation Its pharmaceutically acceptable salts. The ACE inhibitor is selected from the group consisting of: Arapley 123701.doc 200817054 (alacepril), benazepril, benazeprilat, captopril, sirop Ceronapdl, cilazapril, deLapril, enalapril, enaprilat, fosinopril, 17-meter imidapril, lisino Lisinopril, moteltopril, perindopril, quinapril, ramipril, spirapril, temocapril ( Temocapril), and trandolapril, or in any case a pharmaceutically acceptable salt thereof. The compositions of the invention, especially including valsartan or a releasable form thereof, are particularly useful for inhibiting the treatment of conditions and diseases associated with angiotensin II receptor activity by receptor (ie, treatment, prevention) Or delay development). Exemplary diseases and conditions include hypertension, congestive heart failure, and myocardial infarction. pH Modifier The term pH adjusting agent as used herein generally refers to a pharmaceutically acceptable organic or inorganic chemical material that releases hydrogen ions (acids), such as organic or inorganic acids, acidic polymers (such as carbomers) or Potential acidity. The present invention uses a pH adjusting agent to change the microenvironment pH of the acidic drug formulation in the weakly acidic portion of the intestinal tract to a more acidic state. The term "microenvironmental pH" as used herein means the pH in and around the pharmaceutical formulation. The term "intestinal" as used herein means the small intestine (including the duodenum, jejunum and ileum) and the large intestine (such as the colon). The pH may include one or more pH adjusting agents. The pH adjusting agent may be an acid having a pKa of from about 1 to about 7, specifically from about 2 to about 6.5, more specifically from about 3 to about 6.5. Refers to a pH adjusting agent having a pKa of 3.5 or lower, for example, less than 3.1, such as about 3 or lower; 123701.doc -12-200817054 The value is particularly preferred in the case of valsartan, and the lowest pKa is 3.9. When the pKa values are mentioned herein, they are generally considered to be determined in water at a temperature of 25 ° C. In some cases, the acid strength of the pH adjusting agent is at least equal to the acid strength of the acidic drug compound. , that is, its pKa should be lower than or equal to (especially lower than) the pKa of the acidic drug compound. If there are two or more acidic groups, the pKa should be lower than the most acidic pKa (referred to herein as "pKal)) . The pH adjusting agent can be an acid, specifically a latent acid, or a pharmaceutically acceptable salt thereof. A latent acid is a compound which can be hydrolyzed to the free acid in the presence of water, such as gluconic acid-delta-lactone. The use of a solid acid or a pharmaceutically acceptable salt thereof as a pH adjusting agent is especially suitable for preparing the composition of the present invention. In a preferred embodiment of the invention, the pH adjusting agent is an organic acid or a pharmaceutically acceptable salt thereof. Suitable organic acids comprise one or more acidic groups, especially those comprising an acidic group selected from the group consisting of tickic acid and sulfonic acid groups, especially if they are solid at ambient temperature and have 2 or more acidic groups. By. Further, there may be a functional group capable of modulating (e.g., strengthening or weakening) the acidic functional group, such as a trans group or an amine group. In another embodiment, the pH adjusting agent is a water soluble organic acid. Suitable water-soluble organic acids include, but are not limited to, water-soluble or poorly water-soluble organic acids selected from the group consisting of mono-, di- or polycarboxylic acids and mono-, di- or tri-sulfonic acids, preferably at ambient temperature. Solid state. Specific solid water-soluble carboxylic acids include, for example, aliphatic singly or carboxylic acids, for example, which contain from 1 to 2 carbon atoms, specifically 2 to 6 carbon atoms, more specifically 4 to 6 and In particular, all of the four carbon atoms of citric acid or T: gambling can be a carboxylic acid I, any of which may be saturated or unsaturated or 123701.doc -13 - 200817054 having a chain of branched or unbranched carbon atoms. Examples of suitable solid water-soluble aliphatic monocarboxylic acids include sorbic acid (2,4-hexadienoic acid). Examples of suitable solid water-soluble aliphatic dibasic acids include adipic acid, malonic acid, crotonic acid, glutaric acid, maleic acid or fumaric acid. The aliphatic tetamine may optionally be substituted with one or more groups (e.g., 1, 2 or 3) which are the same or different and are selected, for example, from a carboxyl group, an amine group or a starting group. Suitable substituted water-soluble aliphatic carboxylic acids include, for example, hydroxy-substituted aliphatic monocarboxylic acids (eg, gluconic acid, solid form of lactic acid, glycolic acid or ascorbic acid) a diveric acid (such as malic acid, tartaric acid, propanol diacid (hydroxymalonic acid) or galactonic acid (mucosic acid)); a hydroxyl 2-substituted aliphatic tricarboxylic acid (such as citric acid); Or an amino acid with an acidic side chain such as a face acid or aspartic acid. In another embodiment, the pH adjusting agent is an aromatic carboxylic acid. Suitable aromatic carboxylic acids include water soluble aryl carboxylic acids containing up to 20 carbon atoms. Suitable aryl carboxylic acids $ contain an aryl group (e.g., phenyl or naphthyl) having one or more carboxyl groups (e.g., 1, 2 or 3 carboxyl groups). The aryl group may be optionally substituted by one or more groups (e.g., 1, 2 or 3) which are the same or different and are selected from the group consisting of a hydroxyl group, a (1-4C) alkoxy group (e.g., a methoxy group), and a sulfonyl group. . Suitable examples of the aromatic acid include, for example, benzal warm, ortho-benzene, formic acid, isophthalic acid, p-dicarboxylic acid or trimellitic acid (1,2,4-benzenetricarboxylic acid). The paste may comprise a polymeric organic acid or a pharmaceutically acceptable salt thereof. The polymer may have a property or have a branch or a combination thereof. The polymer can be crosslinked by one or more crosslinking agents. Suitable polymeric acids comprise a backbone having an acidic backbone, a polymer comprising a branched backbone having an acidic group, or a mixture of i.123701 (ΐ〇ς-14·200817054), in particular a synthesis which may be crosslinked. A high molecular weight acrylic acid polymer (such as Carb-71G) or a methyl methacrylate polymer that is crosslinked with, for example, diethylbenzene benzene, AmbermeIRP_64). It can also be mentioned that the person is sultry. The pH adjusting agent may include a water-soluble inorganic acid such as a water-soluble or poorly water-soluble inorganic acid having a range of pH adjusting agents as defined above. Examples of such inorganic acids are sodium dihydrogen phosphate and disodium hydrogen phosphate containing all hydrates such as dihydrate or monohydrate. Preferably, the pH adjusting agent is selected from the group consisting of organic acids, acidic polymers, and latent acids.

