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TW201136582A - Improved pharmaceutical compositions of aliskiren and methods of delivery - Google Patents

Improved pharmaceutical compositions of aliskiren and methods of delivery Download PDF

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Publication number
TW201136582A
TW201136582A TW100108966A TW100108966A TW201136582A TW 201136582 A TW201136582 A TW 201136582A TW 100108966 A TW100108966 A TW 100108966A TW 100108966 A TW100108966 A TW 100108966A TW 201136582 A TW201136582 A TW 201136582A
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weight
pharmaceutical composition
sodium
fatty acid
combination
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TW100108966A
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Chinese (zh)
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Paul Salama
Irina Karmeli
Shmuel Tuvia
Karen Marom
Oshrat Harush-Frenkel
Sam Rebello
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The pharmaceutical compositions described herein include a suspension which comprises an admixture in solid form of a therapeutically effective amount of aliskiren, at least one salt of a medium chain fatty acid, a matrix forming polymer and a hydrophobic medium. Surfactants may be incorporated into the pharmaceutical compositions which may be encapsulated in a capsule for oral delivery. Methods of treating or preventing diseases by administering such compositions to affected subjects are also disclosed.

Description

201136582 六、發明說明： 【發明所屬之技術領域】 “本發明概言之係關於能夠改良阿利克备之經口傳遞之醫 藥組合物及使用該等組合物之方法。 【先前技術】 腎素抑制劑阿利克备（尤其係其半富馬酸鹽）已知可有效 地用於降低血麗之治療中(不論年齡、性別或種族如何)， 且亦耐受良好。然而，阿利克奋在習用調配物中之吸收性 較差（生物利用度為約2.5%)，且具有約⑷、時之累積半衰 期。此外，阿利克备係因其物理化學性質而難以調配之藥 物物質，且以可靠及穩定之方式來製備口服調配物甚為重 要。因生物利用度低，故需要高藥物載量，且此在技術上 難以達成且會導致成本增加。因&，業内需要可改良阿利 克备之經口傳遞之有效、特異性、σ服調配物。 【發明内容】 本文閣述新穎阿利克奋組合物、製備該等組合物之方 法、及使用該等組合物治療個體之方法。本發明者已設計 出製備醫藥組合物（原料藥（bulk drug)產物）之方法，其涉 及製備包括治療有效量之治療劑阿利克崙、中鏈脂肪酸： 及形成基質之聚合物之水溶性組合物，乾燥(例如藉由束 乾）該水溶性組合物以獲得固體粉末，謂;東乾材料（固體 粉末）懸浮於疏水性（油性）介質、較佳藥麻油或三辛酸甘油 酿（包含其他成份，例如表面活性劑，黏度改良劑，參見 下文)以製備含有固體形式之治療劑、中鏈脂肪酸鹽：形 154767.doc 201136582 % 成基質之聚合物的油性懸浮液，由此製得原料藥產物。固 體形式可包括顆粒（例如，基本上由顆粒組成，或由顆教 組成）。顆粒可藉由；東乾或粒化或其他方式製得。然後可 將原料藥產物囊封於膠囊中，該等膠囊可塗覆有pH敏感性 塗層且可用於經口傳遞。製備所主張調配物之典型一般方 法示於圖1中。 本發明之發明者已發現，在以本文所述之組合物形式投 與時，可改良某些治療劑（例如阿利克崙或其他腎素抑制 劑）在個體中之吸收。舉例而言，相對於經由相似途徑但 以實質上不含本文所述組份或具有較低量之本文所述組份 之組合物形式投與的相同治療劑，以一或多個實施例之調 配物形式投與之阿利克崙會顯示改良之生物利用度（BA); 該等組份係（例如）中鏈脂肪酸鹽、形成基質之聚合物、疏 水性介質。相對B A之該改良可為大約至少約1 5倍、2倍、 3倍、5倍、7倍、1〇倍、20倍或更高倍。在至少一個態樣 中’本文所述之組合物藉由增強藥物分子之GI壁/障壁滲 透性來改良生物利用度。舉例而言，本文所述之阿利克崙 組合物可藉由經由使GI上皮細胞間之緊密連結不密封而透 過GI壁/障壁來增強吸收，從而除現有跨細胞吸收外達成 細胞旁吸收》 本發明顯示可將阿利克崙傳遞至腸（此係經口傳遞模 型）’且自此以高生物利用度傳遞至血流。 下文將詳細論述其他態樣、實施例、及優點。另外，應 理解’前文資訊及下文詳細闡述僅係各個態樣及實施例之 154767.doc 201136582 闡釋性實例，且意欲提供概述或構架來理解所主張 實施例之性質及特徵。包含附〜 a ^ 阐擇並進一步理解各個 例，且將附圖納入本說明書令並其構成本說明 曰…圖式、以及說明書之剩餘部分用於閣釋所闡 述及所主張態樣及實施例之原理及作業。 斤闡 二=篇以作者及年份及專利與申請案號引用包含 =專财内U個公開案。該等公開案、專利及專利申 5月案之全部揭示内容皆以引用方式併入本申請案中以更士 整地闡述本發明所涉及領域之狀態。 凡 【實施方式】 =备：本發明係關於存於改良載劑介質中之口服劑 醫举劑型包括口服活性腎素抑制劑（阿利克备）或其 定而^ i鹽（或其他腎素抑制劑）作為活性成份。特 =另=供包括阿利克备、較佳其半富馬酸鹽單 =广活性劑相組合之調配物。本發明亦係關於其製 備方法，且係關於其作為藥劑之用途。 =本申請案通篇中，若未具體定義，則應將術語「阿利 」理解為既可呈游離鹼形式亦可呈其㈣式，尤 其醫藥上可接受之鹽、最佳係其半富馬酸鹽。 …、 自腎臟釋放之腎素可在循環中解離 :肽:管緊縮素I。此物質依次在肺、腎及其 血S緊縮素轉化酶解離而形成辛肽血管緊 =:脈血管收縮直接地亦可藉由自腎上腺釋放鈉： 子保留激素㈣㈣伴隨有細胞外流體體積增加）間接地增 I54767.doc 201136582 高血壓。腎素酶活性之抑制 女私、Λ、， π 〗j导致血管緊縮素ι之形成 =咸、。最終產生較少#之血管緊縮素π。活性肽激素 小：(例如)腎素抑制劑之抗高血壓作用的直接原 壓藥^言’可將腎素抑制劑或其鹽用作抗高血 壓樂或用於治療充血性心臟衰竭。 腎素抑制劑阿利克备（尤其係其半富馬酸鹽）已知可有效 地用於降低血壓之治療％論年齡、性別或種族如何）， 且亦耐受良好。游離驗形式之阿利克备可由w〇 簡/_373A2巾之切）代表，且料2⑻，4⑻，⑽聊 N-(3-胺基·2,2_二甲基_3_側氧基丙基甲基乙基)_ 胺基_8_[4_甲氧基_3_(3甲氧基_丙氧基）苯朴辛 醢胺。如上所述，最佳者係具體揭示之其半富馬酸鹽，且 可如EP 678503 A中所述製得；參見實例83。亦參見相關 的美國專利第5’559，U1號。在本中請案通篇中，若未具體 定義，則應將術語「阿利克崙」理解為既可呈游離鹼形式 亦可呈其鹽形式，尤其係其醫藥上可接受之鹽，例如半富 馬酸鹽、硫酸氫鹽、乳清酸鹽或硝酸鹽，最佳係其半富馬 酸鹽。 經由口服途徑來投與此一醫藥藥劑優於非經腸投與，此 乃因别者使得患者可自我投與而非經腸調配物通常應由醫 師或輔助醫務人員來投與。然而，阿利克崙在習用調配物 中之吸收性較差（生物利用度為約2.5%)，且具有約24小時 之累積半衰期。在約7-8天内達到穩態血液濃度。此外， 阿利克奋係因其物理化學性質而難以調配之藥物物質，且 I54767.doc 201136582 以可靠及穩定之方式來製備口服調配物甚為重要。因生物 利用度較低’故需要較高藥物載量，且此在技術上難以達 成且會導致成本增加。 因此’期望可克服與阿利克崙性質有關之上述問題的適 宜及穩定調配物。因此，本發明係關於包括治療有效量之 阿利克崙、或其醫藥上可接受之鹽之新穎口服劑型，其中 生物利用度較現有調配物有所改良^較佳地，生物利用度 高於3°/。。在本發明之較佳實施例中，生物利用度為 5%-40% ’舉例而言，生物利用度為約5_1〇%、約ι〇_15〇/〇、 約 15-20。/。、約 20-25%、約 25-30% 或高於 30%。 在本發明之一較佳實施例中，活性劑完全由阿利克崙、 或其醫藥上可接受之鹽組成，且其存在量介於約5_6〇〇 mg 游離驗/單位劑型之間’或更具體而言其存在量為約5 mg、1〇 mg、20 mg、30 mg、40 mg、50 mg、60 mg、70 mg、80 mg、90 mg、100 mg、200 mg ' 300 mg、400 mg、500 mg或600 mg游離鹼/單位劑型。 在本發明之另一較佳實施例中，阿利克崙劑量呈其半富 馬酸鹽形式且其存在量介於約5_65〇 mg/單位劑型之間或更 小，亦即對應於約5-600 mg或更小之游離鹼/單位劑型。在 本發明之另一較佳實施例中，阿利克备劑量呈其半富馬酸 鹽形式且其存在量介於約5-75 mg/單位劑型、或約75_15〇 mg/單位劑型、或約15〇_3〇〇 mg/單位劑型、或約⑽ mg/單位劑型之間，或者更具體而言其存在量為約5 mg、 10 mg、20 mg、30 mg、40 mg、50 mg、60 mg、70 mg、 154767.doc 201136582 80 mg、90 mg、loo mg、200 mg、300 mg、4〇〇 叫、5〇〇 mg或600 mg/單位劑型。 本發明之口服劑型使得可以低於迄今為止可用於給定活 性劑單位劑量之載量的載量值來投與活性成份。另外，所 獲得之口服劑型在製備過程及儲存期間皆係穩定的。上下 文給出之百分比皆係基於使用諸如半富馬酸鹽等鹽，且若 使用游離酸或其他鹽，則應相應地改變該等百分比。對於 本文所用之百分比，其數值係指阿利克崙，由此係指游離 酸或鹽，特地而言其係指半富馬酸鹽。 醫藥組合物：本文所述之醫藥組合物包含與實質上疏水性 介質緊密接觸或結合之阿利克崙（或其他腎素抑制劑）、中 鏈脂肪酸鹽及形成基質之聚合物。舉例而言可將治療 劑、中鏈月曰肪酸或其衍生物及形成基質之聚合物塗覆、懸 浮、喷塗或浸潰於實質上疏水性介質中以形成懸浮液。本 發明組合物並非乳液。幾乎所有本發明組合物皆係油性懸 浮液（且很少係溶液）且組合物中之水量極低。懸浮液可為 、’内入固體材料之液體懸浮液、或納入固體材料之半固體懸 浮液（軟膏）。 本文所述之許多組合物包括懸浮液，㈣浮液包括疏水 性介質與m體形式之混合物，其中該固體形式包括治療有 效量之/合療劑、至少-種中鏈脂肪酸鹽及形成基質之聚合 物’其中該中鏈脂肪酸鹽以10重量％或更高之量存在於組 合物令。固體形式可包括顆粒(例如，基本上由顆粒組 成、或由顆粒組成）。顆粒可藉由;東乾或藉由粒化或藉由 154767.doc 201136582 喷霧乾燥或相似方式製得。在一些實施例中，較佳地在研 磨之後’約10% (v/v)之顆粒大於12〇14〇微米，且約50〇/〇 (v/v)之顆粒大於約40-50微米。 貨物化合物係如本文所述調配至本發明組合物内之治療 蜊（例如阿利克崙）或測試化合物（例如高分子量聚葡糖）。 在些較佳實施例中，本發明組合物僅包含基於人類應 用中之可用據、動物安全性及監管導則公認為安全之賦 形劑（例如GRAS賦形劑）。一些本發明組合物可具有其他 類型之賦形劑（例如非GRAS類）。在一些實施例中，本發 月、’且σ物中之賦形劑量落在如關於每一特定賦形劑之該可 用數據中所示之最大日劑量内。 中鏈月曰肪酸鹽通常可促進或增強治療劑之滲透及/或吸 收形成基質之聚合物（參見下文）用於增加滲透性增強劑 之作用在些實施例中’中鏈脂肪酸鹽包含中鏈脂肪酸 鹽之何生物。治療劑、中鏈脂肪酸鹽及形成基質之聚合物 呈固體形式，例如固體顆粒’例如凍乾顆粒、粒化顆粒、 或微球體。在較佳實施例中，治療劑、中鏈脂肪酸鹽 及形成基質之聚合物皆I相同固體形式，例如皆呈相同 顆粒开/式在其他實施例中，治療劑、中鏈脂肪酸鹽及形 成基質之聚合物可各自呈不同固體形式，例如各自呈不同 顆粒形式或其各種組合。 本文所述之組合物實質上不含任何「膜流化劑」，該等 膜：化劑定義為直鏈、具支鏈、芳族及環狀中鏈醇，特定 而。係香葉醇及辛醇。舉例而言’組合物較佳不含膜流化 154767.doc 201136582 :卜但某些實施例可包含(例如)小於或小於〇 5重 量°/❶或小於0.1重量％之膜流化劑。 與乳液不同，若水係調配物之基本組份，則本文所述之 組合物提供含有治療劑之固體形式（例如顆粒），該固體形 式然後與疏水性（油性）介質結合。組合物中之水量通常小 於3重量％、經常小於約2重量％或約夏重量％或更小。 本文所述之組合物係包括疏水性介質及固體形式之混合 物之懸浮液，其中該固體形式包括治療有效量之阿利克 崙、至少一種中鏈脂肪酸鹽及形成基質之聚合物。固體形 式可為顆粒（例如，基本上由顆粒組成，或由顆粒組成）。 顆粒可藉由凍乾或藉由粒化或藉由其他方式製得。中鏈脂 肪酸鹽通常以1 〇重量。/。或更小之量存在於本文所述之組合 物中。在某些實施例中，中鏈脂肪酸鹽在組合物中之存在 量為10重量％-50重量％、較佳丨丨重量％_18重量％、約11重 量1 7重量。/◦、1 2重量％_丨6重量％、丨2重量丨5重量％、 13重量％_16重量％、13重量％_15重量％、14重量％_16重量 %、14重量％-15重量％、15重量。/。_16重量％或最佳15重量 0/〇或16重量％ ’且中鏈脂肪酸具有約6至約14個碳原子、較 佳8、9或1 〇個碳原子之鏈長度。 本發明者意外發現，在本文所述之本發明組合物中， PVP(特定而言係PVP-12)可用於以協同方式增加滲透性增 強劑之作用。另外，將PVP-12之含量增至10%可增加API 在血液中之吸收’此乃因調配物之生物利用度有所改良。 本發明者證實聚葡糖具有與PVP相似（但較低）之作用。其 154767.doc -10- 201136582 他形成基質之聚合物亦具有相似作用。可將調配物中之 PVP代替為各種形成基質之聚合物，例如卡波普 (Carbopol)聚合物或海藻酸鹽或透明質酸鹽或聚丙稀酸鈉 鹽；亦可代替為葡糖胺或葡萄糖（參見表所有 調配物皆顯示生物利用度。卡波普聚合物係丙烯酸與聚烯 基麵或二乙烯基二醇交聯之聚合物。卡波普⑧934p聚合物 係丙稀酸與蔗糖之稀丙基喊交聯之高分子量聚合物。pVA 係乙烯基醇單體之水溶性合成聚合物。 在藉由（例如）卡波普934Ρ或藉由pva、或藉由所示之一 些其他形成基質之聚合物代替調配物中之pvp_丨2時，可減 小調配物之顆粒相（亦即固體形式）（親水性部分）中形成基 質之聚合物的總量且由此賦予將更多阿利克崙載入調配物 中之能力，此可適用於達成期望血液濃度或減小膠囊之大 小及數量。 本發明調配物中之固體形式（亦即親水性部分）的量通常 為調配物的約10%至約50%(w/w)。在本發明之某些態樣 中’固體形式之量為約17%至約36%。 在上述組合物之一些實施例中，包含治療劑之固體形式 亦包含阿利克崙穩定劑。 在本文所述之組合物之一肖定實施例中，；台療劑係阿利 克崙且脂肪酸鹽係辛酸鈉，且疏水性介質係三辛酸甘油 酯。在另一特定實施例中，組合物進一步包括pvp ^在另 -特定實施例中’組合物進一步包括膽鹽(例如牛磺膽酸 鈉或脫氧膽酸鈉或甘膽酸鈉或鵝去氧膽酸鈉或膽酸鈉或石 154767.doc 201136582 膽酸鈉）及印磷脂及至少一種阿利克崙穩定劑。 治療劑··本文所述之醫藥組合物可與各種治療劑（亦稱作 活性醫藥成份=API)-起使用。在—些實施例中，醫藥組 合物包含複數種治療劑（效應物）(3治療劑可呈相同固體形 式（例如，呈相同顆粒形式），或者治療劑可各自呈獨立= 固體形式（例如，各自呈不同顆粒形式）。在較佳實施例 中，治療劑呈顆粒形式，例如粒化或固體顆粒。顆粒與實 質上疏水性介質（例如，本文所述之疏水性介質）結合或緊 密接觸。本文所述之較佳治療劑係腎素抑制劑且特定而言 係阿利克崙。其他治療劑可與腎素抑制劑相組合，例如， ΑΊΠ觉體括抗劑、HMG-Co-A還原酶抑制劑、血管緊縮素 轉化酶（ACE)抑制劑、鈣通道阻斷劑、醛固酮合酶抑制 劑、醛固酮拮抗劑、雙重血管緊縮素轉化酶/中性内肽酶 (ACE/NEP)抑制劑、内皮素拮抗劑或利尿藥。 AT丨受體拮抗劑可（例如）選自绳沙坦（vaisartan)、氣沙扭 (losartan)、依普羅沙坦（eprosartan)、厄貝沙坦（irbesartan)、 替米沙坦（telmisartan)、坎地沙坦（candesartan)、沙普立沙 坦（saprisartan)及其鹽。 HMG-Co-A還原酶抑制劑可（例如）選自阿托伐他丁 (atorvastatin)、西立伐他汀（cerivastatin)、康帕丁（compactin)、 達伐他 ’/丁（dalvastatin)、二氮康帕丁（dihydrocompactin)、 氟多他汀（fluindostatin)、氟伐他汀（fluvastatin)、洛伐他汀 (lovastatin)、匹伐他汀（pitavastatin)、美伐他汀（mevastatin)、 普伐他汀（pravastatin)、瑞伐他汀（rivastatin)、辛伐他汀 154767.doc -12- 201136582 (simvastatin)及菲羅他汀（velostatin)。 ACEI可（例如）選自阿拉普利（alacepril)、貝那普利 (benazepril)、貝那普利拉（benazeprilat)、卡托普利 (captopril)、西羅普利（ceronapril)、西拉普利（cilazapril)、 地拉普利（delapril)、依那普利（enalapril)、依那普利拉 (enaprilat)、福辛普利（f0Sin0pril)、咪達普利（imidapril)、 賴諾普利（lisinopril)、莫維普利（movehopril)、培哚普利 (perindopril)、喹那普利（qUinapru)、雷米普利（ramipril)、 螺普利（spirapril)、替莫普利（temocapril)、群多普利 (trandolapril)及其鹽。 名弓通道阻斷劑可（例如）選自胺氣地平（amlodipine)、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（niiudipine)、 尼莫地平（nimodipine)、尼索地平（nis〇idipine)、尼群地平 (nitrendipine)及尼伐地平（nivaidipine)。酸固_合酶抑制劑 可（例如）選自非類固醇芳香酶抑制劑阿那曲唑 (anastrozole)、法倔唑（fa(jroz〇ie)(包含其（+)_ 對映異構 體）、以及類固醇^香酶抑制劑依西美坦（exernestane)。酸 固_拮抗劑可（例如）選自依普利_ (epleren〇ne)或螺内g旨 (spironolactone) θ雙重血管緊縮素轉化酶/中性内肽酶 (ACE/NEP)抑制劑可（例如）選自奥帕拉特（〇mapatrUate)(參 見EP 629627)、法西多曲（fasid〇tril)或法西多曲拉 (fasidotrilate)、或Z 13752A(參見 WO 97/24342)。内皮素拮 154767.doc 13 201136582 抗劑可（例如）選自波生坦（bosentan)、恩拉生坦（enrasentan)、 阿曲生坦（atrasentan)、達盧生坦（darusentan)、BMS 193 884 (參見EP 702012 A)、西他生坦（sitaxentan)(尤其西他生坦 鈉）、YM 598(參見EP 882719 A)、S 0139(參見WO 97/27314)、 J 104132(參見 EP 714897 A 或 WO 97/37665)以及替唑生坦 (tezosentan)。利尿藥可（例如）選自噻嗪（thiazide)利尿藥， 例如氣。塞嗓（chlorothiazide)、氫氣 〇塞唤（hydrochlorothiazide)、 甲氣嗟°秦（1116111丫1〇1〇1；1^321(16)或氣<1塞酮（(：]11〇1>〇1；11311(1〇11)。 在本文所述之組合物之一些實施例中，包含治療劑之固 體形式亦包含穩定劑’特定而言係阿利克崙穩定劑。 中鍵脂肪酸鹽：本文所述之組合物包含中鏈脂肪酸或其衍 生物之固體形式鹽。舉例而言，中鏈脂肪酸鹽呈顆粒形 式，例如固體顆粒。在一些實施例中，可將顆粒描述為粒 化顆粒。在至少一些實施例中，固體形式通常可自喷霧乾 燥或蒸發過程產生。在較佳實施例中，中鏈脂肪酸鹽呈與 治療劑相同之顆粒形式。舉例而言，治療劑及中鏈脂肪酸 鹽可藉由以下方式一起製得：首先製備包括治療劑及中鏈 脂肪酸鹽二者之溶液（例如水溶液），且共凍乾該溶液以提 供包括治療劑及中鏈脂肪酸鹽二者（及其他成份）之固體形 式或顆粒。如上所述，使所得固體顆粒與疏水性介質結 合。舉例而言’可將固體顆粒懸浮或浸潰於疏水性介質 中0 ，在本文所述之組合物之不同實施例中，巾鏈脂肪酸鹽及 形成基質之聚合物（參見下文）可與API呈相同顆粒或不同 I54767.doc •14· 201136582 顆粒形式《我們發現，若中鏈脂肪酸與治療劑具有不同顆 粒形式’則貨物化合物之生物利用度較低，亦即，若在中 鏈脂肪酸鹽及貨物化合物在親水性部分中一起溶解之後將 其乾燥’則生物利用度有所改良《在一實施例中，中鍵脂 肪酸鹽、形成基質之聚合物及貨物化合物在最終粉末中皆 呈相同顆粒形式。 中鏈脂肪酸鹽包含彼等碳鏈長度為約6至約14個碳原子 者。脂肪酸鹽之實例係己酸鈉、庚酸鈉、辛酸鈉（s〇dium octanoate)(亦稱作辛酸鈉（s〇dium caprylate))、壬酸鈉、癸 酉夂納、十一 g文鈉、十一酸納、十三酸納及十四酸鈉。在一 些實施例中，中鏈脂肪酸鹽含有選自由鉀、鋰、銨及其他 饧陽離子組成之群的陽離子，例如，中鏈脂肪酸鹽選自 辛酸鋰或辛酸鉀或精胺酸辛酸鹽或其他一價中鏈脂肪酸 鹽。本發明者先前已確^，增加中鏈脂肪酸鹽之量會增加 所得調配物之生物利用度。特定而言，將中鏈脂肪酸鹽 (特定而言係辛酸鈉）之量增加至高於1〇%至約i2%_i5%範 圍會增加本文所述之醫藥組合物中治療劑的生物利用度。 一般而f ’中鍵脂月嫌鹽在纟文所述之組合詩勿中之量可 為原料醫藥組合物之1G重量％至多達約5〇重量％。舉例而 吕’中鏈脂肪酸鹽之存在量可為原料醫藥組合物之約1〇重 里/。50重里/〇或存在量為約1〇重量重量％或約1 〇重 量。/。-15重量％或存在鼍致&，c ‘ θ 為約1 5重置％-20重量％、較佳約11 重量％-40重量％、最佳的〗丨壬旦η/ 佳、力11重量❶/。-28重量％，例如約12重 量0/〇-13重量％、13重量。/ 14舌曰 1 0 14重 1〇/〇、14重量％-15重量0/〇、 154767.doc 201136582 15重量％-16重量％、16重量。/。_17重 0 17重量％-18重量 〇/〇、18重量％-19重量％、19重量％_2 ^董置❶/。、20重量％_21 重量％、21重量％-22重量❶/。、22重 里。23重量％、23重量 %-24重量％、24重量％-25重量％、25重量 ▲且η/丄 里夏/〇-26重量〇/〇、26 重量％-27重量/❶、或27重量％_28重 ^ 童/()。在其他實施例 中，中鏈脂肪I鹽之存在量可為原料 1 w樂級合物之至少約 i i重量％、至少約12重量％、至少 J 1J重量％、至少約14 重量％、至少約15重量。/◦、至少約16 ' $置/〇、至少約17重 量％、直少約18重量％、至少約19重量 里篁/〇、至少約20重量 %、至少約21重量。/。、至少約22重量％、至少約η重量。 至少約24重量。/。、至少約25重量％、至少約％重量％、至 少約27重㈣至少約28重量％。在具體實施例中，中鏈 脂肪酸鹽（鈉、鉀、鋰或銨鹽或其混合物）之存在量為原料 醫藥組合物之約12重量％_21重量％，較佳如重量㈣重 量％、約U重量。/。-17重量％、12重量％_16重量％、12重量 重量％、13重量％-16重量％、13重量％_15重量％、μ 重量。/。-16重量❶/。、14重量％·15重量％、15重量％16重量 %，或最佳為15重量％或16重量％。在具體實施例中中 鏈脂肪酸鹽（碳鏈長度為約6至約14個碳原子，尤其為8、9 或ίο個碳原子）之存在量為原料醫藥組合物之約12重量 21重量％，較佳為11重量％_18重量％、約u重量％_17重量 %、12重量％-16重量。/◦、12重量％_15重量％、13重量％16 重量％、13重量％-15重量％、14重量％_16重量％、14重量 %-15重量。/。、15重量。/。-16重量％，或最佳為15重量％或16 I54767.doc -16- 201136582 重量％。在具體實施例中，中鏈脂肪酸鹽（例如辛酸鹽、辛 二酸鹽、龍牛兒酸鹽）之存在量為本體醫藥組合物之約12 重量％-2 1重量％，較佳為11重量。/。· 1 8重量％、約11重量 %-17重量％、12重量％“6重量％、12重量％-15重量％、13 重量％-16重量％、13重量15重量％、14重量16重量 °/。、14重量％_15重量％、15重量％_16重量％，或最佳為15 重量％或1 6重量％。在某些實施例中，中鏈脂肪酸鹽在固 體粉末中之存在量為約30%至90%，較佳量為40%至60%。 本發明一實施例包括含有懸浮液之組合物，該懸浮液基 本上由疏水性介質及固體形式之混合物組成，其中該固體 形式包括治療有效量之治療劑、至少一種中鏈脂肪酸鹽及 形成基質之聚合物’且其中該中鏈脂肪酸鹽並非鈉鹽。鹽 可為另一陽離子（例如鋰、鉀或精胺酸）之鹽；精胺酸鹽較 佳。 形成基質之聚合物：在某些實施例中，本發明組合物包括 含有疏水性介質及固體形式之混合物的懸浮液，其中該固 體形式包括治療有效量之治療劑 '至少一種中鍵脂肪酸鹽 及形成基質之聚合物。在某些實施例中，組合物包括基本 上由疏水性介質及固體形式之混合物組成的懸浮液，其中 該固體形式包括治療有效量之治療劑、至少一種中鏈脂肪 酸鹽及形成基質之聚合物。形成基質之聚合物在組合物中 之存在量較佳為約0.5重量％至約1 〇重量❶/((，最佳量為約1 重量％至約1 0重量％。 形成基質之聚合物包含聚乙烯基吡咯啶酮（PVP)、直鏈 154767.doc -17- 201136582 N-乙烯基吡咯啶酮之聚合物（已知會產生「基質樣」結 構）、及交聯PVP(交聯聚維酮）；離子型多糖（例如透明質酸/ 透明質酸鹽及海藻酸/海藻酸鹽）；中性多糖（例如聚葡糖、 曱基纖維素及羥丙基甲基纖維素（HPMC));直鏈聚丙稀酸 聚合物（包含聚曱基丙烯酸聚合物）；交聯聚丙烯酸聚合物 (卡波姆（carbomer));胺基多糖（例如殼聚糖）；含s聚合物 (硫醇鹽聚合物（thiomer));及高分子量直鏈及橋接有機醇 (例如直鏈聚乙烯醇）。 卡波姆係丙稀酸交聯聚合物之通用名稱；卡波姆可為與 諸如以下物質交聯之丙烯酸均聚物：烯丙基醚異戊四醇、 或嚴糖之烯丙基醚或丙烯之烯丙基醚或烯丙基蔗糖或其他 糖或烯丙基異戊四醇或聚烯基醚或二乙烯基二醇。 在特定實施例中，形成基質之聚合物係聚乙烯基吡咯啶 酮（PVP)、卡波姆、聚乙烯醇（PVA)、聚葡糖、海藻酸鹽、 透明身酸鹽或聚丙烯酸鹽或其組合。在某些特定實施例 中’形成基質之聚合物係聚乙烯基„比„各β定酮（pVp)、卡波 普聚合物或聚乙烯醇（PVA)或其組合。 在特定實施例中，聚乙烯基吼咯啶酮在組合物中之存在 量為約2重量％至約20重量％，較佳量為約3重量％至約18 重量。/。’更佳量為約5重量％至約15重量％，最佳量為約1〇 重量％。在某些特定實施例中’ $乙烯基吡咯啶_係 PVIM2及/或分子量為約3刚，且其在組合物中之存在量 為約2重量。/〇至約20重量％，較佳景垚的ς击真。/广 千又1主重為約5重量。/〇至約丨5重 量％，最佳量為約10重量〇/〇。 I54767.doc -18- 201136582 在本發明之一態樣中，形成基質之聚合物係交聯丙烯酸 ts物（亦稱作卡波姆）。卡波普聚合物係丙稀酸之交聯聚 合物之實例。交聯丙烯酸聚合物之黏度為約20〇〇 8〇〇〇〇 cP、較佳 4000-65000、最佳 25000-45000 cP ;黏度係以 cp 形式以0.5%溶液在pH 7 5下量測。在本發明之一特定態樣 中’交聯丙烯酸聚合物係黏度為約29000至約4〇〇〇〇之與烯 丙基蔗糠連接之卡波姆，尤其係卡波普934p。交聯丙烯酸 ♦ &物在組合物中之存在量可為約〇丨重量％至約6重量 /〇，較佳量為約〇·5重量％至約4重量％，例如存在量為約丄 重量％或約2重量％或約3重量％ » 在本發明之另一態樣中，形成基質之聚合物係分子量為 10000-60000 Da、較佳 2〇〇〇〇_3〇〇〇〇 Da之聚乙烯醇。在特 定實施例中，聚乙烯醇係分子量為約27〇〇〇 〇3之聚乙烯 醇，且其在組合物中之存在量可為約〇1重量％至約6重量 %，較佳量為約0.5重量％至約4重量％，例如，存在量為約 1重量％、約2重量❹/。、或約3重量％。 在某些實施例中，可使用葡萄糖及/或其他糖及/或甘露 醇代替形成基質之聚合物。 阿利克崙穩定劑：本發明者發現，為減少阿利克崙尤其在 約25°C下儲存時之降解，必須向調配物、尤其向固體形式 中添加穩定劑。該等穩定劑包含金屬鹽及/或胺基酸或其 組合。金屬鹽之實例係鎂鹽、鈣鹽及鋅鹽或其組合。金屬 鹽之特定實例係MgCl2、ZnC】2、CaCi2、乙酸鋅、乙酸鎂 及乙酸鈣。胺基酸實例係甘胺酸及精胺酸。在其他實施例 154767.doc •19· 201136582 中，可選擇疏水性介質作為穩定性介質，你丨& _ Λ ^ 例如二辛酸甘油 酯及其他極性無羥基液體。 親水性部分：在一些實施例中，將上述化合物（包含治療 劑、中鏈脂肪酸鹽及形成基質之聚合物（或替代物）及視需 要阿利克备穩定劑）溶於水性介質中且然後乾燥以製備粉 末。可（例如）藉由凍乾或粒化、喷霧乾燥或藉由其他、方式 來達成乾燥過程。所獲得之粉末稱作「親水性部分」。在 親水性部分中’水通常以小於6%之量存在且最終本體組 合物+之水包括來自親水性部分之殘餘水。 可如本文實例中所示及藉由業内已知之方法來實施康 乾’例如’如 Lyophilization: Introduction and Basic Principles，Thomas Jennings，Interpharm/CRC Press有限 公司出版（1999, 2002)中所述。可視需要將凍乾物在研蛛 中研磨（例如低於150微米）或礙磨。在工業製備期間，較佳 地’在混合親水性部分及疏水性介質之前研磨凍乾物以獲 得批次間再現性* 可如本文實例中所示及藉由業内已知之方法來實施粒 化，例如’如 Granulation，Salman等人編輯，Elsevier (2006) 及 Handbook of Pharmaceutical Granulation Technology，第 2版，Dilip M. Parikh編輯’（2005)中所述。在粒化方法中 可使用各種黏合劑，如前文兩篇參考文獻中所述。 可藉由業内已知之方法來實施喷霧乾燥，例如，如由 Patel等人，（2009) Indian Journal 〇f Science and Technology 2(10) 44-47及 Shabde，Vikram (2006) Ph.D. thesis，Texas 154767.doc -20- 201136582201136582 VI. Description of the Invention: [Technical Field of the Invention] "The present invention relates to a pharmaceutical composition capable of improving the oral delivery of Alix and a method of using the same. [Prior Art] Renin inhibition Alec (especially its hemifumarate) is known to be effective in reducing the treatment of blood spleen (regardless of age, gender or race) and is well tolerated. However, Alec is in the habit of The formulation has poor absorbency (bioavailability of about 2.5%) and has a cumulative half-life of about (4) and time. In addition, Alec is a drug substance that is difficult to formulate due to its physicochemical properties, and is reliable and stable. The way to prepare oral formulations is very important. Because of the low bioavailability, high drug loading is required, and this is technically difficult to achieve and leads to increased costs. Because of the need in the industry, it can improve Alec Effective, specific, sigma-based formulation for oral delivery. SUMMARY OF THE INVENTION [0007] The novel Alixene compositions, methods of making the compositions, and the use of such compositions are described herein. Methods of treating a subject. The inventors have devised a method of preparing a pharmaceutical composition (bulk drug product) which involves the preparation of a therapeutically effective amount of a therapeutic agent, aliskiren, a medium chain fatty acid: and a matrix-forming polymerization. a water-soluble composition, dried (for example, by bundling) the water-soluble composition to obtain a solid powder, that is, an east dry material (solid powder) suspended in a hydrophobic (oily) medium, preferably sesame oil or