若該酸性藥物化合物係纈沙坦或其醫藥上可接受之鹽，則pH調節劑較佳地係選自以下的一種：富馬酸、天冬胺酸、琥珀酸、麩胺酸、己二酸、琥珀酸酐、肉桂酸、抗壞血酸、棕櫚酸抗壞血酯、檸檬酸、穀胺酸鈉、蘋果酸、酒石I、L-乳酸、馬來酸、草酸、硬脂酸、乳清酸、癸二酸或在任一情形下其醫藥上可接受之鹽，包括兩種或更多酸及/或鹽之混合物在内。更佳為富馬酸及琥珀酸。在2 5 〇C 下’画馬酸之pKal為約3，更具體為3·03，而琥珀酸之pKal 為約4.2。因此該組合物較佳經改造以使得在至少GI道之一部分、較佳在十二指腸、空腸、回腸與結腸之一或更多中局部實貝保持其微環境pH值。具體而言，該組合物可在至少gi道之一部分、較佳地在十二指腸、空腸、回腸及結腸之一或更多中保持5或更低（例如，4或更低，具體而言3.5或更低）之微環境pH值。因此，pH調節劑之數量及性質應適合於 123701.doc -15 - 200817054 k化該酸性藥物化合物之吸收。此可包括使用具有實質上與i性藥物化合物相等之溶解速率之pH調節劑及/或保持微環境pH之足量ph調節劑。在本發明之一較佳實施例中，醫藥組合物中pH-調節劑與酸性藥物化合物之重量比例係〇〇1:1或更大，或介於 0·05:1與ι〇:1之間，或介於oomhj之間。其中尤其係包括纈沙坦之組合物，其中pH調節劑與纈沙坦之比例為自約〇·2··1至約ι··〇·3，較佳為自約〇·25:1至約1:〇·5，例如約 0.25:1、約〇·5··ι、約1:1或約1:〇·5。例示性組合物包括自約至、、句60重里％之pH調郎劑及自約5至約6〇重量％之顯沙坦。較佳地，組合物包括2pH調節劑為自約1〇至約5〇重量 %、或自約15至約40重量％、或自約2〇至約4〇重量％、或自約20至30重量％或約30至約45重量％。較佳地，組合物包括之纈沙坦為自約1〇至約5〇重量％、或自約1〇至約4〇重里％、或自約10至約30重量％、或自約20至約30重量％或自約30至約40重量％。其中PH調節劑尤其係選自富馬酸及琥珀酸。為達成在持續釋放組合物中使用之目的，端視意欲作用之持續時間，較佳選用水溶性相對較差（例如，小於約 5%(克/100毫升水）)之pH調節劑。經調節释放形式該組合物可適合於提供酸性藥物化合物在一段時間（例如至多約24小時，例如至多約16小時或至多約4小時）上之級調節（例如持續或間斷）釋放。該組合物能在一段時間内 123701.doc -16- 200817054 在相對窄之範圍内保持藥物血 ^ 十同樣，該組合物亦 k供胸即劑在相同時間段上之經調節釋放。經調節釋放系統之具體類丨制手统-般… 擴散控制系統。擴散-控 = 性材料，其可控制水進至組合物中解樂物隨後自組合物中釋出。在該等系統t既包 ;擴：過，又包括溶解過程。該等擴散控制系統之實例包 :形、减膠的,基質錠劑或包括擴散調節薄膜衣之包膜錠〆。此外，該等系統可具有溶韻性並藉此釋放藥物，且pH 調節劑至少部分地受該機制控制。擴散-控制系統之實例係其中藥物與pH調節劑分散於整個基質材料中之基質組合物。基質材料至少與酸性藥物化合物及PH調節劑相結合以使藥物化合物及/或pH調節劑可在腸道内隨時間逐漸釋放。藥物在聚合物基質中之擴散通常係限速步驟’釋放速率由所選擇之基質材料及其對待釋 :藥物之擴散及分佈係數之必然影響而決定。其中尤其係早=質系統’亦即包括含有酸性藥物化合物及pH調節劑之只貝上均-分散物之基質的組合物。實例包括基質旋劑及多顆粒基質系統’例如微錠劑、顆粒劑或微丸劑1等系統可具有溶餘性或不具有溶钱性，且可具有分散性^溶解〖生或顯示该專釋放機制之混合體。基質材料可包括-種或更多可形成基質或形成凝膠之聚合物。舉例而言’該組合物可包括―種或更多選自纖維素何生物、丙烯酸衍生物、乙烯基聚合物、聚氧乙烯聚合物、聚乙二醇聚合物及多糖之聚合物。丙烯酸衍生物之實 I23701.doc 200817054 例包括甲基丙烯酸共聚物（例如Eudragit E30D、L100或 S100)、甲基丙烯酸胺烧基酉旨共聚物（例如Eudragit RL100 或RS 100)、曱基丙烯酸酯共聚物（例如Eudragit NE3 0D)及交聯丙烯酸聚合物（例如Carbopol 71G)。乙浠基聚合物之實例包括聚乙酸乙烯酯（例如Kollidone SR的一部分）、聚乙酸乙烯酯共聚物（例如Kollidone VA64)、聚乙烯吡咯啶酮（例如Kollidone K30)及其混合物。其他適宜聚合物包括聚氧乙浠（例如由Dow Chemicals，USA製造之Polyox WSR3 10)、聚乙二醇（例如分子量大於4000之PEG)、多糖 (例如黃原膠(xanthan、xanthan gum)、半乳甘露聚糠、果膠及藻酸鹽）。較佳之聚合物係羥丙基甲基纖維素。該等聚合物可包括（例如）不同聚合鏈長度、不同聚合主鏈與官能團之取代率或（若存在多於一個官能團）不同官能團之比率。後者之實例係Hypromelose 2208 (Methocel K100LV CR，Dow Chemicals製造），對應於該纖維素聚合物上葡萄糠主鏈中最多3個羥基之1.4的平均取代率，其甲氧基含量為19-24%，且對應於其0.21之平均取代率，羥丙基含量為7-12%。而且，聚合物可以不同粒度使用，例如纖維素衍生物可以不同粒度分佈來製造。一實例係 Methocel K100LC，其能以微細或粗糙形式獲得。基質材料可包括含有自聚合物主鏈至官能團之鏈接基團之纖維素衍生物，該等鏈接基團可為在同一纖維素主鏈聚合物上之醚、酯或醚與酯之組合。實例包括烷基-醚纖維素（例如甲基或乙基纖維素）、羥基-烷基-醚纖維素（例如羥 123701.doc -18· 200817054 乙基或羥丙基纖維素）、混合的烷基與羥_烷基纖維素（例如羥丙基曱基-或羥乙基曱基纖維素）、碳酸酯纖維素（例如乙醯基纖維素）、混合的醚與酯纖維素（例如羧曱基纖維素鈉、或鄰苯二甲酸羥丙基曱基纖維素、或乙酸鄰笨二甲酸纖維素、或乙酸丙酸纖維素、或乙酸丁酸纖維素、或丁酸纖維素、或硝酸纖維素、或羧曱基乙氧基纖維素、或琥珀 •酸乙酸羥丙基甲基纖維素）。參另頭擴散-控制系統包括一個核心（内”層”）與一個外層。在一貫施例中，核心含有pH調節劑而外層含有藥物化 ά物在另一貝施例中，核心含有藥物化合物而外層含有 pH調節劑。在另一實施例中，核心含有ρΗ調節劑與藥物化合物二者。該核心、外層或二者可含有一種或更多控制藥物及/或pH調節劑釋放之水不溶性聚合物。此一系統之實例係緊壓包膜錠劑。本發明之組合物可包括能控制水份進入及溶解藥物自組 • 合物中溶出之擴散包膜。因此，擴散包膜通常（至少部分）透水該組合物可包括含有藥物化合物及pH調節劑之核心、及可調節酸性藥物化合物及/或pH調節劑之釋放的擴 • 散包膜。此外，該核心亦可包括一種或更多可控制藥物及/ -或pH調節劑釋放之水不溶性聚合物。該等系統之實例包括 _劑(例如單片基質錠劑)、及包膜多顆粒系統(例如微錠劑、微丸劑、顆粒劑及珠粒）。當該組合物以錠劑形式存在時，較佳為能在口腔、胃或小腸中崩解或溶解以得到經改良釋放包膜多顆粒之錠劑。與單片系統相比，當多顆 I23701.doc -19- 200817054 粒:得^以經由幽門排泄時，其展示出平均胃排空更快且對言養狀態依賴小之優點。多顆粒可具有多種調配物應用。舉例而言’其可填人膠囊殼中或作為藥囊或其可壓製成錠劑。㈣釋放可由另外諸如渗透活性材料（例如㈣）或表面活性劑（例如SDS或吐溫（Tween)化合物）之賦形劑支持。擴散包膜可有小孔以使得水份進入組合物内。或者或另外，該擴散包膜可含有孔形成劑，亦即一種可在使用期間在包膜中形成一個或更多小孔之藥劑。擴散包膜可包括水不溶性材料及水溶性孔形成劑。當包膜與水接觸時，孔形成劑會溶解並藉此在包膜中形成一個或更多小孔。水不溶陘材料之實例包括基於乙基纖維素、丙烯酸自旨及甲基丙烯 I i曰中之一種或更多之聚合物。孔形成劑之實例包括諸如每丙基甲基纖維素及聚乙二醇之水溶性聚合物。該組合物可包括立即釋放與改良釋放單片固體劑型或多顆粒之混合物，其可填充於膠囊殼内或以藥囊形式呈現。投與該劑型後，藥物自該系統總體釋放的特徵在於該藥物首先快速釋放且隨後該藥物以改良方式（例如持續或連續）隨時間釋放。其他組份在本發明之某些例示性實施例中，該醫藥組合物可包含常見於醫藥組合物中之其他賦形劑，此等賦形劑之實例包括（但不限於）填充劑、滑動劑、潤滑劑、黏結劑、抗氧化劑、抗微生物劑、酵素抑制劑、穩定劑、防腐劑、矯味 123701.doc -20- 200817054 劑、甜味劑及以引用方式併入本文中之（例如）闡述於If the acidic pharmaceutical compound is valsartan or a pharmaceutically acceptable salt thereof, the pH adjusting agent is preferably selected from the group consisting of fumaric acid, aspartic acid, succinic acid, glutamic acid, and dimethoate. Acid, succinic anhydride, cinnamic acid, ascorbic acid, ascorbyl palmitate, citric acid, sodium glutamate, malic acid, tartar I, L-lactic acid, maleic acid, oxalic acid, stearic acid, orotic acid, Azelaic acid or a pharmaceutically acceptable salt thereof in either case, including a mixture of two or more acids and/or salts. More preferably fumaric acid and succinic acid. At 25 ° C, the pKal of tartaric acid is about 3, more specifically 3·03, and the pKal of succinic acid is about 4.2. The composition is therefore preferably adapted such that the local scallop maintains its microenvironmental pH in at least a portion of the GI tract, preferably in one or more of the duodenum, jejunum, ileum and colon. In particular, the composition may be maintained at 5 or less (eg, 4 or lower, specifically 3.5 or more) in at least one part of the gi tract, preferably in one or more of the duodenum, jejunum, ileum, and colon. Lower) microenvironment pH. Therefore, the amount and nature of the pH adjusting agent should be suitable for the absorption of the acidic drug compound. This may include the use of a pH adjusting agent having a dissolution rate substantially equal to that of the i-pharmaceutical compound and/or a sufficient amount of pH adjusting agent to maintain the pH of the microenvironment. In a preferred embodiment of the present invention, the weight ratio of the pH-adjusting agent to the acidic drug compound in the pharmaceutical composition is 1:1 or greater, or between 0.05:1 and ι〇:1. Between, or between oomhj. In particular, the composition includes valsartan, wherein the ratio of the pH adjuster to valsartan is from about 〇·2··1 to about ι····3, preferably from about 〇·25:1 to Approximately 1: 〇·5, for example about 0.25:1, about 〇·5··ι, about 1:1 or about 1: 〇·5. Exemplary compositions include from about 60% by weight of the pH to about 60% by weight of the formula and from about 5 to about 6% by weight of the sirtan. Preferably, the composition comprises 2 pH adjusting agent from about 1 Torr to about 5 重量%, or from about 15 to about 40% by weight, or from about 2 Torr to about 4,000 重量%, or from about 20 to 30 % by weight or from about 30 to about 45% by weight. Preferably, the composition comprises valsartan of from about 1 to about 5 weight percent, or from about 1 to about 4 weight percent, or from about 10 to about 30 weight percent, or from about 20 to about 20 percent by weight. About 30% by weight or from about 30 to about 40% by weight. Among them, the pH adjusting agent is especially selected from the group consisting of fumaric acid and succinic acid. For the purpose of achieving the use in sustained release compositions, it is preferred to use a pH adjusting agent which is relatively poorly water soluble (e.g., less than about 5% (grams per 100 milliliters of water)). Modified Release Form The composition may be adapted to provide a graded (e.g., sustained or intermittent) release of the acidic pharmaceutical compound over a period of time (e.g., up to about 24 hours, such as up to about 16 hours or up to about 4 hours). The composition is capable of maintaining drug blood within a relatively narrow range for a period of time 123701.doc -16-200817054. Similarly, the composition is also modified for release of the thoracic agent over the same period of time. Specific types of regulated release systems - general... diffusion control systems. Diffusion-controlled = Sexual material that controls the ingress of water into the composition and then releases it from the composition. In these systems t are both packaged; expanded: and included in the dissolution process. Examples of such diffusion control systems include: shaped, gelatinized, matrix troches or coated ingots comprising diffusion conditioned film coatings. Moreover, such systems can be lyrical and thereby release the drug, and the pH adjusting agent is at least partially controlled by the mechanism. An example of a diffusion-control system is a matrix composition in which a drug and a pH adjusting agent are dispersed throughout the matrix material. The matrix material is combined with at least the acidic pharmaceutical compound and the pH adjusting agent to allow the pharmaceutical compound and/or pH adjusting agent to be gradually released over the intestinal tract over time. The diffusion of the drug in the polymer matrix is typically a rate limiting step. The release rate is determined by the selected matrix material and its inevitable effect on the diffusion and distribution coefficient of the drug. In particular, the composition is a composition comprising a matrix of a homogenous-dispersion of an acidic pharmaceutical compound and a pH adjusting agent. Examples include matrix spinners and multiparticulate matrix systems such as microtablets, granules or pellets1, etc., which may or may not have solubility, and may have dispersibility, dissolve or display the specific release. A mixture of mechanisms. The matrix material may comprise one or more polymers which form a matrix or form a gel. For example, the composition may include one or more polymers selected from the group consisting of cellulose, acrylic acid derivatives, vinyl polymers, polyoxyethylene polymers, polyethylene glycol polymers, and polysaccharides. Acrylic acid derivative I23701.doc 200817054 Examples include methacrylic acid copolymers (such as Eudragit E30D, L100 or S100), methacrylic acid amine based copolymers (such as Eudragit RL100 or RS 100), mercapto acrylate copolymerization (eg Eudragit NE3 0D) and crosslinked acrylic polymer (eg Carbopol 71G). Examples of the ethyl ruthenium polymer include polyvinyl acetate (e.g., a part of Kollidone SR), a polyvinyl acetate copolymer (e.g., Kollidone VA64), polyvinylpyrrolidone (e.g., Kollidone K30), and mixtures thereof. Other suitable polymers include polyoxyethyl hydrazine (e.g., Polyox WSR3 10 manufactured by Dow Chemicals, USA), polyethylene glycol (e.g., PEG having a molecular weight greater than 4,000), polysaccharides (e.g., xanthan, xanthan gum, half) Milk nectar, pectin and alginate). A preferred polymer is hydroxypropyl methylcellulose. Such polymers may include, for example, different polymeric chain lengths, ratios of substitution of different polymeric backbones to functional groups, or ratios of functional groups if more than one functional group is present. An example of the latter is Hypromelose 2208 (Methocel K100LV CR, manufactured by Dow Chemicals), which corresponds to an average substitution rate of 1.4 of up to 3 hydroxyl groups in the ruthenium backbone of the cellulose polymer, and a methoxy group content of 19-24%. And corresponding to its average substitution ratio of 0.21, the hydroxypropyl content is 7-12%. Moreover, the polymers can be used in different particle sizes, for example, the cellulose derivatives can be produced in different particle size distributions. An example is Methocel K100LC, which is available in fine or coarse form. The matrix material may comprise a cellulose derivative comprising a linking group from the polymer backbone to the functional group, which may be an ether, an ester or a combination of an ether and an ester on the same cellulose backbone polymer. Examples include alkyl-ether cellulose (such as methyl or ethyl cellulose), hydroxy-alkyl-ether cellulose (such as hydroxy 123701.doc -18·200817054 ethyl or hydroxypropyl cellulose), mixed alkane And hydroxy-alkyl cellulose (such as hydroxypropyl decyl- or hydroxyethyl decyl cellulose), carbonate cellulose (such as acetamino cellulose), mixed ether and ester cellulose (such as carboxy hydrazine) Cellulose sodium, or hydroxypropyl decyl cellulose phthalate, or cellulose acetate o-dicarboxylate, or cellulose acetate propionate, or cellulose acetate butyrate, or cellulose butyrate, or nitrocellulose Or carboxymethyl ethoxy cellulose, or succinic acid hydroxypropyl methyl cellulose acetate). The other part of the diffusion-control system consists of a core (inner layer) and an outer layer. In a consistent embodiment, the core contains a pH adjusting agent and the outer layer contains a pharmaceutical mash. In another embodiment, the core contains a drug compound and the outer layer contains a pH adjusting agent. In another embodiment, the core contains both a rhomodulin and a pharmaceutical compound. The core, outer layer or both may contain one or more water insoluble polymers that control the release of the drug and/or pH adjusting agent. An example of such a system is a compression coated lozenge. The compositions of the present invention may include a diffusion envelope that controls the ingress of water into and dissolution of the drug from the composition. Thus, the diffusion envelope is typically (at least partially) permeable to water. The composition may comprise a core comprising a pharmaceutical compound and a pH adjusting agent, and a diffusion envelope which modulates the release of the acidic pharmaceutical compound and/or the pH adjusting agent. In addition, the core may also include one or more water-insoluble polymers that control the release of the drug and/or pH modifier. Examples of such systems include _agents (e.g., monolithic substrate troches), and coated multiparticulate systems (e.g., microtablets, pellets, granules, and beads). When the composition is in the form of a tablet, it is preferably capable of disintegrating or dissolving in the oral cavity, stomach or small intestine to obtain a lozenge of modified release coated multiparticulates. Compared to the monolithic system, when multiple I23701.doc -19-200817054 granules were obtained for excretion via the pylorus, they exhibited the advantage of a faster average gastric emptying and a small dependence on the state of speech. Multiparticulates can have a variety of formulation applications. For example, it can be filled into a capsule shell or used as a sachet or it can be compressed into a tablet. (d) Release may be supported by additional excipients such as osmotically active materials (e.g., (iv)) or surfactants (e.g., SDS or Tween compounds). The diffusion envelope can have small pores to allow moisture to enter the composition. Alternatively or additionally, the diffusion envelope may contain a pore former, i.e., an agent that forms one or more pores in the envelope during use. The diffusion envelope can include a water insoluble material and a water soluble pore former. When the envelope is in contact with water, the pore former dissolves and thereby forms one or more pores in the envelope. Examples of the water-insoluble cerium material include polymers based on one or more of ethyl cellulose, acrylic acid, and methacrylic acid I i . Examples of the pore former include water-soluble polymers such as per propylmethylcellulose and polyethylene glycol. The composition may comprise a mixture of immediate release and modified release monolithic solid dosage forms or multiparticulates which may be filled into a capsule shell or presented in the form of a sachet. Upon administration of the dosage form, the overall release of the drug from the system is characterized by a rapid release of the drug first and subsequent release of the drug over time in a modified manner (e.g., continuous or continuous). Other Components In certain exemplary embodiments of the invention, the pharmaceutical composition may comprise other excipients commonly found in pharmaceutical compositions, examples of such excipients including, but not limited to, fillers, slips Agents, lubricants, binders, antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavors 123701.doc -20- 200817054 agents, sweeteners and incorporated herein by reference (for example) Explained in