trioctanoic acid Glycerol brewing (including other ingredients such as surfactants, viscosity modifiers, see below) to prepare an oily suspension containing a solid form of therapeutic agent, medium chain fatty acid salt: Form 154767.doc 201136582 % matrix-forming polymer, This produces a drug substance product. The solid form may comprise particles (for example consisting essentially of particles or consisting of a squad). The granules may be prepared by east drying or granulation or other means. Encapsulated in capsules that can be coated with a pH sensitive coating and can be used for oral delivery. A typical general method for preparing the claimed formulations is shown in Figure 1. The inventors of the present invention have discovered that upon administration in the form of a composition described herein, the absorption of certain therapeutic agents (e.g., aliskiren or other renin inhibitors) in an individual can be improved. The same therapeutic agent administered via a similar route but in a form substantially free of the components described herein or having a lower amount of the components described herein, in the form of a formulation of one or more embodiments The aliskiren administered will exhibit improved bioavailability (BA); such components are, for example, medium chain fatty acid salts, matrix forming polymers, hydrophobic media. The improvement over BA can be at least about 1 5 fold, 2 fold, 3 fold, 5 fold, 7 fold, 1 fold, 20 fold or more. In at least one aspect, the composition described herein enhances the GI wall/barrier penetration of the drug molecule. Sex to improve bioavailability. For example, the aliskiren composition described herein can enhance absorption by permeable to the GI wall/barrier by making the tight junction between the GI epithelial cells unsealed, thereby achieving paracellular absorption in addition to the existing transcellular absorption. The invention shows that aliskiren can be delivered to the intestine (this is an oral delivery model) and has since been delivered to the bloodstream with high bioavailability. Other aspects, embodiments, and advantages are discussed in detail below. In addition, it is to be understood that the foregoing description of the preferred embodiments of the present invention is intended to Included with a a ^ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The principle and operation.斤解二=篇 By author and year and patent and application number reference contains = public disclosure of U public case. The disclosures of the publications, patents, and patents are hereby incorporated by reference in its entirety in its entirety in its entirety in the extent of the disclosure of the disclosure of the disclosure. [Embodiment] = Preparation: The present invention relates to oral dosage forms for oral administration in a modified carrier medium, including an oral active renin inhibitor (Alix) or its salt (or other renin inhibition). Agent) as an active ingredient. Special = another = for the formulation including Alec, preferably its semi-fumarate single = broad active agent combination. The invention is also directed to methods of preparation thereof and to its use as a medicament. = In the whole of the application, if not specifically defined, the term "Ali" should be understood to mean either a free base or a formula (IV), especially a pharmaceutically acceptable salt, preferably a semi-rich horse. Acid salt. ..., renin released from the kidney can be dissociated in the circulation: peptide: tube tightening hormone I. This substance is in turn dissociated in the lungs, kidneys and its blood S-binding enzyme to form octyl vascular tight =: vasoconstriction can also be directly released from the adrenal gland: sub-retaining hormone (4) (four) accompanied by an increase in extracellular fluid volume) Intermittent increase I54767.doc 201136582 hypertension. Inhibition of renin enzyme activity Female private, Λ,, π 〗 〖 j lead to the formation of angiotensin ι = salty. Eventually less vasopressin π is produced. Active Peptide Hormone Small: A direct prodrug of, for example, an antihypertensive effect of a renin inhibitor can use a renin inhibitor or a salt thereof for antihypertensive therapy or for treating congestive heart failure. The renin inhibitor Aleks (especially its hemifumarate) is known to be effective in lowering blood pressure treatments in terms of age, sex or race, and is well tolerated. The free form of Alec can be represented by w〇/_373A2 towel, and material 2(8), 4(8), (10) talk N-(3-amino-2,2-dimethyl-___oxypropyl Methyl ethyl)_amino-8-[4-methoxy-3-(3methoxy-propoxy) phenylpodoxime. As noted above, the best disclosed are the hemifumarates thereof, and can be prepared as described in EP 678503 A; see Example 83. See also related U.S. Patent No. 5'559, U1. In the context of this application, the term "Alikron" should be understood to mean either as a free base or as a salt, especially as a pharmaceutically acceptable salt, such as half. Fumarate, hydrogen sulfate, orotate or nitrate, preferably a hemifumarate. Administration of this pharmaceutical agent via the oral route is superior to parenteral administration, as it allows the patient to self-administer rather than enteral formulation and should normally be administered by a physician or paramedical staff. However, aliskiren is less absorptive in conventional formulations (bioavailability is about 2.5%) and has a cumulative half-life of about 24 hours. Steady-state blood concentration is reached in about 7-8 days. In addition, Alec is a drug substance that is difficult to formulate due to its physicochemical properties, and I54767.doc 201136582 is important for the preparation of oral formulations in a reliable and stable manner. Higher drug loading is required due to lower bioavailability, and this is technically difficult to achieve and leads to increased costs. Therefore, it is desirable to have an appropriate and stable formulation that overcomes the above problems associated with the properties of aliskiren. Accordingly, the present invention is directed to a novel oral dosage form comprising a therapeutically effective amount of aliskiren, or a pharmaceutically acceptable salt thereof, wherein the bioavailability is improved over prior formulations. Preferably, the bioavailability is higher than 3 °/. . In a preferred embodiment of the invention, the bioavailability is from 5% to 40%'. For example, the bioavailability is about 51-1%, about ι〇_15〇/〇, about 15-20. /. , about 20-25%, about 25-30% or higher than 30%. In a preferred embodiment of the invention, the active agent consists entirely of aliskiren, or a pharmaceutically acceptable salt thereof, and is present in an amount between about 5-6 mg of free test per unit dosage form or more Specifically, it is present in amounts of about 5 mg, 1 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg '300 mg, 400 mg. , 500 mg or 600 mg free base per unit dosage form. In another preferred embodiment of the invention, the aliskiren dose is in the form of its hemi-fumarate salt and is present in an amount between about 5 and 65 mg/unit dosage form or less, i.e., corresponding to about 5 Free base/unit dosage form of 600 mg or less. In another preferred embodiment of the invention, the Alix dosage is in the form of its hemi-fumarate salt and is present in an amount between about 5 and 75 mg per unit dosage form, or about 75 to 15 mg per unit dosage form, or about 15〇_3〇〇mg/unit dosage form, or about (10) mg/unit dosage form, or, more specifically, about 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 Mg, 70 mg, 154767.doc 201136582 80 mg, 90 mg, loo mg, 200 mg, 300 mg, 4 bark, 5 mg or 600 mg per unit dosage form. The oral dosage form of the present invention allows administration of the active ingredient below the loading value of the loading of the unit dosages that have hitherto been used for a given active agent. In addition, the oral dosage forms obtained are stable during the preparation and storage period. The percentages given above are based on the use of salts such as hemi-fumarate, and if free acids or other salts are used, the percentages should be varied accordingly. For the percentages used herein, the values refer to aliskiren, and thus to free acids or salts, and in particular to hemifumarate. Pharmaceutical Compositions: The pharmaceutical compositions described herein comprise aliskiren (or other renin inhibitor), a medium chain fatty acid salt, and a matrix forming polymer in intimate contact or association with a substantially hydrophobic medium. For example, a therapeutic agent, a medium chain fatty acid or a derivative thereof, and a matrix forming polymer can be coated, suspended, sprayed or impregnated into a substantially hydrophobic medium to form a suspension. The composition of the invention is not an emulsion. Almost all of the compositions of the present invention are oily suspensions (and rarely solution) and the amount of water in the composition is extremely low. The suspension may be, a liquid suspension of the solid material incorporated therein, or a semi-solid suspension (ointment) incorporated into the solid material. Many of the compositions described herein include a suspension, and (iv) a suspension comprising a mixture of a hydrophobic medium and an m-form, wherein the solid form comprises a therapeutically effective amount of a therapeutic agent, at least a medium chain fatty acid salt, and a matrix-forming material. The polymer 'wherein the medium chain fatty acid salt is present in the composition in an amount of 10% by weight or more. The solid form can include particles (e.g., consisting essentially of, or consisting of, particles). The granules can be prepared by spray drying or the like by granulation or by 154767.doc 201136582. In some embodiments, preferably about 10% (v/v) of the particles are greater than 12〇14〇 microns after grinding, and about 50〇/〇 (v/v) of the particles is greater than about 40-50 microns. The cargo compound is a therapeutic hydrazine (e.g., aliskiren) or a test compound (e.g., high molecular weight polyglucose) formulated as described herein to the compositions of the present invention. In preferred embodiments, the compositions of the present invention comprise only excipients (e.g., GRAS excipients) that are recognized as safe based on available data, animal safety, and regulatory guidelines in human applications. Some compositions of the invention may have other types of excipients (e.g., non-GRAS). In some embodiments, the amount of excipient in the present month,' and sigma falls within the maximum daily dose as shown in the available data for each particular excipient. The medium chain laurate may generally promote or enhance the penetration of the therapeutic agent and/or absorb the matrix forming polymer (see below) for increasing the effect of the permeability enhancer. In some embodiments, the medium chain fatty acid salt is included. What is the chain fatty acid salt? The therapeutic agent, medium chain fatty acid salt and matrix forming polymer are in solid form, such as solid particles' such as lyophilized particles, granulated particles, or microspheres. In a preferred embodiment, the therapeutic agent, the medium chain fatty acid salt, and the matrix-forming polymer are all in the same solid form, for example, all of the same particles. In other embodiments, the therapeutic agent, the medium chain fatty acid salt, and the matrix are formed. The polymers may each be in different solid forms, for example each in a different particle form or in various combinations thereof. The compositions described herein are substantially free of any "membrane fluidizing agents" which are defined as linear, branched, aromatic and cyclic medium chain alcohols, specifically. It is a geraniol and an octanol. For example, the composition preferably does not contain membrane fluidization 154767.doc 201136582: However, certain embodiments may comprise, for example, less than or less than 5% by weight ❶/❶ or less than 0.1% by weight of the membrane fluidizing agent. Unlike emulsions, if a basic component of a water-based formulation, the compositions described herein provide a solid form (e.g., granules) containing a therapeutic agent which is then combined with a hydrophobic (oily) medium. The amount of water in the composition is typically less than 3% by weight, often less than about 2% by weight or about about 3% by weight or less. The compositions described herein comprise a suspension of a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of aliskiren, at least one medium chain fatty acid salt, and a matrix forming polymer. The solid form can be a particle (e.g., consisting essentially of or consisting of particles). The particles can be prepared by lyophilization or by granulation or by other means. The medium chain fatty acid salt is usually 1 〇 by weight. /. Or smaller amounts are present in the compositions described herein. In certain embodiments, the medium chain fatty acid salt is present in the composition in an amount from 10% to 50% by weight, preferably from 8% to 18% by weight, and from about 11% by weight. /◦, 12% by weight _ 6% by weight, 丨2 weight 丨 5% by weight, 13% by weight _16% by weight, 13% by weight -155% by weight, 14% by weight _16% by weight, 14% by weight to 15% by weight, 15 weight. /. _16% by weight or optimally 15% 0/〇 or 16% by weight' and the medium chain fatty acid has a chain length of from about 6 to about 14 carbon atoms, more preferably 8, 9 or 1 carbon atoms. The inventors have unexpectedly discovered that in the compositions of the invention described herein, PVP (specifically PVP-12) can be used to synergistically increase the effectiveness of the osmotic enhancer. In addition, increasing the PVP-12 content to 10% increases the absorption of the API in the blood' due to improved bioavailability of the formulation. The inventors have demonstrated that polyglucose has a similar (but lower) effect as PVP. Its 154767.doc -10- 201136582 his matrix-forming polymer also has a similar effect. The PVP in the formulation may be replaced by various matrix-forming polymers, such as Carbopol polymers or alginate or hyaluronate or sodium polysodium salt; alternatively, it may be replaced by glucosamine or glucose. (See Table for all formulations showing bioavailability. Carbopol polymers are polymers crosslinked with acrylic acid or polyalkenyl or divinyl glycol. Carbopol 8934p polymer is a thinner of acrylic acid and sucrose The propyl group is a crosslinked high molecular weight polymer. The pVA is a water soluble synthetic polymer of a vinyl alcohol monomer. The matrix is formed by, for example, Carbopol 934 or by pva, or by some of the others shown. When the polymer is substituted for pvp_丨2 in the formulation, the total amount of the polymer forming the matrix in the particulate phase (ie, the solid form) (hydrophilic portion) of the formulation can be reduced and thus more The ability of lyclamine to be loaded into the formulation, which may be adapted to achieve a desired blood concentration or to reduce the size and amount of the capsule. The amount of solid form (i.e., hydrophilic portion) in the formulation of the invention is typically about the formulation. 