Handbook of Pharmaceutical Excipients，專尺编辑，第 4版，Pharmaceutical Press (2003)中之其他組份。除填充劑及/或黏結劑以外之其他賦形劑可佔總醫藥組合物之約0.05-11重量％，例如該總組合物之約〇1_8重量 %，或約0.5-3.5重量％。抗氧化劑、抗微生物劑、酵素抑制劑或底物、穩定劑或防腐劑通常佔總醫藥組合物之至多約0.05至10重量％。甜味劑或矯味劑通常佔總醫藥組合物之至多約2·5%或約5重量％。潤滑劑通常佔總醫藥組合物重量之約0.1-10%、或約〇·5_5%、或約〇5%、或約1%或約 2%。填充劑及/或黏結劑以重量計佔約1 %至約6〇%、較佳地約1%至約50%、約1%至約4〇%、或約5%至約35%、或約 1%、3%、5%、10%、15〇/〇、2〇0/〇、25〇/〇、3〇0/〇、35〇/〇、4〇% 或 45% 〇本文所用”潤滑劑”之實例包括（但不限於）硬脂酸鎂、滑石粉、氫化蓖麻油、甘油二十二烷酸酯、甘油單硬脂酸酯、聚乙二醇、環氧乙烷聚合物、月桂基硫酸鈉、月桂基 Μ 油®欠鈉、硬脂基富馬酸鈉、DL-白胺酸、膠態二氧化梦及業内習知之其他潤滑劑。本文所用”填充劑，，之實例包括（但不限於）乳糖（其可係無 K或K θ开^/式）糖、殿粉（例如縠物、小麥、玉米、馬鈴薯）、k性澱粉（例如，澱粉水解產物或預膠凝澱粉）、甘露糖醇、山梨醇、海藻糠、麥芽糖、脫水葡萄糖；無機鹽 (例如，妷fee鈣、碳酸鎂、磷酸氫鈣、磷酸三鈣、硫酸 I23701.doc -21 · 200817054 妈）、微晶纖維素、纖維素衍生物。本文所用’’滑動劑π之實例包括（但不限於）如Aerosil 200 或滑石粉之矽氣凝膠。本文所用”黏結劑”之實例包括（但不限於）羥丙基甲基纖維素（HPMC)，例如，具有低表觀黏度（如對於2重量％水溶液在20°C下量測，例如低於100 cps，例如低於50 cps，較佳低於20 cps)之HMPC，例如習知且以商標名Pharmacoat® 603購自Shin-Etsu公司之HPMC 3 cps。用於本發明組合物之其他適宜黏結劑係聚乙浠σ比洛咬酮（PVP)，例如習知且以商標名Povidone®購自BASF公司之PVP Κ30或PVP Κ12。抗氧化劑之實例包括（但不限於）抗壞血酸及其衍生物、生育酚及其衍生物、丁基羥基苯甲醚及丁基羥基曱苯。維他命E如α-生育酚尤其有用。本發明之組合物可包括腸溶包膜以防止藥物及/或酸在到達小腸之前自固體劑型形式中溶解。可使用底衣以將腸溶包膜與包括pH調節劑之基質分開。舉例而言，腸溶包膜（最終重量之％)可包含： • 2-40%用於腸溶包膜之聚合物，例如鄰苯二曱酸羥丙基甲基纖維素（例如購自Shin Etsu之HP 50、HP 55)、琥珀酸乙酸羥丙基曱基纖維素（例如購自Shin Etsu之 Aqoat Η、Μ、L型）、曱基丙烯酸·乙基丙烯酸共聚物 (曱基丙烯酸共聚物，USP)(例如購自R5hm Pharma之 Eudragit L、S、L100-55、L30D、購自 Colorcon 之 Acryl-Eze、購自 BASF之Kollicoat MAE 30 DP)、乙酸 123701.doc -22- 200817054 鄰苯二甲酸纖維素（例如購自FMC Biopolymer之 Aquacoat CPD、或購自 Eastman Kodak 之聚合物）、聚乙酸鄰苯二曱酸乙烯醋（Sureteric，Colorcon); •用於底衣之0-15%聚合物：羥丙基甲基纖維素 (Pharmacoat 603 或 606)、乙基纖維素（例如 Aquacoat ECD、FMC Biopolymer，Surelease，Colorcon)及/或其中乙基纖維素：HPMC為1:1至l:l〇比率之混合物、聚乙烯醇（Opadry II HP，85F型，Colorcon); • 0-50%增塑劑（乙酸甘油、檸檬酸三乙酯、peg 4000、 PEG 6000、PEG 8000、鄰苯二甲酸二乙酉旨、癸二酸二乙酯、乙醯基檸檬酸三乙酯等）； • 0-15% 抗黏合劑（例如 Aerosil 200、Syloid 244 FP、滑石粉、甘油單硬脂酸酯等）； •含有及不含有部分水之有機溶劑或其混合物（乙醇、丙酮、異丙醇）、或水（適量）以溶解或分散用於包膜溶液之包膜聚合物及賦形劑；及 •用於再分散含水腸溶包膜懸浮液之聚合物（例如 EudragitL100-55)之 0-0.5% 氫氧化納。下列實例係闡釋（而非用於限制）本文所述本發明之範圍。該等實例僅意在建議實施本發明之方法。每一實例中所使用的以佔該醫藥組合物的重量百分數表示的組份之量皆闡述於置於相應描述内容後之相應表中。實例 1. 單片基質改良釋放系統 123701.doc -23- 200817054 ι·ι組合物組份及範圍 • 0.01-80%活性組份 • ^70% pH調節劑（例如諸如擰檬酸、富馬酸、琥珀酸、己二酸、馬來酸之有機酸) • 3-60% 聚合物（例如 Methocel K100M、Methocel K100LV、Klucel HF、Methol〇Se 60SR或其混合物）及 ^ 視情況以下之一種或更多： • Ο·1·2%之滑動劑，例如Aerosil 200 • · 之潤滑劑’例如硬脂酸鎖 • 其他製錠賦形劑，例如填充劑（例如乳糖）或黏結劑 1.2用於錄劑及微錠劑之顆粒之製備藉由濕法製粒或碾壓過程製備顆粒。 1·2·1藉由濕法製粒製備顆粒將活丨生、、且伤、有機酸、聚合物、及任一其他製錠賦形劑混合並用水或有機溶劑實施濕法製粒。用於製備單片基質 • 錠劑之乾顆粒過適宜大小之篩網（例如具有1.0毫米直徑之開孔）。在微錠劑情形下，顆粒適宜過更小開孔（例如0 4毫米）之篩網。添加並充分混合由Aerosil、硬脂酸鎂及任何 - 其他製錠賦形劑組成之外部相。將該摻合物壓製成（例如） • I徑為5至12毫米之單片基質錠劑或直徑為（例如）1.7至2毫米之微錠劑。 1·2·2藉由碾壓製備顆粒將活性組份、有機酸、聚合物及任何其他㈣賦形劑混合並隨後用㈣機塵製。將礙壓機所形成之絲帶通過適宜 123701.doc -24 - 200817054 篩網（例如1毫米）研磨以製備單片基質錠劑。在微錠劑情形下，該絲帶使用更小開孔（例如0.4毫米）之篩網研磨。添加由Aerosil、硬脂酸鎂及任何其他製錠賦形劑組成之外部相並完全混合。將該摻合物壓製成直徑為5至12毫米之單片基質錠劑或直徑為（例如）1.7至2毫米之微錠劑。 1.3用於基質微錠劑之錠劑核心組合物以下微錠劑組合物係藉由濕法製粒所製備且重量為250土 5毫克（010毫米）。將已製備的250毫克±5毫克微錠劑填充入膠囊。在任一情形下，原料藥為顯沙坦（Diovan)酸或其妈鹽，例如鈣鹽的四水合物形式（作為活性部分計算）。Handbook of Pharmaceutical Excipients, Special Edition, 4th Edition, Other Components in Pharmaceutical Press (2003). Excipients other than fillers and/or binders may comprise from about 0.05% to about 11% by weight of the total pharmaceutical composition, for example from about 1% to about 8% by weight of the total composition, or from about 0.5% to about 3.5% by weight. The antioxidant, antimicrobial, enzyme inhibitor or substrate, stabilizer or preservative typically comprises up to about 0.05 to 10% by weight of the total pharmaceutical composition. Sweeteners or flavoring agents typically comprise up to about 2.5% or about 5% by weight of the total pharmaceutical composition. The lubricant typically comprises from about 0.1% to about 10%, or from about 5% to about 5%, or from about 5%, or about 1% or about 2% by weight of the total pharmaceutical composition. The filler and/or the binder comprises from about 1% to about 6%, preferably from about 1% to about 50%, from about 1% to about 4,000%, or from about 5% to about 35% by weight, or About 1%, 3%, 5%, 10%, 15〇/〇, 2〇0/〇, 25〇/〇, 3〇0/〇, 35〇/〇, 4〇% or 45% are used in this article. Examples of lubricants include, but are not limited to, magnesium stearate, talc, hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers, Sodium lauryl sulfate, lauryl eucalyptus® under-sodium, sodium stearyl fumarate, DL-leucine, colloidal dioxide, and other lubricants known in the art. As used herein, "filler," examples include, but are not limited to, lactose (which may be without K or K θ open), sugar, temple powder (eg, mash, wheat, corn, potato), k-starch ( For example, starch hydrolysate or pregelatinized starch), mannitol, sorbitol, seaweed, maltose, anhydroglucose; inorganic salts (for example, 妷fee calcium, magnesium carbonate, calcium hydrogen phosphate, tricalcium phosphate, sulfuric acid I23701. Doc -21 · 200817054 Ma), microcrystalline cellulose, cellulose derivatives. Examples of ''sliding agent π' used herein include, but are not limited to, aerogels such as Aerosil 200 or talc. "Adhesives" as used herein. Examples include, but are not limited to, hydroxypropyl methylcellulose (HPMC), for example, having a low apparent viscosity (eg, measured at 20 ° C for a 2% by weight aqueous solution, such as below 100 cps, such as low) HMPC at 50 cps, preferably less than 20 cps), such as HPMC 3 cps, which is commercially available under the trade name Pharmacoat® 603 from Shin-Etsu Corporation. Other suitable binders for use in the compositions of the present invention are polyethyl hydrazine. σ pirone (PVP), such as conventional and PVP Κ30 or PVP Κ12 from BASF under the trade name Povidone®. Examples of antioxidants include, but are not limited to, ascorbic acid and its derivatives, tocopherol and its derivatives, butyl hydroxyanisole and butyl hydroxy hydrazine. Benzene. Vitamin E such as alpha-tocopherol is especially useful. The compositions of the present invention may include an enteric coating to prevent dissolution of the drug and/or acid from the solid dosage form prior to reaching the small intestine. A subcoat may be used to encapsulate the enteric solution. The membrane is separated from the matrix comprising the pH adjusting agent. For example, the enteric coating (% of final weight) may comprise: • 2-40% of a polymer for enteric coating, such as hydroxypropyl phthalate Methyl cellulose (for example, HP 50, HP 55 from Shin Etsu), hydroxypropyl decyl cellulose succinate (for example, Aqoat Μ, Μ, L type from Shin Etsu), methacrylic acid · B Acrylic acid copolymer (mercaptoacrylic acid copolymer, USP) (for example, Eudragit L, S, L100-55, L30D from R5hm Pharma, Acryl-Eze from Colorcon, Kollicoat MAE 30 DP from BASF), acetic acid 123701.doc -22- 200817054 Cellulose phthalate For example, Aquacoat CPD from FMC Biopolymer, or Polymer from Eastman Kodak), Sureteric, Colorcon; • 0-15% polymer for the coat: Hydroxypropyl Methylcellulose (Pharmacoat 603 or 606), ethylcellulose (eg, Aquacoat ECD, FMC Biopolymer, Surelease, Colorcon) and/or a mixture of ethylcellulose:HPMC in a ratio of 1:1 to 1:1, Polyvinyl alcohol (Opadry II HP, Model 85F, Colorcon); • 0-50% plasticizer (glyceric acetate, triethyl citrate, peg 4000, PEG 6000, PEG 8000, phthalic acid diethyl hydrazine, hydrazine Diethyl diacrylate, triethyl citrate triethyl ethoxide, etc.); • 0-15% anti-adhesive (such as Aerosil 200, Syloid 244 FP, talc, glyceryl monostearate, etc.); An organic solvent containing a part of water or a mixture thereof (ethanol, acetone, isopropanol), or water (suitable amount) to dissolve or disperse the coating polymer and excipients used for the coating solution; and • for redispersing water Polymer of enteric coated suspension (eg Eudragit L100-55) 0 -0.5% sodium hydroxide. The following examples are illustrative, and not intended to be limiting, of the scope of the invention described herein. These examples are only intended to suggest a method of practicing the invention. The amounts of the components used in each example, expressed as a percentage by weight of the pharmaceutical composition, are set forth in the corresponding tables placed after the corresponding description. Example 1. Monolithic matrix modified release system 123701.doc -23- 200817054 Composition and range of ι·ι composition • 0.01-80% active ingredient • ^70% pH adjuster (eg such as citric acid, fumaric acid , succinic acid, adipic acid, organic acid of maleic acid) • 3-60% polymer (eg Methocel K100M, Methocel K100LV, Klucel HF, Methol 〇 Se 60SR or mixtures thereof) and / or one of the following or more More: • Ο·1% of a slip agent, such as Aerosil 200 • · Lubricants such as stearic acid locks • Other tableting excipients such as fillers (eg lactose) or binders 1.2 for recording agents Preparation of granules of micro troches The granules are prepared by a wet granulation or rolling process. 1·2·1 Preparation of granules by wet granulation Active granules, wounds, organic acids, polymers, and any other tableting excipients are mixed and wet granulation is carried out with water or an organic solvent. For the preparation of a single-piece substrate • The dry particles of the tablet are passed through a screen of suitable size (for example, an opening with a diameter of 1.0 mm). In the case of micro-tablets, the particles are suitably passed through a smaller opening (e.g., 0.4 mm) screen. Add and mix the external phase consisting of Aerosil, magnesium stearate, and any other excipients. The blend is compressed into, for example, a single-piece base tablet having a diameter of 5 to 12 mm or a micro-tablet having a diameter of, for example, 1.7 to 2 mm. 1·2·2 Preparation of granules by roller compaction The active component, organic acid, polymer and any other (iv) excipients are mixed and subsequently prepared by (4) machine dust. The ribbon formed by the barrier press is ground through a suitable 123701.doc -24 - 200817054 screen (e.g., 1 mm) to prepare a monolithic substrate lozenge. In the case of microtablets, the ribbon is ground using a screen of smaller openings (e.g., 0.4 mm). An external phase consisting of Aerosil, magnesium stearate and any other ingot excipient is added and thoroughly mixed. The blend is compressed into a single tablet base tablet having a diameter of 5 to 12 mm or a micro-tablet having a diameter of, for example, 1.7 to 2 mm. 1.3 Tablet core composition for matrix micro-tablets The following micro-tablet compositions were prepared by wet granulation and weighed 250 mg 5 mg (010 mm). The prepared 250 mg ± 5 mg micro-tablets were filled into capsules. In either case, the drug substance is a diovan acid or a mom salt thereof, for example, a tetrahydrate form of the calcium salt (calculated as the active fraction).