10% to about 50% (w/w) In some aspects of the invention, the amount of the solid form is from about 17% to about 36%. In some embodiments of the above compositions, the solid form comprising the therapeutic agent also comprises an aliskiren stabilizer. In one embodiment of the composition, the therapeutic agent is aliskiren and the fatty acid salt is sodium octanoate, and the hydrophobic medium is tricaprylin. In another specific embodiment, the composition further comprises pvp ^ In another specific embodiment, the composition further comprises a bile salt (eg, sodium taurocholate or sodium deoxycholate or sodium glycocholate or sodium hyodeoxycholate or sodium cholate or stone 154767.doc 201136582 biliary Sodium phosphate) and phospholipids and at least one aliskiren stabilizer. Therapeutic agents · The pharmaceutical compositions described herein can be used with various therapeutic agents (also known as active pharmaceutical ingredients = API). In some embodiments The pharmaceutical composition comprises a plurality of therapeutic agents (effectors) (3 therapeutic agents may be in the same solid form (eg, in the same particle form), or the therapeutic agents may each be in separate = solid form (eg, each in a different particle form) ).in In a preferred embodiment, the therapeutic agent is in the form of particles, such as granulated or solid particles. The particles are bound or in intimate contact with a substantially hydrophobic medium (e.g., a hydrophobic medium as described herein). Preferred therapeutic agents described herein The renin inhibitor and in particular is aliskiren. Other therapeutic agents can be combined with a renin inhibitor, for example, a scorpion inhibitor, an HMG-Co-A reductase inhibitor, an angiotensin converting enzyme ( ACE) inhibitors, calcium channel blockers, aldosterone synthase inhibitors, aldosterone antagonists, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitors, endothelin antagonists or diuretics. The purine receptor antagonist can, for example, be selected from the group consisting of vaisartan, losartan, eprosartan, irbesartan, telmisartan, kan Dessartan (candesartan), saprisartan and its salts. The HMG-Co-A reductase inhibitor can, for example, be selected from the group consisting of atorvastatin, cerivastatin, compactin, dalvastatin, and Dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, Rivaratin, simvastatin 154767.doc -12- 201136582 (simvastatin) and philostatin. ACEI can, for example, be selected from the group consisting of alapril, benazepril, benazeprilat, captopril, ceralopril, cilap Cilayapril, delapril, enalapril, enaprilat, fosinopril (f0Sin0pril), imidapril, lisinopril (lisinopril), moveopril, perindopril, qUinapru, ramipril, spirapril, temocapril, Trandolapril and its salts. The bow channel blocker can, for example, be selected from the group consisting of amlodipine, felodipine, ry0Sidine, isradipine, lacidipine, nicardipine. (nicardipine), nifedipine, nigdiidi, niiudipine, nimodipine, nis〇idipine, nitrendipine, and nigra Ground level (nivaidipine). The acid-solid synthase inhibitor can, for example, be selected from the group consisting of the non-steroidal aromatase inhibitor anastrozole, fa (jroz〇ie) (including its (+)-enantiomer), And a steroid inhibitor, exernestane. The acid-solid antagonist can be, for example, selected from the group consisting of epleren® or spironolactone θ dual angiotensin converting enzyme. /Neutral endopeptidase (ACE/NEP) inhibitors can, for example, be selected from 〇mapatrUate (see EP 629627), fasidotril or fasidotrilate Or, Z 13752A (see WO 97/24342). Endothelin antagonist 154767.doc 13 201136582 The anti-agent may, for example, be selected from the group consisting of bosentan, enrasentan, atrasentan (atrasentan) ), darusentan, BMS 193 884 (see EP 702012 A), sitaxentan (especially sitaxsentan sodium), YM 598 (see EP 882719 A), S 0139 (see WO 97) /27314), J 104132 (see EP 714897 A or WO 97/37665) and tezosentan. Diuretics may, for example, be selected from thiazines (th) Iazide) a diuretic, such as gas, chlorothiazide, hydrochlorothiazide, gastrozine (1116111丫1〇1〇1; 1^321(16) or gas <1 ketene ( (:] 11〇1>〇1;11311 (1〇11). In some embodiments of the compositions described herein, the solid form comprising the therapeutic agent also comprises a stabilizer, in particular an aliskiren stabilizer. Middle Bond Fatty Acid Salt: The compositions described herein comprise a solid form salt of a medium chain fatty acid or a derivative thereof. For example, the medium chain fatty acid salt is in the form of particles, such as solid particles. In some embodiments, the particles may be Described as granulated particles. In at least some embodiments, the solid form is typically produced from a spray drying or evaporation process. In a preferred embodiment, the medium chain fatty acid salt is in the form of the same granules as the therapeutic agent. The therapeutic agent and the medium chain fatty acid salt can be prepared by first preparing a solution (eg, an aqueous solution) comprising both a therapeutic agent and a medium chain fatty acid salt, and co-freezing the solution to provide a therapeutic agent and a medium chain fatty acid. salt Those (and other components) of the solid or particulate form. As described above, the resulting solid particles with a hydrophobic binding medium. For example, 'solid particles may be suspended or impregnated in a hydrophobic medium. In various embodiments of the compositions described herein, the towel chain fatty acid salt and the matrix forming polymer (see below) may be The same granule or different I54767.doc •14· 201136582 granule form “We found that if the medium chain fatty acid and the therapeutic agent have different granule forms”, the bioavailability of the cargo compound is lower, ie if the medium chain fatty acid salt and the cargo The compound is dried after it is dissolved together in the hydrophilic portion', and the bioavailability is improved. In one embodiment, the mid-bond fatty acid salt, the matrix-forming polymer, and the cargo compound are all in the same particle form in the final powder. The medium chain fatty acid salts comprise those having a carbon chain length of from about 6 to about 14 carbon atoms. Examples of fatty acid salts are sodium hexanoate, sodium heptanoate, sodium octanoate (also known as s〇dium caprylate), sodium citrate, cannes, eleven g of sodium, Sodium decanoate, sodium tridecanoate and sodium tetradecanoate. In some embodiments, the medium chain fatty acid salt comprises a cation selected from the group consisting of potassium, lithium, ammonium, and other phosphonium cations, for example, the medium chain fatty acid salt is selected from lithium octoate or potassium octoate or arginine octanoate or the other A medium chain fatty acid salt. The inventors have previously determined that increasing the amount of medium chain fatty acid salt increases the bioavailability of the resulting formulation. In particular, increasing the amount of medium chain fatty acid salt (particularly sodium octanoate) to above about 1% to about i2% to about 5% increases the bioavailability of the therapeutic agent in the pharmaceutical compositions described herein. In general, the amount of the serotonin salt in the f' can be from 1% by weight to as much as about 5% by weight of the medicinal composition of the medicinal composition. For example, the medium-chain fatty acid salt may be present in an amount of about 1 Torr/ppm of the raw material pharmaceutical composition. 50 weights/twist or present is about 1 weight percent or about 1 weight. /. -15% by weight or in the presence of bismuth &, c ' θ is about 1 5 reset % -20% by weight, preferably about 11% by weight to 40% by weight, optimal 丨壬 η η / good, force 11 Weight ❶ /. -28% by weight, for example, about 12 by weight 0/〇-13% by weight, 13 parts by weight. / 14 tongue 曰 1 0 14 weight 1 〇 / 〇, 14% by weight -15 weight 0 / 〇, 154767.doc 201136582 15% by weight - 16% by weight, 16 weight. /. _17 weight 0 17% by weight - 18 weight 〇 / 〇, 18% by weight - 19% by weight, 19% by weight _2 ^ Dong set ❶ /. 20% by weight to 21% by weight, 21% by weight to 22% by weight. 22 miles. 23% by weight, 23% by weight to 24% by weight, 24% by weight to 25% by weight, 25 parts by weight ▲ and η/丄里夏/〇-26 weight 〇/〇, 26% by weight -27 weight/❶, or 27 weight %_28重^童/(). In other embodiments, the medium chain fat I salt can be present in an amount of at least about ii weight percent, at least about 12 weight percent, at least J 1 J weight percent, at least about 14 weight percent, at least about 15 weight. /◦, at least about 16' $/〇, at least about 17% by weight, about 18% by weight less, at least about 19% by weight, at least about 20% by weight, at least about 21% by weight. /. At least about 22% by weight, at least about η by weight. At least about 24 weights. /. At least about 25% by weight, at least about % by weight, and at least about 27 (four) at least about 28% by weight. In a particular embodiment, the medium chain fatty acid salt (sodium, potassium, lithium or ammonium salt or mixtures thereof) is present in an amount of from about 12% to about 21% by weight of the pharmaceutical composition of the starting material, preferably such as weight (four)% by weight, about U. weight. /. 17% by weight, 12% by weight to 16% by weight, 12% by weight, 13% by weight to 16% by weight, 13% by weight to 15% by weight, and μ by weight. /. -16 weight ❶ /. 14% by weight, 15% by weight, 15% by weight, 16% by weight, or most preferably 15% by weight or 16% by weight. In a particular embodiment, the medium chain fatty acid salt (having a carbon chain length of from about 6 to about 14 carbon atoms, especially 8, 9, or ί a carbon atoms) is present in an amount of about 12 weight percent and 21 weight percent of the starting pharmaceutical composition, It is preferably 11% by weight to 18% by weight, about 5% by weight to 17% by weight, and 12% by weight to 16% by weight. /◦, 12% by weight _15% by weight, 13% by weight, 16% by weight, 13% by weight to 15% by weight, 14% by weight to 16% by weight, 14% by weight to 15% by weight. /. , 15 weight. /. - 16% by weight, or preferably 15% by weight or 16 I54767.doc -16 - 201136582% by weight. In a particular embodiment, the medium chain fatty acid salt (e.g., octanoate, suberate, aconite) is present in an amount from about 12% to about 21% by weight of the bulk pharmaceutical composition, preferably 11 weight percent. . /. · 18% by weight, about 11% by weight to 17% by weight, 12% by weight "6% by weight, 12% by weight to 15% by weight, 13% by weight to 16% by weight, 13 parts by weight by weight, 14 parts by weight and 16 parts by weight 14% by weight - 15% by weight, 15% by weight - 16% by weight, or most preferably 15% by weight or 16% by weight. In certain embodiments, the medium chain fatty acid salt is present in the solid powder in an amount of about 30% to 90%, preferably 40% to 60%. One embodiment of the invention comprises a composition comprising a suspension consisting essentially of a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises A therapeutically effective amount of a therapeutic agent, at least one medium chain fatty acid salt and a matrix forming polymer ' and wherein the medium chain fatty acid salt is not a sodium salt. The salt may be a salt of another cation (eg, lithium, potassium or arginine); The arginine salt is preferred. The matrix forming polymer: In certain embodiments, the compositions of the present invention comprise a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of a therapeutic agent' At least one medium bond fatty acid salt A matrix-forming polymer. In certain embodiments, the composition comprises a suspension consisting essentially of a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of a therapeutic agent, at least one medium chain fatty acid salt And a polymer forming the matrix. The matrix forming polymer is preferably present in the composition in an amount of from about 0.5% by weight to about 1% by weight/((, the optimum amount is from about 1% by weight to about 10% by weight) The matrix-forming polymer comprises polyvinylpyrrolidone (PVP), a linear 154767.doc -17- 201136582 N-vinylpyrrolidone polymer (known to produce a "matrix-like" structure), and cross-linking PVP (cross-linked povidone); ionic polysaccharides (eg hyaluronic acid / hyaluronate and alginic acid / alginate); neutral polysaccharides (eg polyglucose, thiol cellulose and hydroxypropyl methyl) Cellulose (HPMC)); linear polyacrylic acid polymer (including polyacrylic acid polymer); crosslinked polyacrylic acid polymer (carbomer); aminopolysaccharide (eg chitosan); s polymer (thiomer); High molecular weight linear and bridged organic alcohols (eg linear polyvinyl alcohol). Common name for carbomer-based acrylic cross-linked polymers; carbomer can be a homopolymer of acrylic acid cross-linked with: Propyl ether isopentanol, or allyl ether of sulphur or allylic ether or allyl sucrose of propylene or other sugar or allyl pentaerythritol or polyalkenyl ether or divinyl glycol In a particular embodiment, the matrix forming polymer is polyvinylpyrrolidone (PVP), carbomer, polyvinyl alcohol (PVA), polyglucose, alginate, hyaluronic acid salt or polyacrylate. Or a combination thereof. In certain particular embodiments, the polymer forming the matrix is a polyvinyl group, such as each β-butanone (pVp), carbopol polymer or polyvinyl alcohol (PVA), or a combination thereof. In a particular embodiment, the polyvinylpyrrolidone is present in the composition from about 2% to about 20% by weight, preferably from about 3% to about 18% by weight. /. More preferably, the amount is from about 5% by weight to about 15% by weight, and the optimum amount is about 1% by weight. In certain particular embodiments, 'vinylpyrrolidine® is PVIM2 and/or has a molecular weight of about 3 and is present in the composition in an amount of about 2 weight. / 〇 to about 20% by weight, better 垚 垚 真 。. / Wide thousand and 1 main weight is about 5 weight. /〇 to about 5% by weight, the optimum amount is about 10% 〇/〇. I54767.doc -18- 201136582 In one aspect of the invention, the matrix forming polymer is a crosslinked acrylic acid ts (also known as carbomer). An example of a crosslinked polymer of carbopol polymer is acrylic acid. The crosslinked acrylic polymer has a viscosity of about 20 〇〇 8 〇〇〇〇 cP, preferably 4000-65000, and most preferably 25000-45000 cP; and the viscosity is measured in a cp form with a 0.5% solution at pH 7.5. In a particular aspect of the invention, the crosslinked acrylic polymer has a viscosity of from about 29,000 to about 4 Å, and is particularly carbopol 934p. The crosslinked acrylic acid ♦ & an amount may be present in the composition in an amount from about 5% by weight to about 6% by weight, preferably from about 5% by weight to about 4% by weight, for example, in an amount of about 丄% by weight or about 2% by weight or about 3% by weight » In another aspect of the invention, the polymer forming the matrix has a molecular weight of from 10,000 to 60,000 Da, preferably 2 Å to 3 Å Da Polyvinyl alcohol. In a particular embodiment, the polyvinyl alcohol is a polyvinyl alcohol having a molecular weight of about 27 〇〇〇〇 3 and is present in the composition in an amount of from about 1% by weight to about 6% by weight, preferably in an amount of From about 0.5% by weight to about 4% by weight, for example, is present in an amount of about 1% by weight, about 2% by weight. Or about 3% by weight. In certain embodiments, glucose and/or other sugars and/or mannitol may be used in place of the matrix forming polymer. Aleclon Stabilizer: The inventors have found that in order to reduce degradation of aliskiren, especially when stored at about 25 ° C, it is necessary to add stabilizers to the formulation, especially to the solid form. The stabilizers comprise a metal