實例1 實例2 [%] 毫克/録：/膠囊 [%] 1毫克/錠/膠囊 Methocel K100LV 30.00 75.00 Methocel K100LV | 30.00 75.00 Diovan酸或舞鹽 10.00 25.00 Diovan酸或妈鹽 10.00 25.00 富馬酸 20.00 ϋ 50.00 ϋ 富馬酸 0.00 0,00 S1碎乳糖磨碎乳糖 54.80 137.00 HPMC 3cps 2.67 6,68 H0PMC 3cps 2.67 6.68 硬脂酸鎂 LOO 2.50 硬脂酸鎂 1.00 2.50 Aerosil 1.53 moo 3.83 25αοο Aerosil 1.53 3.83 100.00 250.00 實例3 實例4 [%] 亳克/旋/膠囊 [%] 亳克/錠/膠囊 Methocel K100LV 30.00 75.00 Methocel K100LV 30.00 75.00 Diovan酸或妈鹽 20.00 | 50.00 Diovan酸或妈鹽 ! 20.00 50.00 富馬酸 20.00 50.00 富馬酸 0.00 0.00 磨碎乳糖 24.80 62.00 磨碎乳糖 44.80 112.00 HPMC 3cps 2.67 6.68 HPMC 3cps 2.67 6.68 硬脂酸鎂 1.00 2.50 逢脂酸S 1.00 2.50 Aerosil 1.53 3.83 Aerosil 1.53 3.83 100.00 250.00 100,00 250.00 123701.doc -25- 200817054Example 1 Example 2 [%] mg/record: /capsule [%] 1 mg / tablet / capsule Methocel K100LV 30.00 75.00 Methocel K100LV | 30.00 75.00 Diovan acid or dance salt 10.00 25.00 Diovan acid or mom salt 10.00 25.00 Fumaric acid 20.00 ϋ 50.00 ϋ Fumaric acid 0.00 0,00 S1 ground lactose ground lactose 54.80 137.00 HPMC 3cps 2.67 6,68 H0PMC 3cps 2.67 6.68 Magnesium stearate LOO 2.50 Magnesium stearate 1.00 2.50 Aerosil 1.53 moo 3.83 25αοο Aerosil 1.53 3.83 100.00 250.00 Examples 3 Example 4 [%] 亳克/旋/胶囊 [%] 亳克/锭/胶囊Methocel K100LV 30.00 75.00 Methocel K100LV 30.00 75.00 Diovan acid or mom salt 20.00 | 50.00 Diovan acid or mom salt! 20.00 50.00 Fumaric acid 20.00 50.00 Fumaric acid 0.00 0.00 Ground lactose 24.80 62.00 Ground lactose 44.80 112.00 HPMC 3cps 2.67 6.68 HPMC 3cps 2.67 6.68 Magnesium stearate 1.00 2.50 Acidic acid S 1.00 2.50 Aerosil 1.53 3.83 Aerosil 1.53 3.83 100.00 250.00 100,00 250.00 123701.doc -25- 200817054

實例7 [%] 毫克/錠/膠囊 Methocel K100LV 30.00 75.00 磨碎乳糖 34.00 85.00 Diovan酸或約鹽 30.00 75.00 富馬酸 0.00 0.00 HPMC 3cps 2.67 6.68 硬脂酸鎂 1.33 3.33 Aerosil 2.00 5.00 100.00 250.00 實例9 [%] 毫克/旋/膠囊 Methocel K100LV 30.00 75.00 磨碎乳糖 4.00 10.00 Diovan酸或妈鹽 30.00 75.00 富馬酸 30.00 75.00 HPMC 3cps 2.67 6.68 硬脂酸鎂 1.33 3.33 Aerosil 2.00 5.00 100.00 250.00 實例8 [%] 毫克/鍵/膠囊 Methocel K100LV 30.00 75.00 Diovan酸或4弓鹽 30.00 75.00 富馬酸 15.00 37.50 磨碎乳糖 19.00 47.50 HPMC 3cps 2.67 6.68 硬脂酸鎂 1.33 3.33 Aerosil 2.00 5.00 100.00 250.00 實例5 實例6 [%] 毫克/鍵/膠囊 [%] 亳克/鍵/谬囊 Methocel K4M 30.00 75.00 Methocel K4M 30.00 75.00 Diovan酸或#5鹽 10.00 25.00 Diovan酸或妈鹽 10.00 25.00 富馬酸 20.00 50.00 富馬酸 0.00 0.00 磨碎乳糖 34.00 85.00 磨碎乳糖 54.00 135.00 HPMC 3cps 2.67 6.68 EQPMC 3cps 2.67 6.68 硬脂酸鎂 1.33 3.33 硬脂酸鎂 1.33 3.33 Aerosil 2.00 5.00 Aerosil 2.00 5.00 100.00 250.00 100.00 250.00 1·4用於基質錠劑之錠劑核心組合物製備具有以下組合物之基質鍵劑藉由濕法製粒製備實例10之錠劑，而實例11至20之錠劑藉由碾壓製備。在任一情形下，原料藥為纈沙坦（Diovan)酸或其鈣鹽，例如鈣鹽的四水合物形式（作為活性部分計算）。 123701.doc -26- 200817054Example 7 [%] mg/ingot/capsule Methocel K100LV 30.00 75.00 ground lactose 34.00 85.00 Diovan acid or about salt 30.00 75.00 Fumaric acid 0.00 0.00 HPMC 3cps 2.67 6.68 Magnesium stearate 1.33 3.33 Aerosil 2.00 5.00 100.00 250.00 Example 9 [% ] mg / spin / capsule Methocel K100LV 30.00 75.00 ground lactose 4.00 10.00 Diovan acid or mom salt 30.00 75.00 Fumaric acid 30.00 75.00 HPMC 3cps 2.67 6.68 magnesium stearate 1.33 3.33 Aerosil 2.00 5.00 100.00 250.00 Example 8 [%] mg / key / Capsule Methocel K100LV 30.00 75.00 Diovan acid or 4 bow salt 30.00 75.00 Fumaric acid 15.00 37.50 Milled lactose 19.00 47.50 HPMC 3cps 2.67 6.68 Magnesium stearate 1.33 3.33 Aerosil 2.00 5.00 100.00 250.00 Example 5 Example 6 [%] mg / key / Capsule [%] 亳克/key/谬 capsule Methocel K4M 30.00 75.00 Methocel K4M 30.00 75.00 Diovan acid or #5 salt 10.00 25.00 Diovan acid or mom salt 10.00 25.00 Fumaric acid 20.00 50.00 Fumaric acid 0.00 0.00 Ground lactose 34.00 85.00 Grinding Lactose 54.00 135.00 HPMC 3cps 2.67 6.68 EQPMC 3cps 2.67 6.68 Stearic acid 1.33 3.33 Magnesium stearate 1.33 3.33 Aerosil 2.00 5.00 Aerosil 2.00 5.00 100.00 250.00 100.00 250.00 14.4 Tablet core composition for matrix lozenges Preparation of matrix binders with the following compositions Preparation of Example 10 by wet granulation Tablets, while the tablets of Examples 11 to 20 were prepared by roller compaction. In either case, the drug substance is iosaric acid or a calcium salt thereof, such as the tetrahydrate form of the calcium salt (calculated as the active fraction). 123701.doc -26- 200817054

實例10 % 實例11 % 毫克/鍵内部相I 内部相I 顯沙坦辦 30 纈沙坦鈣 30 200.10 Methocel K100LV 30 ~^20〇〇〇^ Methocel K100LV 30 200.10 富馬酸 00 2〇〇1〇^ 富馬酸 30 200.10 嘴務乾燦乳糖 8 53J8^ 嘴務乾餘乳糖 6.5 43.36 水適^^ Aerosil 200 1 6.67 外部相II 硬脂酸鎂 0.5 3.34 Aerosil 200 1 外部相II 硬脂酸鎂 1 ~6J0^ Aerosil 200 1 6.67 總計 1U0 667,00 硬脂酸鎂 I 6,67 總計 100 667.01 實例12 % 毫見安' 實例13 % 毫克/鍵内部相I 内部相I 纈沙坦鈣 30 20000^ 纈沙坦游離酸 30 160.00 Methocel K100LV 30 200.10 Methocel K100LV 30 160.00 喷霧乾燥乳糖 36.5 243.46 富馬酸 30 160.00 Aerosil 200 1 6.67 喷霧乾燥乳糖 6.5 34.50 硬脂酸鎂 0.5 3.34~" Aerosil 200 1 5.30 外部相II 硬脂酸鎂 0.5 2,60 Aerosil 200 1 6.67— 外部相II 硬脂酸鎂 1 6.67 Aerosil 200 1 5.30 總計 100 667.01 硬脂酸鎂 1 5.30 總計 100 533.00Example 10% Example 11% mg/bond internal phase I internal phase I salicillin 30 valsartan calcium 30 200.10 Methocel K100LV 30 ~^20〇〇〇^ Methocel K100LV 30 200.10 Fumaric acid 00 2〇〇1〇^ Fumaric acid 30 200.10 Mouth dry canola Lactose 8 53J8^ Mouth dry lactose 6.5 43.36 Water suitable ^^ Aerosil 200 1 6.67 External phase II Magnesium stearate 0.5 3.34 Aerosil 200 1 External phase II Magnesium stearate 1 ~6J0 ^ Aerosil 200 1 6.67 Total 1U0 667,00 Magnesium Stearate I 6,67 Total 100 667.01 Example 12 % mA See' Example 13 % mg/bond Internal Phase I Internal Phase I Valsartan 30 20000^ Valsartan Free acid 30 160.00 Methocel K100LV 30 200.10 Methocel K100LV 30 160.00 Spray dried lactose 36.5 243.46 Fumaric acid 30 160.00 Aerosil 200 1 6.67 Spray dried lactose 6.5 34.50 Magnesium stearate 0.5 3.34~" Aerosil 200 1 5.30 External phase II Hard Magnesium citrate 0.5 2,60 Aerosil 200 1 6.67—External phase II Magnesium stearate 1 6.67 Aerosil 200 1 5.30 Total 100 667.01 Magnesium stearate 1 5.30 Total 100 533.00

實例14 % 亳克/鍵實例15 % 毫克/鍵内部相I 内部相I 纈沙坦游離酸 30 160.00 纈沙坦游離酸 30 80.00 Methocel K100LV 30 160.00 Methocel K100LV 30 80.00 噴霧乾燥乳糖 36.5 194.50 噴霧乾燥乳糖 36.5 97.25 Aerosil 200 1 5.30 Aerosil 200 1 2.65 硬脂酸鎂 0.5 2.60 硬脂酸鎂 0.5 1.30 外部相II 外部相II Aerosil 200 1 5.30 Aerosil 200 1 2.65 硬脂酸鎂 1 5.30 硬脂酸鎂 1 2.65 總計丨1〇〇 533.00 總計 100 266.50 123701.doc 27- 200817054Example 14% gram/bond example 15% mg/bond internal phase I internal phase I valsartan free acid 30 160.00 valsartan free acid 30 80.00 Methocel K100LV 30 160.00 Methocel K100LV 30 80.00 spray dried lactose 36.5 194.50 spray dried lactose 36.5 97.25 Aerosil 200 1 5.30 Aerosil 200 1 2.65 Magnesium stearate 0.5 2.60 Magnesium stearate 0.5 1.30 External phase II External phase II Aerosil 200 1 5.30 Aerosil 200 1 2.65 Magnesium stearate 1 5.30 Magnesium stearate 1 2.65 Total 丨1 〇〇533.00 Total 100 266.50 123701.doc 27- 200817054

實例16 % 毫克/鍵實例17 % 亳克/錠内部相I 内部相I 纈沙坦鈣 40.02 200.10 纈沙坦鈣 40.02 200.10 Methocel K100LV 30.00 150.00 Methocel K100LV 30.00 150.00 富馬酸 10.00 50.00 富馬酸 10.00 50.00 喷霧乾燥乳糖 15.28 76.40 噴霧乾燥乳糖 15.28 76.40 Aerosil 200 1.00 5.00 Aerosil 200 1.00 5.00 硬脂酸鎂 1.70 8.50 硬脂酸鎂 1.70 8.50 外部相II 外部相II Aerosil 200 1.00 5.00 Aerosil 200 1,00 5.00 硬脂酸鎂 1.00 5.00 硬脂酸鎂 1.00 5.00 總計 100 500.00 總計 100 500.00 實例18 % 毫克/鍵實例19 % 毫克/旋内部相I 内部相I 纈沙坦鈣 40.02 200.10 纈沙坦鈣 40.02 200.10 Metolose 60SH-50 30.00 150.00 Methocel K100LV 30.00 150.00 富馬酸 10.00 50.00 琥珀酸 10.00 50.00 喷霧乾燥乳糖 15.28 76.40 喷霧乾燥乳糖 15.28 76.40 Aerosil 200 1.00 5.00 Aerosil 200 1.00 5.00 硬脂酸鎂 1.70 8.50 硬脂酸鎂 1.70 8.50 外部相II 外部相II Aerosil 200 1.00 5.00 Aerosil 200 1.00 5.00 硬脂酸鎂 1.00 5.00 硬脂酸鎂 1.00 5.00 總計 1.00 500.00 總計 100.00 500.00 實例20 % 毫克/録：實例21 % 毫克/旋内部相I 内部相纈沙坦鈣 40.02 200.10 纈沙坦鈣 21.96 200.30 Metolose 60SH-50 30.00 150.00 Hypromellose 2910 (Metolose 60SH-50) 26.00 237.20 琥珀酸 10.00 50.00 喷霧乾燥乳糖 15.28 76.40 富馬酸 43.85 400.00 Aerosil 200 1.00 5.00 喷霧乾燥乳糖 3.75 34.20 硬脂酸鎂 1.70 8.50 Aerosil 200 0.99 9.00 外部相π 硬脂酸鎂 1.48 13.50 Aerosil 200 1.00 5.00 外部相 0.00 硬脂酸鎂 1.00 5.00 Aerosil 200 0.99 9.00 總計 100.0 500.00 硬脂酸鎂 0.99 9.00 總計 100.00 912.20 123701.doc -28- 200817054 實例22 % 亳克/鍵實例23 % 毫克/鍵内部相内部相纈沙坦鈣 32.31 200.30 纈沙坦鈣 20.89 200.30 Hypromellose 2910 (Metolose 60SH-50) 26.00 161.20 Hypromellose 2910 (Metolose 60SH-50) 21.12 202.50 富馬酸 24.19 150.00 富馬酸 41.71 400.00 喷霧乾燥乳糖 13.00 80.60 喷霧乾燥乳糖 12.06 115.70 Aerosil 200 1.00 6.20 Aerosil 200 0.94 9.00 硬脂酸鎂 1.50 9.30 硬脂酸鎂 1.41 13.50 外部相 0.00 外部相 0.00 Aerosil 200 1.00 6.20 Aerosil 200 0.94 9.00 硬脂酸鎂 1.00 6.20 硬脂酸鎂 0.94 9.00 總計 100.00 620.00 總計 100.00 959.00 1.5 包括pH調節劑之壓製包衣錠劑對於製備包含酸之内部核心錠劑而言，錠劑係由與潤滑劑混合之純酸（例如純琥珀酸）藉由人工裝入單沖製錠機 (EKO，Korsch，Germany)之模具中而製成。在另一實施例中，該内部核心錠劑係由與潤滑劑混合之酸與水溶性或水不溶性、較佳為水不溶性填充劑所製成之顆粒壓製而成。根據上述方法（1.2及1.4)製備用於外層之基質顆粒，但亦可僅包含藥物及聚合物而不含任何酸。對於壓製包膜疑劑而言，將該核心錠劑置於外層中心處 (例如，將外層顆粒填入模具中以形成粉末床，在由外層其他顆粒覆蓋前將該核心錠劑放置於其中心處）並施加壓力。由基質顆粒製成之壓製包衣錠劑組合物包括琥珀酸内部核心及包含琥珀酸之外部層： I23701.doc -29- 200817054 實例24 組合物重量(亳克) % % 外部層纈沙坦鈣(160亳克) 200 37.3 25.5 Methocel K100LV 200 37.3 25.5 一水合乳糖 38 7.1 4.8 琥珀酸 85 15.9 10.8 硬脂酸鎂 7.5 1.4 1.0 Aerosil 5 0.9 0.6 535.5 100.0 内部核心琥珀酸 250 31.8 共計 785.5 100.0 1·6腸溶包膜及底衣之製備上述基質微錠劑及基質錠劑可包有腸溶衣。自HPMC (4-8%)、增塑劑（0-3%)及抗黏合劑（0-3%)之水溶液施用分離包膜。可在1:10至1:1(乙基纖維素：HPMC) 範圍内添加Aquacoat ECD或Surelease(水溶性乙基纖維素分散液）以改進底衣之分離效果。基於錠劑大小，所施用底衣之總量介於3-15%(更佳為5-10%)之間。有效底衣可使用核心重量之2-10%範圍内之聚乙烯醇（Opadry II HP)。另外，HPMC底衣可自存在於乙醇/丙酮1·.1(每單位溶劑約孚 1 0%聚合物）中而無任何其他添加劑之有機懸浮液實施包膜。若為有機腸溶包膜溶液，則在腸溶包膜聚合物及增塑劑溶於有機溶劑之後，分散抗黏合劑。就自水性分散液包膜而言，首先使增塑劑溶於或充分分散於水中，然後分散抗黏合劑，且最後添加重構懸浮液（即，Aqoat或Eudragit L 100-5 5)或購得之水性聚合物分散液（£11(!1^§^1^300，八(^71-Aze，Kollicoat MAE 3 0 D) 〇 123701.doc -30- 200817054 使用帶有或不帶Wxn*ste；r成份之盤式塗佈機或流化床塗佈機實施包膜直至在產品溫度介於28°C至50°C之間時包膜層介於2-35%(對於大錠劑更1為約5-10%且對於小錠劑/微錠劑為10-20%)。該包衣層依賴於錠劑大小來確保在人工胃液或0·1 N HCL溶液（根據Ph Eur或USP)中具有1-3小時之腸抵抗性。而且，錠劑核心在胃抵抗性測試過程中之溶脹應減至最小。Example 16 % mg/bond Example 17 % 亳 / ingot internal phase I internal phase I valsartan calcium 40.02 200.10 valsartan calcium 40.02 200.10 Methocel K100LV 30.00 150.00 Methocel K100LV 30.00 150.00 fumaric acid 10.00 50.00 fumaric acid 10.00 50.00 spray Fog-dried lactose 15.28 76.40 Spray-dried lactose 15.28 76.40 Aerosil 200 1.00 5.00 Aerosil 200 1.00 5.00 Magnesium stearate 1.70 8.50 Magnesium stearate 1.70 8.50 External phase II External phase II Aerosil 200 1.00 5.00 Aerosil 200 1,00 5.00 Magnesium stearate 1.00 5.00 Magnesium Stearate 1.00 5.00 Total 100 500.00 Total 100 500.00 Example 18 % mg/bond Example 19 % mg/spin internal phase I internal phase I valsartan calcium 40.02 200.10 valsartan calcium 40.02 200.10 Metolose 60SH-50 30.00 150.00 Methocel K100LV 30.00 150.00 Fumaric acid 10.00 50.00 Succinic acid 10.00 50.00 Spray dried lactose 15.28 76.40 Spray dried lactose 15.28 76.40 Aerosil 200 1.00 5.00 Aerosil 200 1.00 5.00 Magnesium stearate 1.70 8.50 Magnesium stearate 1.70 8.50 External phase II External phase II Aerosil 200 1.00 5.00 Aerosil 200 1.00 5.00 Magnesium stearate 1.00 5.00 Magnesium stearate 1.00 5.00 Total 1.00 500.00 Total 100.00 500.00 Example 20 % mg/record: Example 21 % mg/spin internal phase I Internal phase valsartan calcium 40.02 200.10 Valsartan calcium 21.96 200.30 Metolose 60SH -50 30.00 150.00 Hypromellose 2910 (Metolose 60SH-50) 26.00 237.20 Succinic acid 10.00 50.00 Spray dried lactose 15.28 76.40 Fumaric acid 43.85 400.00 Aerosil 200 1.00 5.00 Spray dried lactose 3.75 34.20 Magnesium stearate 1.70 8.50 Aerosil 200 0.99 9.00 External Phase π Magnesium stearate 1.48 13.50 Aerosil 200 1.00 5.00 External phase 0.00 Magnesium stearate 1.00 5.00 Aerosil 200 0.99 9.00 Total 100.0 500.00 Magnesium stearate 0.99 9.00 Total 100.00 912.20 123701.doc -28- 200817054 Example 22 % gram / Key example 23% mg/bond internal phase internal phase valsartan calcium 32.31 200.30 valsartan calcium 20.89 200.30 Hypromellose 2910 (Metolose 60SH-50) 26.00 161.20 Hypromellose 2910 (Metolose 60SH-50) 21.12 202.50 Fumaric acid 24.19 150.00 Fumar Acid 41.71 400.00 Spray dried lactose 13.00 80.60 Spray dried Lactose 12.06 115.70 Aerosil 200 1.00 6.20 Aerosil 200 0.94 9.00 Magnesium stearate 1.50 9.30 Magnesium stearate 1.41 13.50 External phase 0.00 External phase 0.00 Aerosil 200 1.00 6.20 Aerosil 200 0.94 9.00 Magnesium stearate 1.00 6.20 Magnesium stearate 0.94 9.00 Total 100.00 620.00 Total 100.00 959.00 1.5 Press-coated lozenges comprising pH adjusters For the preparation of internal core lozenges containing acids, the tablets are loaded manually by a pure acid (eg pure succinic acid) mixed with a lubricant It is made in a mold of a single punching machine (EKO, Korsch, Germany). In another embodiment, the inner core tablet is compressed from a mixture of an acid mixed with a lubricant and a water soluble or water insoluble, preferably water insoluble filler. The matrix particles for the outer layer are prepared according to the above methods (1.2 and 1.4), but may also contain only the drug and the polymer without any acid. For pressing the envelope suspect, the core tablet is placed at the center of the outer layer (for example, the outer layer particles are filled into a mold to form a powder bed, and the core tablet is placed in the center before being covered by other particles on the outer layer And apply pressure. The press-coated lozenge composition made of matrix granules comprises an inner core of succinic acid and an outer layer comprising succinic acid: I23701.doc -29- 200817054 Example 24 Weight of composition (grams) % % External layer of valsartan calcium (160 gram) 200 37.3 25.5 Methocel K100LV 200 37.3 25.5 Lactose monohydrate 38 7.1 4.8 Succinic acid 85 15.9 10.8 Magnesium stearate 7.5 1.4 1.0 Aerosil 5 0.9 0.6 535.5 100.0 Internal core succinic acid 250 31.8 Total 785.5 100.0 1·6 Preparation of the Solution Film and Subcoat The above-mentioned matrix micro-tablets and matrix troches may be coated with an enteric coating. The separation envelope was applied from an aqueous solution of HPMC (4-8%), plasticizer (0-3%) and anti-adhesive (0-3%). Aquacoat ECD or Surelease (water-soluble ethylcellulose dispersion) can be added in the range of 1:10 to 1:1 (ethylcellulose: HPMC) to improve the separation effect of the primer. The total amount of the applied subcoat is between 3-15% (more preferably 5-10%) based on the tablet size. An effective subcoat can use polyvinyl alcohol (Opadry II HP) in the range of 2-10% of the core weight. Alternatively, the HPMC subcoat can be coated with an organic suspension of ethanol/acetone 1·.1 (about 10% polymer per unit solvent) without any additional additives. In the case of an organic enteric coating solution, the anti-adhesive agent is dispersed after the enteric coating polymer and the plasticizer are dissolved in the organic solvent. In the case of an aqueous dispersion coating, the plasticizer is first dissolved or sufficiently dispersed in water, then the anti-adhesive is dispersed, and finally a reconstituted suspension (ie, Aqoat or Eudragit L 100-5 5) or purchased is added. Aqueous polymer dispersion (£11(!1^§^1^300, eight (^71-Aze, Kollicoat MAE 3 0 D) 〇123701.doc -30- 200817054 with or without Wxn*ste The disc coating machine or fluidized bed coater of the r component is coated until the coating layer is between 2-35% at a product temperature between 28 ° C and 50 ° C (for larger lozenges) 1 is about 5-10% and for small tablets/microdoses 10-20%). The coating layer depends on the size of the tablet to ensure in artificial gastric juice or 0·1 N HCL solution (according to Ph Eur or USP) It has 1-3 hours of intestinal resistance. Moreover, the swelling of the tablet core during the gastric resistance test should be minimized.