salt and/or an amino acid or a combination thereof. Examples of metal salts are magnesium salts, calcium salts and zinc salts or combinations thereof. Specific examples of metal salts are MgCl2, ZnC2, CaCi2, zinc acetate, magnesium acetate and calcium acetate. Examples of amino acids are glycine and arginine. In other examples 154767.doc •19·201136582, a hydrophobic medium can be selected as the stability medium, and you 丨& _ Λ ^ such as dicaprylin and other polar non-hydroxyl liquids. Hydrophilic moiety: In some embodiments, the above compounds (including therapeutic agents, medium chain fatty acid salts, and matrix-forming polymers (or substitutes) and, if desired, Alix stabilizer) are dissolved in an aqueous medium and then dried To prepare a powder. The drying process can be achieved, for example, by lyophilization or granulation, spray drying or by other means. The obtained powder is referred to as a "hydrophilic portion". In the hydrophilic portion, water is usually present in an amount of less than 6% and the water of the final bulk composition + comprises residual water from the hydrophilic portion. It can be as described in the Examples herein and by methods known in the art, for example, as described in Lyophilization: Introduction and Basic Principles, Thomas Jennings, published by Interpharm/CRC Press, Inc. (1999, 2002). The lyophilizate can be ground (eg, less than 150 microns) or obstructed in a drifting spider as needed. During industrial preparation, it is preferred to 'mill the lyophilizate prior to mixing the hydrophilic portion and the hydrophobic medium to achieve inter-batch reproducibility*. Granulation can be carried out as shown in the Examples herein and by methods known in the art, For example, as described in Granulation, Salman et al., Elsevier (2006) and Handbook of Pharmaceutical Granulation Technology, 2nd edition, edited by Dilip M. Parikh (2005). Various binders can be used in the granulation process as described in the two references above. Spray drying can be carried out by methods known in the art, for example, as by Patel et al., (2009) Indian Journal 〇f Science and Technology 2(10) 44-47 and Shabde, Vikram (2006) Ph.D. Thesis,Texas 154767.doc -20- 201136582

Tech University所述。 疏水性介質： 油：如上所述，在本文所述之本發明組合物中，治療劑及 中鏈脂肪酸鹽與疏水性介質緊密接觸或結合。舉例而言， 可使一或兩者塗覆、懸浮、浸潰於疏水性介質中或另外與 疏水性介質結合。適宜疏水性介質可含有（例如）脂肪族、 環狀或芳族分子。適宜脂肪族疏水性介質之實例包含但不 限於礦物油、脂肪酸甘油單酯、甘油二酸酯、甘油三酸 酯、醚、酯及其組合。適宜脂肪酸之實例係辛酸、癸酸及 十二烷酸、以及C7及C9脂肪酸及二元酸（例如癸二酸及辛 一 ^ )、及其竹生物。甘油三酸醋之實例包含但不限於長 鏈甘油三酸酯、中鏈甘油三酸酯及短鏈甘油三酸酯。舉例 而言，長鏈甘油三酸酯可為蓖麻油或撖欖油，且短鏈甘油 三酸酯可為三丁酸甘油酯，且令鏈甘油三酸酯可為三辛酸 甘油酯或椰子油。甘油單酯可視為表面活性劑且闡述於下 文中。實例性酯包含異戊酸乙酯及乙酸丁酯。適宜環狀疏 X J·生"質之貫例包含但不限於類萜、膽固醇、膽固醇衍生 物（例如，硫酸膽固醇）、及脂肪酸之膽固醇酯。芳族疏水 性介質之非限制性實例包含苯甲酸苄基酯。 在本文所述之組合物之一些實施例中，期望疏水性介質 包3複數個疏水性分+。在纟文所述之組合物之具體實施 疏水丨生介質亦包含一或多種表面活性劑見下 文）。 表面活化劑（表面活性劑）：本文所述之本發明址合物可進 154767.doc -21· 201136582 一步包含表面活化劑。舉例而言，表面活化劑可為上述疏 水性介質之組份，及/或表面活化劑可為上述固體形式（例 如包含治療劑之固體形式或顆粒）之組份。 適宜表面活化劑包含離子型及非離子型表面活性劑。離 子型表面活性劑之實例係卵磷脂（磷酯醯膽鹼）、膽鹽（例如 牛磺膽酸鈉、脫氧膽酸鈉、甘膽酸鈉、鵝去氧膽酸鈉、膽 酸鈉、石膽酸鈉）及洗滌劑。非離子型表面活性劑之實例 包3甘油單酯、克瑞莫福（crem〇ph〇re)、聚乙二醇脂肪醇 喊、山梨醇針脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯、色 魯托（Solutol) HS1 5、泊洛沙姆（p〇i〇xamer)、烧基糖（例如 辛基糖苷、四癸基麥芽糖苷）或其組合。甘油單酯之實例 係單辛酸甘油酯（glyceryl m〇n〇caprylate)(亦稱作單辛酸甘 油酯（glyceryl monooctanoate))、單癸酸甘油酯、單月桂酸 甘油8θ、單肉豆宼酸甘油g旨、單硬脂酸甘油酿、單掠摘酸 甘油酯及單油酸甘油酯。山梨醇酐脂肪酸酯之實例包含山 梨醇酐單月桂酸酯、山梨醇酐單油酸酯、及山梨醇酐單棕 櫚酸酯（Span 40)或其組合。聚氧乙烯山梨醇酐脂肪酸酯之 特疋實例包含聚氧乙稀山梨醇肝單油酸g旨（Tween 80)、聚 氧乙烯山梨醇酐單硬脂酸酯、聚氧乙烯山梨醇酐單棕櫚酸 酯或其組合。所用之甘油單酯的商業製劑亦含有不同量之 甘油二酸醋及甘油三酸醋。 包含表面活化劑之本文所述之組合物通常總共包含小於 約12重量％之表面活化劑（例如，小於約1 〇重量％、小於約 8重量％、小於約6重量％、小於約4重量％、小於約2重量 154767.doc •22· 201136582 %、或小於約i重量％)。在本發明之特定實施例中，所有 表面活性劑之總量佔組合物之約6_7重量％。在某些實施例 中，表面活性劑包含約2重量％2Tween 8〇及約4·5重量％ 之單辛酸甘油S旨。在特定實施例中，表面活性劑包含存於 疏水性（親脂性）介質中之卵磷脂及存於親水性（固體）部分 中之膽鹽（特定而言係牛續膽酸納）。 製備醫藥組合物之方法及所製得之組合物：本發明亦包含 製備本文所述之組合物之方法。因此，本發明之一實施例 係製備醫藥組合物之方法，其包括：製備包括以下之水溶 性組合物：治療有效量之至少一種治療劑（腎素抑制劑/阿 利克备）、中鏈脂肪酸鹽及形成基質之聚合物或替代物（如 上所述）’乾燥該水溶性組合物以獲得固體粉末，且將該 固體粉末懸浮於疏水性介質中以製得含有固體形式之治療 劑、中鏈脂肪酸鹽及形成基質之聚合物的懸浮液，由此製 得醫藥組合物，其中該醫藥組合物通常含有約1 〇重量j 5 重量％之中鏈脂肪酸鹽》參見圖1。 一實施例係製備醫藥組合物之方法，其包括提供治療有 效量之至少一種治療劑（腎素抑制劑/阿利克崙）之固體粉 末、包括中鏈脂肪酸鹽之固體粉末及包括形成基質之聚合 物之固體粉末，且將該等固體粉末懸浮於疏水性介質中以 製得含有固體形式之治療劑及中鏈脂肪酸鹽的懸浮液，由 此製得醫藥組合物，其中該醫藥組合物含有10重量❶/。或更 多之中鏈脂肪酸鹽。 在本文所述之方法及組合物之一實施例中，水溶性組合 154767.doc -23- 201136582 物係水溶液。在某些實施例中，II由凍乾或藉由粒化或藉 由喷霧乾燥或藉由其他方式來乾燥水溶性組合物。在粒= 過程中，可在乾燥之前向水溶性組合物中添加黏合劑。在 某些實施财，乾燥步驟可去除足量水從而使醫藥組合物 中之水含量低於約6重量％、約5重量％、約4重量。、約3 重量％、約2重量％或約丨重量％。在本文所述之方法及組 合物之某些實施例中，乾燥步驟可去除一定量之水從而使 固體粉末中之水含量低於6重量％、5重量％、4重量％或3 重量。/〇或較佳低於2重量％。水含量通常較低且水在凍乾期 間可吸收至固相中，亦即，水可由分子間鍵保留。在某些 實施例中，水溶性組合物另外包括穩定劑，特定而言係阿 利克崙穩定劑。 在一實施例中，提供疏水性介質基本上由三辛酸甘油酯 組成之調配物；在基本調配物之另一實施例中，親水性部 分基本上由阿利克崙、PVP-12及辛酸鈉組成。 在一實施例中，提供特定調配物，其中疏水性（親脂性） "質基本上由二辛酸甘油酯及表面活性劑（特定而言係卵 磷脂）組成，且親水性部分基本上由阿利克崙、pvp_12及 辛酸納及視需要膽鹽組成。在一實施例中，提供另一特定 調配物，其中疏水性介質包括三辛酸甘油酯及表面活性劑 (特定而言係卵磷脂），且親水性部分基本上由阿利克崙、 PVP-12、辛酸鈉、視需要膽鹽（特定而言係牛續膽酸鈉）及 視需要阿利克崙穩定劑（例如金屬鹽或胺基酸或其組合）組 成0 154767.doc -24· 201136582 本文所述之許多組合物包括含有疏水性介質及固體形式 之混合物的懸浮液，其中該固體形式包括治療有效量之阿 利克崙、形成基質之聚合物及至少一種中鏈脂肪酸鹽，且 其中該中鏈脂肪酸鹽在組合物中之存在量為10重量％或更 兩。固體形式可為顆粒（例如，基本上由顆粒組成、或由 顆粒組成）。顆粒可藉由凍乾或藉由粒化或藉由噴霧乾燥 或藉由其他方式製得。 在一特疋貫施例中，調配物基本上由包括疏水性介質及 固體形式之混合物的懸浮液組成’其中該固體形式包括約 1-20%較佳約5-1〇。/。之阿利克崙、約1〇_2〇%較佳15%之中鏈 脂肪酸鹽（較佳係辛酸鈉）、約5-1 〇%較佳丨〇%之pvp_丨2、 約0.1-2.0%較佳〇.5%之膽鹽（較佳係牛磺膽酸鈉）及視需要 阿利克崙穩定劑；且其中該疏水性介質包括約2〇 8〇%、較 佳50-70%之甘油三酸酯（較佳三辛酸甘油酯或三丁酸甘油 酯或蓖麻油或其組合）、約3-10。/。表面活性劑（較佳約6%， 較佳係印磷脂）。阿利克崙穩定劑可為金屬鹽或胺基酸或 其組合。金屬鹽之實例係鎂鹽、鈣鹽及鋅鹽或其組合，且 。金屬鹽之特定實例係 乙酸鎂及乙酸鈣。胺基 其存在量為約1 -1 〇%、較佳約2_6%。 MgCl2、ZnCl2、CaCl2、乙酸鋅、乙 酸之實例係甘胺酸、天門冬胺酸及精胺酸且其存在量為約 1-10%、較佳約 3-7%。 另一特定實施例係包括懸浮液之醫藥組合物，該懸浮液 包括疏水性介質及固體形式之说.厶舲，* U- _____ ..According to Tech University. Hydrophobic Medium: Oil: As described above, in the compositions of the invention described herein, the therapeutic agent and the medium chain fatty acid salt are in intimate contact or combined with a hydrophobic medium. For example, one or both can be coated, suspended, impregnated in a hydrophobic medium or otherwise combined with a hydrophobic medium. Suitable hydrophobic media can contain, for example, aliphatic, cyclic or aromatic molecules. Examples of suitable aliphatic hydrophobic media include, but are not limited to, mineral oils, fatty acid monoglycerides, diglycerides, triglycerides, ethers, esters, and combinations thereof. Examples of suitable fatty acids are caprylic acid, capric acid and dodecanoic acid, as well as C7 and C9 fatty acids and dibasic acids (e.g., azelaic acid and octane), and their bamboo organisms. Examples of triglycerides include, but are not limited to, long chain triglycerides, medium chain triglycerides, and short chain triglycerides. For example, the long-chain triglyceride may be castor oil or eucalyptus oil, and the short-chain triglyceride may be tributyrin, and the chain triglyceride may be tricaprylin or coconut oil. . Monoglycerides can be considered as surfactants and are described below. Exemplary esters include ethyl isovalerate and butyl acetate. Suitable examples of the ring-shaped X J·sheng "quality include, but are not limited to, steroids, cholesterol, cholesterol derivatives (e.g., cholesterol sulfate), and cholesterol esters of fatty acids. A non-limiting example of an aromatic hydrophobic medium comprises benzyl benzoate. In some embodiments of the compositions described herein, it is desirable for the hydrophobic medium package 3 to have a plurality of hydrophobic scores +. DETAILED DESCRIPTION OF THE COMPOSITIONS DESCRIBED AS WELL AS A hydrophobic hydrophobic medium also contains one or more surfactants (see below). Surfactant (Surfactant): The present invention described herein can be incorporated into a 154767.doc -21·201136582 one-step surfactant. For example, the surfactant can be a component of the above hydrophobic medium, and/or the surfactant can be a component of the above solid form (e.g., a solid form or granule comprising a therapeutic agent). Suitable surfactants include both ionic and nonionic surfactants. Examples of ionic surfactants