實例包衣A 份數 % 毫克/250毫克核心毫克/8毫克核心底衣 HPMC 3 cps 5 25 12.5 0.8 檸檬酸三乙酯 0.5 2.5 1.25 0.08 滑石粉 0.5 2.5 1.25 0.08 水適量腸溶包衣 EudragitL30D(乾） 10 50 25 1.6 PEG 6000 2 10 5 0.32 Syloid 244 FP 2 10 5 0.32 水適量總計(乾） 20 100 50 3.2 實例包衣B 份數 % 亳克/250亳克核心毫克/8亳克核心底衣 HPMC 3 cps 6 26.67 15.0 0.96 Aquacoat ECD(乾) 2 8.89 5.0 0.32 ~ 檸檬酸三乙酯 0.6 2.67 1.5 0.096 單硬脂酸甘油酯 0.4 1.77 1.0 0.064 水適量腸溶包衣 HPMC AS (Aqoat)MF 10 44.44 25.0 1.60 檸檬酸三乙酯 2.5 11.11 6.25 0.40 滑石粉 1 4.44 2.5 0.16 水適量總計(乾） 22.5 100.0 56.25 3.60 123701.doc -31 - 200817054Example Coating A Part% mg/250 mg Core mg/8 mg Core Primer HPMC 3 cps 5 25 12.5 0.8 Triethyl citrate 0.5 2.5 1.25 0.08 Talc 0.5 2.5 1.25 0.08 Water Appropriate Enteric Coated Eudragit L30D (Dry 10 50 25 1.6 PEG 6000 2 10 5 0.32 Syloid 244 FP 2 10 5 0.32 Total amount of water (dry) 20 100 50 3.2 Example coating B parts % gram / 250 gram core mg / 8 gram core coat HPMC 3 cps 6 26.67 15.0 0.96 Aquacoat ECD (dry) 2 8.89 5.0 0.32 ~ Triethyl citrate 0.6 2.67 1.5 0.096 glyceryl monostearate 0.4 1.77 1.0 0.064 Water-soluble enteric coated HPMC AS (Aqoat) MF 10 44.44 25.0 1.60 Triethyl citrate 2.5 11.11 6.25 0.40 Talc powder 4.44 2.5 0.16 Total amount of water (dry) 22.5 100.0 56.25 3.60 123701.doc -31 - 200817054

實例包衣c 份數 % 亳克/250亳克核心亳克/8亳克核心底衣 HPMC 3 cps 5 32.5 12.5 0.8 乙醇/丙酮U :適量腸溶包衣 HP 50 8 5L9 20.0 1.28 乙酸甘油 0.8 5.2 2.0 0.13 Aerosil 200 1.6 10.4 4.0 0.26 乙醇/丙酮U :適量總計(乾） 15.4 100.0 38.5 2.47 實例包衣D 份數 % 毫克/250亳克核心亳克/8毫克核心底衣 Opadry II HP 4 21.46 10 0.64 水適量腸溶包衣 EudragitLl 00-55 10 53.65 25 1.6 氫氧化鈉 0.14 0.75 0.35 . 0.022 擰檬酸三乙酯 2.5 13.41 6.25 0.4 Syloid 244 FP 2 10.73 5.0 0.32 水適量總計乾燥 18.64 100.0 46.6 2.982 實例包衣E 份數 % 亳克/250毫克核心毫克/8毫克核心底衣 HP 50 10 71.43 25 1.6 癸二酸二乙酯 1 7.14 2.5 0,16 滑石粉 3 21.43 7,5 0.48 乙醇/丙酮1.1 :適量總計乾燥 14 100.0 34 2.24 實例包衣F 份數 % 毫克/250亳克核心亳克/8毫克核心底衣 Eudragit L 100-55 10 76.92 25 1.6 擰檬酸三乙酯 1 7.69 2.5 0.16 Syloid 244 FP 2 15.38 5.0 0.32 異丙醇/水97.3 :適量總計乾燥 13 100.0 32.5 2.08 I23701.doc -32- 200817054 2. 擴散包膜改良釋放系統 2.1多顆粒系統之製備 2-1.1 微錠劑之製備將/舌性組份、pH调節劑、及任一其他製旋賦形劑混合並使用水或有機溶劑實施濕法製粒。將乾顆粒過（例如）4〇〇微米篩網並壓製成微錠劑。出於壓製之目的，添加由除 Aerosil及硬脂酸鎂外之物質組成之外部相並充分混合。將該摻合物壓製成直徑為（例如）125至4毫米、尤其為17至2 毫米之微錠劑。最後用使用下文所述聚合物之包膜調配物 (亦即’擴散包膜、帶有附加腸溶包膜之擴散包膜、包含腸溶聚合物之擴散包膜）之一種對所得微錠劑實施包膜。一種例示性微錠劑調配物具有以下組成：實例25 % 亳克/250亳克錠劑無水乳糖 24.14 60.35 富馬酸 20.00 50.00 Diovan酸或辦鹽 20.00 50.00 Avicel PH 102 33.33 83.33 Aerosil 200 1.53 3.83 硬脂醍鎂 1.00 2.50 100.00 250.00 2#1·2 微丸劑之製備在一實施例中，藉由在一行星式混合器中混合藥物、微晶纖維素（即Avicel PH101)及乳糖來製備乾燥摻合物。添加純水以得到濕物質，隨後使用適宜大小篩網擠壓該濕物質°將該等擠出物在球形機中滾成圓球，充分乾燥並過篩網來選擇適宜大小。最後，將用以下包膜調配物之水溶液或水性分散液對所得微丸劑實施包膜（亦即擴散包膜、帶 123701.doc •33- 200817054 有附加腸溶包膜之擴散包膜、包含腸溶聚合物之擴散包膜）〇例示性微丸劑具有如下組成（數量以％給出）：實例26 [%] 實例27 [%] Diovan酸或#5鹽 20% Diovan酸或#弓鹽 30% (作為活性成份計算） (作為活性成份計算）富馬酸 20% 富馬酸 20% 乳糖(標準質量） 10% 乳糖(標準質量） 8% 微晶纖維素(Avicel PH101) 50% 微晶纖維素(Avicel PH101) 42% 用於濕塊化之水適量$ 用於濕塊化之水適量* 實例28 [%] Diovan酸或#5鹽 10% (作為活性成份計算）富馬酸 20% 乳糖(標準質量） 15% 微晶纖維素(Avicel PH101) 55% 用於濕塊化之水適量*Example coating c parts % gram / 250 gram core gram / 8 gram core primer HPMC 3 cps 5 32.5 12.5 0.8 ethanol / acetone U: appropriate amount of enteric coating HP 50 8 5L9 20.0 1.28 glycerin 0.8 5.2 2.0 0.13 Aerosil 200 1.6 10.4 4.0 0.26 Ethanol/Acetone U: Appropriate amount (dry) 15.4 100.0 38.5 2.47 Example Coating D Parts % mg / 250 gram core gram / 8 mg core smock Opadry II HP 4 21.46 10 0.64 Water amount of enteric coating Eudragit Ll 00-55 10 53.65 25 1.6 Sodium hydroxide 0.14 0.75 0.35 . 0.022 Triethyl citrate 2.5 13.41 6.25 0.4 Syloid 244 FP 2 10.73 5.0 0.32 Water amount total dry 18.64 100.0 46.6 2.982 Example coating E parts % gram / 250 mg core mg / 8 mg core coat HP 50 10 71.43 25 1.6 Diethyl sebacate 1 7.14 2.5 0,16 Talc 3 21.43 7,5 0.48 Ethanol / Acetone 1.1 : Appropriate amount Drying 14 100.0 34 2.24 Example Coating F Parts % mg / 250 gram core gram / 8 mg core smear Eudragit L 100-55 10 76.92 25 1.6 Triethyl citrate 1 7.69 2.5 0.16 Syloid 244 FP 2 15.38 5.0 0.32 Isopropanol / water 97.3 : Appropriate total dry 13 100.0 32.5 2.08 I23701.doc -32- 200817054 2. Diffusion envelope modified release system 2.1 Preparation of multiparticulate system 2-1.1 Microingot Preparation of the Agent The lingual component, the pH adjuster, and any other spinning excipients are mixed and wet granulation is carried out using water or an organic solvent. The dry granules are passed through, for example, a 4 〇〇 micro sieve and pressed into a micro-tablet. For the purpose of pressing, an external phase consisting of substances other than Aerosil and magnesium stearate is added and thoroughly mixed. The blend is compressed into a micro-tablet having a diameter of, for example, 125 to 4 mm, especially 17 to 2 mm. Finally, the resulting micro-tablet is prepared by using a coating formulation of the polymer described below (ie, a diffusion coating, a diffusion envelope with an additional enteric coating, a diffusion coating comprising an enteric polymer). The envelope is applied. An exemplary micropellet formulation has the following composition: Example 25% gram/250 gram lozenge anhydrous lactose 24.14 60.35 Fumaric acid 20.00 50.00 Diovan acid or salt 20.00 50.00 Avicel PH 102 33.33 83.33 Aerosil 200 1.53 3.83 Stearic acid醍Magnesium 1.00 2.50 100.00 250.00 2#1·2 Preparation of pellets In one embodiment, a dry blend is prepared by mixing a drug, microcrystalline cellulose (ie Avicel PH101) and lactose in a planetary mixer. . Pure water is added to obtain a wet mass, which is then extruded using a suitably sized screen. The extrudates are rolled into a sphere in a spherical machine, thoroughly dried and sieved to a suitable size. Finally, the obtained pellets may be coated with an aqueous solution or an aqueous dispersion of the following coating formulations (ie, a diffusion envelope, a diffusion coating with an additional enteric coating, 123101.doc • 33-200817054) Diffusion Coating of Soluble Polymers) Illustrative pellets have the following composition (quantity given in %): Example 26 [%] Example 27 [%] Diovan acid or #5 salt 20% Diovan acid or # bow salt 30% (calculated as active ingredient) (calculated as active ingredient) Fumaric acid 20% Fumaric acid 20% Lactose (standard mass) 10% Lactose (standard mass) 8% Microcrystalline cellulose (Avicel PH101) 50% Microcrystalline cellulose (Avicel PH101) 42% Water for wet blockage $ Appropriate amount of water for wet blockage* Example 28 [%] Diovan acid or #5 salt 10% (calculated as active ingredient) Fumaric acid 20% Lactose ( Standard quality) 15% microcrystalline cellulose (Avicel PH101) 55% water for wet blockage*

$在操作期間去除 2.2 擴散包膜組合物 2.2.1 擴散包膜組份及範圍例示性包膜組份及範圍如下：$ removed during operation 2.2 Diffusion envelope composition 2.2.1 Diffusion envelope composition and range The exemplary envelope components and ranges are as follows:

• 1-20%用於擴散包膜之聚合物，例如乙基纖維素 (Aquacoat ECD” FMC Biopolymer, Surrelease，Colorcon)、丙浠酸酉旨/甲基丙烯酸酯/Eudragit RL、Eudragit RS (Rohm)； • 0-20%作為孔形成劑之水溶性聚合物，例如經丙基甲基纖維素3，6 cps (Pharmacoat 603，606，Shin-Etsu)、聚乙二醇（PEG 2000-PEG 8000); • 0-15%用於底衣之聚合物，例如羥丙基曱基纖維素 I23701.doc -34- 200817054 (Pharmacoat 603 或 606)、乙基纖維素（例如，Aquacoat ECD、FMC Biopolymer，Surelease，Colorcon)及/或其具有乙基纖維素·· ΗΡΜΟ 1··ι至ι··ι〇比率之混合物、聚乙烯醇（Opadry II HP，85F型，Colorcon); • 0-20%作為孔形成劑之腸溶包膜聚合物（例如，參見上表）， ·0_ 10%增塑劑（乙酸甘油、檸檬酸三乙酯、PEG 4000、 PEG 6000、PEG 8000、鄰苯二甲酸二乙酯、癸二酸二乙酯、癸二酸二丁酯、乙醯基擰檬酸三乙酯等）； • 0-15%抗黏合劑（Aerosil 200、Syloid 244 FP、滑石粉、甘油單硬脂酸酯等）；及 •含有及不含有部分水之有機溶劑或其混合物（乙醇、丙酮、異丙醇）或水（適量）以溶解或分散用於包膜溶液之包膜聚合物及賦形劑。對於有機溶液之情形，將增塑劑及聚合物溶於有機溶劑混合物中且最後分散抗黏合劑。對於水性分散液而言，將增塑劑溶於水中並藉助均質器充分分散抗黏合劑。最後將所預備之聚合物分散液（如可購得）或預分散於水中之分散液添加至增塑劑/抗黏合劑/水混合物中並於喷灑之前攪拌一段時間。 2.2.2 基於丙烯酸酯/甲基丙烯酸酯聚合物之擴散包膜用於擴散包膜之聚合物係來自水性懸浮液或有機溶液之比例為1:1至9:1之EudragitRS/RL混合物。適宜之增塑劑係在包膜分散液（5-20%)之1-3 0%範圍内之檸檬酸三乙醋、癸 123701.doc -35- 200817054 二酸二丁酯、乙酸甘油。Eudragit RS可與有機溶液或水性分散液中作為孔形成劑之腸溶包膜聚合物如琥珀酸乙酸羥丙基曱基纖維素、M(MF)或H (HF)型Aqoat組合或與有機溶液中之鄰苯二甲酸羥丙基甲基纖維素（亦即HP 50、HP 5 5)組合。腸溶孔形成劑抑制胃内酸性環境中之藥物釋放。腸溶孔形成劑在ρΗ>5 ·5之腸液中溶解後，由於固體劑型形式内部微環境pH較低，故而藥物將溶解成均一形式。藉此，可預期較小的個體間及個體内變化。• 1-20% polymer for diffusion coating, such as ethylcellulose (Aquacoat ECD” FMC Biopolymer, Surrelease, Colorcon), propionate/methacrylate/Eudragit RL, Eudragit RS (Rohm) • 0-20% water-soluble polymer as a pore former, such as propylmethylcellulose 3,6 cps (Pharmacoat 603,606, Shin-Etsu), polyethylene glycol (PEG 2000-PEG 8000) • 0-15% polymer for the base coat, such as hydroxypropyl decyl cellulose I23701.doc -34- 200817054 (Pharmacoat 603 or 606), ethyl cellulose (eg, Aquacoat ECD, FMC Biopolymer, Surelease) , Colorcon) and / or it has a mixture of ethyl cellulose · · ΗΡΜΟ 1 · · ι to ι · · ι〇 ratio, polyvinyl alcohol (Opadry II HP, 85F, Colorcon); • 0-20% as a hole Forming enteric coated polymer (for example, see above), 0-10% plasticizer (glyceric acetate, triethyl citrate, PEG 4000, PEG 6000, PEG 8000, diethyl phthalate , diethyl sebacate, dibutyl sebacate, triethyl ethyl citrate, etc.; • 0-15% anti-adhesive Aerosil 200, Syloid 244 FP, talc, glyceryl monostearate, etc.; and • organic solvents with or without some water or mixtures thereof (ethanol, acetone, isopropanol) or water (appropriate) to dissolve or Dispersing the coated polymer and excipients for the coating solution. In the case of an organic solution, the plasticizer and the polymer are dissolved in the organic solvent mixture and finally the anti-adhesive is dispersed. For the aqueous dispersion, The plasticizer is dissolved in water and the anti-adhesive agent is sufficiently dispersed by means of a homogenizer. Finally, the prepared polymer dispersion (as commercially available) or a dispersion pre-dispersed in water is added to the plasticizer/anti-adhesive/water. Mix the mixture for a while before spraying. 2.2.2 Diffusion envelope based on acrylate/methacrylate polymer The polymer used in the diffusion coating is from a ratio of 1:1 aqueous suspension or organic solution. Eudragit RS/RL mixture up to 9:1. Suitable plasticizers are triethyl citrate in the range of 1-3 0% of the coating dispersion (5-20%), 癸123701.doc -35- 200817054 Dibutyl diacid, glycerol acetate. Eu Dragit RS can be combined with an enteric coating polymer such as hydroxypropyl decyl cellulose succinate, M (MF) or H (HF) type Aqoat as an aperture forming agent in an organic solution or aqueous dispersion or with an organic solution A combination of hydroxypropyl methylcellulose phthalate (ie, HP 50, HP 5 5). Enteric pore formers inhibit drug release in the acidic environment of the stomach. After the enteric pore former is dissolved in the intestinal juice of ρΗ>5·5, since the pH of the internal microenvironment in the solid dosage form is low, the drug will dissolve into a uniform form. Thereby, smaller inter-individual and intra-individual changes can be expected.

施用介於核心重量之5-40%、通常介於7-15%、亦即10% 之包膜層。Eudragit RS與腸溶孔形成劑之比例可在95:5至 50:50之間變化以適應釋放特徵曲線。實例包衣G 份數 %m %(濕）亳克/8毫克核心 Eudragit RL 30 D 1.52 6.9 4.62 0.06 Eudragit RS 30D 13.76 62 41.70 0.50 檸檬酸三乙酯 2.8 12.5 2.80 0.10 Syloid 244 FP 4.18 18.6 4.18 0.15 水適量 46.70 總計 22.26 100 100.00 0.80 可選比例：Eudragit RS:] 包膜層：核心重量之5-2 EIL9:1 0% (即 10%) 實例包衣Η 份數 %(乾） %(濕）亳克/8亳克核心 Eudragit RL 12.5 1.28 17.75 30.93 0.14 Eudragit RS 12.5 3.86 53.54 10.30 0.43 擰檬酸三乙酯 0.52 7.21 0.52 0.06 Syloid 244 FP 1.55 21.50 L55 0.17 丙嗣適量適量 28.35 異丙醇適量適量 28.35 總計 7.21 100.00 100.00 0.80 可選比例：Eudragit RS:: 包膜層：核心重量之5·2 RL 7.5:2.5 0% (即 10%) 123701.doc -36- 200817054 實例包衣I 份數 %(乾） %(濕）毫克/8毫克核心 HPMCAS(MF 型） 4.29 20 4.29 0.16 Eudragit RS 30 D 13.49 57.5 40.89 0.46 檸檬酸三乙酯 2.68 12.5 2.68 0.10 Syloid244FP 2.14 10 2.14 0.08 水適量適量 50.00 總計 22.60 100 100.00 0.80 可選比例：Eudragit RS:] 包膜層：核心重量之5-2 HPMCAS ： 7.5:2.5 0〇/〇(即 10%) 2.2.3 基於乙基纖維素聚合物（視情況與孔形成劑一起）之擴散包膜該擴散包膜可包含乙基纖維素。基於乙基纖維素之擴散包膜的釋放速率可藉由改變包膜層厚度（包膜量）、親水包膜化合物（例如增塑劑，例如檸檬酸三乙酯、PEG 4000或 PEG 4000)及/或顏料/抗黏合劑（例如膠狀二氧化矽或244 FP)之數量及任何孔形成聚合物之數量中之一或更多而控制。羥丙基甲基纖維素係適宜孔形成劑之實例，且可與自有機包膜溶液施用之乙基纖維素結合或與Aquacoat ECD分散液（乙基纖維素之30%水性分散液)組合。乙基纖維素與孔形成劑之比率可在95:5與30:70之間變化。腸溶聚合物如鄰苯二甲酸羥丙基甲基纖維素（HP 50)或琥珀酸乙酸羥丙基曱基纖維素（Aqoat)亦係適宜之孔形成劑，其可抑制胃内之藥物釋放並控制其在pH > 5_5之腸液中釋放。HP 50可與自有機溶液塗覆之乙基纖維素在5-50%範圍内組合。端視核心微丸劑或微錠劑之大小及體積，可在核心重之5-30%範圍内施加包膜層。 123701.doc -37 - 200817054A coating layer of between 5 and 40%, typically between 7-15%, or 10%, of the core weight is applied. The ratio of Eudragit RS to enteric pore former can vary from 95:5 to 50:50 to accommodate the release profile. Example coating G parts % m % (wet) gram / 8 mg core Eudragit RL 30 D 1.52 6.9 4.62 0.06 Eudragit RS 30D 13.76 62 41.70 0.50 Triethyl citrate 2.8 12.5 2.80 0.10 Syloid 244 FP 4.18 18.6 4.18 0.15 water Appropriate amount 46.70 Total 22.26 100 100.00 0.80 Optional ratio: Eudragit RS:] Envelope layer: Core weight 5-2 EIL9: 1 0% (ie 10%) Example coating Η Parts % (dry) % (wet) 亳克/8 核心 core Eudragit RL 12.5 1.28 17.75 30.93 0.14 Eudragit RS 12.5 3.86 53.54 10.30 0.43 Triethyl citrate 0.52 7.21 0.52 0.06 Syloid 244 FP 1.55 21.50 L55 0.17 Proper amount of appropriate amount 28.35 Isopropyl alcohol amount 28.35 Total 7.21 100.00 100.00 0.80 Optional ratio: Eudragit RS:: Envelope layer: core weight of 5·2 RL 7.5:2.5 0% (ie 10%) 123701.doc -36- 200817054 Example coating I parts % (dry) % (wet) mg/8 mg core HPMCAS (MF type) 4.29 20 4.29 0.16 Eudragit RS 30 D 13.49 57.5 40.89 0.46 Triethyl citrate 2.68 12.5 2.68 0.10 Syloid244FP 2.14 10 2.14 0.08 Water amount 50.00 Total 22.60 100 100.00 0.80 Optional ratio: Eudragit RS:] Coating layer: core weight 5-2 HPMCAS: 7.5:2.5 0〇/〇 (ie 10%) 2.2.3 Based on ethyl cellulose polymer (as appropriate) Diffusion envelope of the forming agent together) The diffusion envelope may comprise ethyl cellulose. The release rate of the ethylcellulose-based diffusion envelope can be changed by changing the thickness of the coating layer (envelope amount), a hydrophilic coating compound (such as a plasticizer such as triethyl citrate, PEG 4000 or PEG 4000) and Controlled by one or more of the amount of pigment/anti-adhesive (eg, colloidal cerium oxide or 244 FP) and the amount of any pore-forming polymer. Hydroxypropyl methylcellulose is an example of a suitable pore former and can be combined with ethylcellulose applied from a proprietary coating solution or with an Aquacoat ECD dispersion (30% aqueous dispersion of ethylcellulose). The ratio of ethylcellulose to pore former can vary between 95:5 and 30:70. Enteric polymers such as hydroxypropyl methylcellulose phthalate (HP 50) or hydroxypropyl thioglycolate acylate (Aqoat) are also suitable pore formers for inhibiting drug release in the stomach. And control its release in the intestinal juice of pH > 5_5. The HP 50 can be combined with the self-organized solution coated ethylcellulose in the range of 5-50%. Depending on the size and volume of the core pellets or microtablets, the coating layer can be applied within 5-30% of the core weight. 123701.doc -37 - 200817054

乙基纖維素·· HPMOS.5:1.5 包膜層：核心重量之5-20% (即10%)Ethylcellulose··HPMOS.5:1.5 Coating layer: 5-20% of core weight (ie 10%)

12370l.doc -38» 200817054 2·3將擴散包膜施用於多顆粒系統使用裝備Wurster成份之流化床設備或Hiittlin型設備 (turbojet)在28°C至45°C之產物溫度範圍内對微錠劑或微丸劑施用擴散包膜。建議在實施包膜後在4〇l (Eudragit)至 60°C(Aquacoat)下於盤式乾燥器或流化床設備中將自水性分散液所施用之包膜固化（回火小時。最終劑型形式可係填充有多顆粒調配物之直條包裝或硬膠囊或可釋放經包膜多顆粒微丸劑之崩解鍵劑。 3· 活艘外溶解研究使用USP I籃式或槳式裝置（s〇tax AT 7 Smart)測定實例 10至20之基質錠劑溶解特徵曲線。使用1〇〇〇毫升磷酸緩衝液（pH 6·8、SDS 0.2%)於 37°C 及旋轉速度為 50 rpm4100 rpm下按一式三份實施溶解性測試。以預定間隔自溶解媒介中取樣，通過膜過濾器過濾並用分光光度法進行分析。添加等效量新鮮緩衝液以保持恆定溶解體積。在實例16 之情形下，在溶解測試中使用轉速為5〇叩瓜之攪拌槳。在所有其他情形下，使用100 rpm之轉籃速率。任一組合物之藥物或酸（若存在）之溶解數據展示於下表中實例10、11、13及18之基質錠劑組合物之溶解特徵曲線分別展示於圖丨、2、3及4中。各圖之八部分展示藥物溶解特徵曲線，而B部分展示酸溶解特徵曲線。在各情形下，可看出藥物與酸以實質相似之速率釋放。 123701.doc -39- 20081705412370l.doc -38» 200817054 2. 3 Applying a diffusion envelope to a multi-particle system using a fluidized bed device or a Hiittlin-type device (turbojet) equipped with a Wurster component in the product temperature range of 28 ° C to 45 ° C The diffusion coating is applied to the lozenge or pellet. It is recommended to cure the coating applied from the aqueous dispersion in a tray dryer or fluidized bed apparatus at 4〇l (Eudragit) to 60°C (Aquacoat) after the application of the coating (hours of tempering. Final dosage form) The form may be a straight-pack or hard-capsule filled with a multi-particulate formulation or a disintegrating agent capable of releasing the coated multiparticulate pellets. 3. The live outer dissolution study uses a USP I basket or paddle device (s 〇tax AT 7 Smart) The dissolution profile of the matrix tablet of Examples 10 to 20 was measured using 1 〇〇〇 ml of phosphate buffer (pH 6.8, SDS 0.2%) at 37 ° C and a rotation speed of 50 rpm 4100 rpm. The solubility test was performed in triplicate. Samples were taken from the dissolution medium at predetermined intervals, filtered through a membrane filter and analyzed spectrophotometrically. An equivalent amount of fresh buffer was added to maintain a constant dissolution volume. In the case of Example 16, A paddle with a speed of 5 ounces was used in the dissolution test. In all other cases, a basket rate of 100 rpm was used. The dissolution data for the drug or acid (if present) of either composition is shown in the table below. 10, 11, 13 and 18 The dissolution profile of the matrix lozenge composition is shown in Figures 2、, 2, 3 and 4. The eight parts of each figure show the drug dissolution profile, while the B section shows the acid dissolution profile. In each case, it can be seen The drug is released at a substantially similar rate to the acid. 123701.doc -39- 200817054

、根據ICH指導原則，當保存於25。。、3〇。。及4〇。。(在封、塑料瓶中）時，實例21 、22及23之調配物在至少6個月内保持穩定【圖式簡單說明】圖1展示（A)纈沙坦與（B)富馬酸當存在於實例10之組合物中時之溶解特徵曲線。圖2展示（A)缬沙坦與富馬酸當存在於實例11之組合物中時之溶解特徵曲線。圖3展示（A)纈沙坦與（B)富馬酸當存在於實例13之組合 I23701.doc -40- 200817054 物中時之溶解特徵曲線。圖4展示（A)纈沙坦與（B)富馬酸當存在於實例18之組合物中時之溶解特徵曲線。According to the ICH guidelines, when stored at 25. . 3〇. . And 4〇. . The formulations of Examples 21, 22 and 23 remained stable for at least 6 months (in the case of seals, plastic bottles) [Simplified illustration] Figure 1 shows (A) valsartan and (B) fumaric acid The dissolution profile of the composition when present in the composition of Example 10. Figure 2 shows the dissolution profile of (A) valsartan and fumaric acid when present in the composition of Example 11. Figure 3 shows the dissolution profile of (A) valsartan and (B) fumaric acid when present in the combination of Example 13, I23701.doc -40-200817054. Figure 4 shows the dissolution profile of (A) valsartan and (B) fumaric acid when present in the composition of Example 18.

123701.doc -41 -123701.doc -41 -

Claims

200817054 X. Patent Application Range: L An acidic pharmaceutical composition comprising the following solid pharmaceutical composition (1) at least one is an angiotensin II receptor antagonist compound or a releasable form thereof; at least one pH adjusting agent: and 111) At least one pharmaceutically acceptable excipient. 2. The pharmaceutical composition of claim 1, which includes the following -

A substance such as a water insoluble polymer. A pharmaceutical composition according to claim 2, wherein the basic cockroach intrusion into the t-binder comprises at least one of the acid physicochemical δ substance and the pH adjuster. The pharmaceutical composition according to claim 3, wherein the base composition comprises the acid lanthanum compound and the pH adjuster. The pharmaceutical composition of claim 3 or claim 4, wherein the pharmaceutical composition of any one of claims 3 to 5, wherein the matrix is polymerized The substance includes methyl propyl cellulose (HPMC). 7. The pharmaceutical composition according to any of the above claims, comprising a core comprising the acidic pharmaceutical compound 5 and the pH adjusting agent, and a coating on the core. The pharmaceutical composition according to claim 7 Wherein the envelope comprises a diffusion envelope. 9. The pharmaceutical composition of claim 8, wherein the diffusion envelope comprises a water insoluble material. The pharmaceutical composition according to claim 9, wherein the diffusion envelope is one or more selected from the group consisting of ethyl cellulose, primary acrylic acid, and thioglycolic acid. 123701.doe 200817054 11. The celite composition of any one of claims 8 to 10, wherein the diffusion envelope is porous. 12. If any of the items 8 to 11 is recorded, the 酉 beam, and the object, wherein the diffusion envelope comprises a pore former. 13. The pharmaceutical composition of claim 12, wherein the diffusion envelope comprises a water soluble polymer. 14. The pharmaceutical composition of claim 13, wherein the diffusion envelope comprises one or both of propylmethylcellulose and polyethylene glycol. - 1 5 - A medical practitioner according to any of the preceding claims, 柰, and s, which is adapted to provide a microenvironment p of 5 or less in at least one region of the gastrointestinal tract. 16. The pharmaceutical composition of claim 15 which is adapted to provide a microenvironmental pH of 4 or less in at least one region of the gastrointestinal tract. 17. The pharmaceutical composition of claim 15 or claim 16, which is adapted to provide a localized acidic environment in one or more of the twelve intestines, the ileum and the colon. A pharmaceutical composition according to claim 17, which is suitable for providing the microenvironment ρΙί in (iv), returning and colonization. - wherein the acidic pharmaceutical compound 19 is a weakly acidic pharmaceutical composition as claimed in any of the above claims. Wherein the acidic pharmaceutical compound 20. The pharmaceutical composition according to any of the preceding claims is at 25. (wherein the pKa is 2.5 or more. wherein the acidic pharmaceutical compound 21) The pharmaceutical composition according to any of the preceding claims has a pKa of 3 or more at 25 ° C, for example 4 or more 22 The pharmaceutical composition of any of the preceding claims, wherein the acidic pharmaceutical compound 123701.doc 200817054 comprises one or more acidic groups. The pharmaceutical composition according to claim 22, wherein the acidic pharmaceutical compound comprises one or more The pharmaceutical composition of claim 22 or claim 23, wherein the acidic pharmaceutical compound comprises one or more tetra-CT sitting groups. 25. The pharmaceutical composition according to any of the preceding claims, wherein The acidic pharmaceutical compound is a pharmaceutical composition of any of the preceding claims, which further comprises one or more other antihypertensive agents. 27. The pharmaceutical composition of claim 26, It comprises one or more agents selected from the group consisting of a diuretic, a calcium-blocking agent, a beta-blocker, and an ace inhibitor. 28. The pharmaceutical composition of claim 27, which comprises hydrogen thiazide. Any of the claimed pharmaceutical compositions The pharmaceutical composition of any one of the preceding claims, wherein the ?11 modulator is an organic acid. 3 1 · The pharmaceutical composition according to claim 30, wherein The pH adjusting agent is selected from the group consisting of citric acid, fumaric acid, succinic acid, adipic acid, and maleic acid. The pharmaceutical composition of any of the preceding claims, wherein the pH adjusting agent is fumaric acid. The pharmaceutical composition of claim 32, wherein the weight/weight ratio of the statin to the acidic drug compound is between 〇.〇1:1 and 1〇:1, more preferably between 0.025:1 and 2: Between 1 and 34. i 34·If the doctor's group of claim 33 is private, the weight/weight ratio of the pH adjuster to the acidic drug 123701.doc 200817054 is about 〇·25 The pharmaceutical composition according to any of the preceding claims, wherein the acidic pharmaceutical compound is lanthanin and the pH adjuster has a maximum acidic pKa value of less than 3.5. 36. The pharmaceutical composition of claim 35, Wherein the pH adjuster has an ipKa of about 3° 37. The pharmaceutical composition of claim 36, wherein the pH adjuster comprises a rich A pharmaceutical composition according to any of the preceding claims, which is in the form of a troche, a microtablet, a granule or a granule. 39. An acidic angiotensin „receptor antagonist or a releasable form thereof The use of a modulator for the preparation of a medicament for the treatment, prevention of hypertension, congestive heart failure or myocardial infarction or delaying the progression of such diseases, wherein the angiotensin II receptor antagonist 40 is as claimed 39 uses, weakly acidic.

41. The use of claim 39 or claim 4, wherein the angiotensin η receptor antagonist is salbutan. Wherein the pH adjusting agent is as used in any one of claims 29 to 41, as defined in any one of claims 29 to 37. 43. - Oral administration of ash tube tension A method of administering an acidic pharmaceutical compound of a π-receptor antagonist or a releasable form thereof. The method comprises administering a pharmaceutical composition according to any one of the claims to 38. 44. The method of claim 44, wherein the acidic drug compound is valsartan, wherein the composition is administered for treatment, pre-123701.doc 200817054 antihypertensive, congestive heart failure or myocardial infarction or Delaying the progression of these diseases. 46. An oral valsartan composition suitable for producing a local acidic environment in the intestinal tract. 47. The composition of claim 46, which is suitable for use in the jejunum, ileum and colon A local acidic environment is produced in one or more places. 48. A pharmaceutically acceptable acid for use in the preparation of an oral drug comprising an acidic drug compound which is a gray tube tension hormone receptor antagonist: Its releasable form, in which The pharmaceutically acceptable acid promotes protonation of the acidic drug compound in the intestinal tract. 4 9. - Can be enhanced to angiotensin! An acidic drug compound of a tau receptor antagonist. A method of channel absorption comprising administering the acidic drug compound or a releasable form together with a pH adjusting agent.

123701.doc