are lecithin (phosphoric acid choline), bile salts (such as sodium taurocholate, sodium deoxycholate, sodium glycocholate, sodium hyodeoxycholate, sodium cholate, stone Sodium cholate) and detergent. Examples of nonionic surfactants include 3 monoglycerides, cremoxifen, polyethylene glycol fatty alcohol, sorbitol needle fatty acid esters, polyoxyethylene sorbitan fatty acid esters , Solutol HS1 5, poloxamer (p〇i〇xamer), burnt sugar (eg, octyl glycoside, tetradecylmaltoside), or a combination thereof. Examples of monoglycerides are glyceryl m〇n〇caprylate (also known as glyceryl monooctanoate), glyceryl monocaprate, glycerol monolaurate 8θ, glycerol monomyristate g, glycerin monostearate, single grazing glycerides and glycerol monooleate. Examples of the sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate, and sorbitan monopalmitate (Span 40) or a combination thereof. Examples of polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleic acid g (Tween 80), polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan Palmitate or a combination thereof. Commercial formulations of the monoglycerides used also contain varying amounts of diglyceride and triacetin. The compositions described herein comprising a surfactant generally comprise less than about 12% by weight total surfactant (eg, less than about 1% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight). Less than about 2 weights 154767.doc • 22·201136582%, or less than about i% by weight). In a particular embodiment of the invention, the total amount of all surfactants is from about 7% to about 7% by weight of the composition. In certain embodiments, the surfactant comprises about 2% by weight of 2 Tween 8 Å and about 4.6 % by weight of monocaprylic glycerol. In a particular embodiment, the surfactant comprises lecithin present in a hydrophobic (lipophilic) medium and a bile salt (specifically, bovine sodium thionate) present in a hydrophilic (solid) portion. Methods of Making Pharmaceutical Compositions and Compositions Made Thereof: The present invention also encompasses methods of preparing the compositions described herein. Accordingly, an embodiment of the invention is a method of preparing a pharmaceutical composition comprising: preparing a water soluble composition comprising: a therapeutically effective amount of at least one therapeutic agent (renin inhibitor/Alix), medium chain fatty acid a salt and a matrix-forming polymer or substitute (as described above) 'dry the water-soluble composition to obtain a solid powder, and suspend the solid powder in a hydrophobic medium to prepare a therapeutic agent containing a solid form, a medium chain A suspension of a fatty acid salt and a matrix-forming polymer, whereby a pharmaceutical composition is prepared, wherein the pharmaceutical composition typically contains about 1 〇 by weight j 5% by weight of the medium chain fatty acid salt" see Figure 1. An embodiment is a method of preparing a pharmaceutical composition comprising providing a solid powder of a therapeutically effective amount of at least one therapeutic agent (renin inhibitor/aliskiren), a solid powder comprising a medium chain fatty acid salt, and a polymerization comprising a matrix forming a solid powder of the material, and the solid powder is suspended in a hydrophobic medium to prepare a suspension containing the therapeutic agent in a solid form and a medium chain fatty acid salt, thereby preparing a pharmaceutical composition, wherein the pharmaceutical composition contains 10 Weight ❶ /. Or more mid-chain fatty acid salts. In one embodiment of the methods and compositions described herein, the water soluble combination 154767.doc -23- 201136582 is an aqueous solution. In certain embodiments, II is dried by lyophilization or by granulation or by spray drying or by other means to dry the water soluble composition. In the particle = process, a binder can be added to the water soluble composition prior to drying. In some implementations, the drying step removes sufficient water to cause the water content of the pharmaceutical composition to be less than about 6% by weight, about 5% by weight, and about 4% by weight. , about 3 wt%, about 2 wt% or about 丨 wt%. In certain embodiments of the methods and compositions described herein, the drying step removes a quantity of water such that the water content of the solid powder is less than 6%, 5%, 4%, or 3 weight. /〇 or preferably less than 2% by weight. The water content is generally low and the water can be absorbed into the solid phase during lyophilization, i.e., the water can be retained by intermolecular bonds. In certain embodiments, the water soluble composition additionally includes a stabilizer, specifically an aliskiren stabilizer. In one embodiment, a formulation is provided in which the hydrophobic medium consists essentially of tricaprylin; in another embodiment of the basic formulation, the hydrophilic portion consists essentially of aliskiren, PVP-12, and sodium octanoate. . In one embodiment, a specific formulation is provided wherein the hydrophobic (lipophilic) " texture consists essentially of dicaprylin and a surfactant (specifically lecithin) and the hydrophilic portion is substantially Likron, pvp_12 and sodium octanoate and optionally bile salts. In one embodiment, another specific formulation is provided wherein the hydrophobic medium comprises tricaprylin and a surfactant (particularly lecithin) and the hydrophilic portion consists essentially of aliskiren, PVP-12, Sodium caprylate, optionally as a bile salt (specifically sodium borate) and as needed aliskiren stabilizer (eg metal salt or amino acid or a combination thereof) 0 154767.doc -24· 201136582 Many of the compositions include a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of aliskiren, a matrix-forming polymer, and at least one medium chain fatty acid salt, and wherein the medium chain fatty acid The salt is present in the composition in an amount of 10% by weight or more. The solid form can be a particle (e.g., consisting essentially of, or consisting of, particles). The granules can be prepared by lyophilization or by granulation or by spray drying or by other means. In a particular embodiment, the formulation consists essentially of a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises from about 1% to about 20%, preferably from about 5% to about 5%. /. Aleclon, about 1〇2〇%, preferably 15% mid-chain fatty acid salt (preferably sodium octanoate), about 5-1 〇%, preferably p% of pvp_丨2, about 0.1-2.0 % preferably 5% of the bile salt (preferably sodium taurocholate) and optionally aliskiren stabilizer; and wherein the hydrophobic medium comprises about 2〇8%, preferably 50-70% Triglyceride (preferably tricaprylin or tributyrin or castor oil or a combination thereof), about 3-10. /. A surfactant (preferably about 6%, preferably a phospholipid). The aliskiren stabilizer can be a metal salt or an amino acid or a combination thereof. Examples of metal salts are magnesium salts, calcium salts and zinc salts or combinations thereof, and. Specific examples of metal salts are magnesium acetate and calcium acetate. The amine group is present in an amount of from about 1% to about 1%, preferably from about 2% to about 6%. Examples of MgCl2, ZnCl2, CaCl2, zinc acetate, and acetic acid are glycine, aspartic acid, and arginine and are present in an amount of about 1-10%, preferably about 3-7%. Another particular embodiment is a pharmaceutical composition comprising a suspension comprising a hydrophobic medium and a solid form. 厶舲, * U- _____ ..

154767.doc -25- 201136582 基質之聚合物、及視需要表面活性劑及視需要阿利克崙穩 定劑。疏水性介質含有至少一種表面活性劑（較佳係卵磷 月曰），較佳地表面活性劑之存在量為約3重量％_9重量％、 較佳約6重量％。中鏈脂肪酸鹽係辛酸鈉，形成基質之聚 合物係PVP-12，且表面活性劑係膽鹽（較佳係牛磺膽酸 鈉）。阿利克崙穩定劑係胺基酸或金屬鹽或其組合。辛酸 鈉之存在量為10重量。/。_20重量。/()、較佳約i 5重量％，且 PVP之存在量為約5_丨5重量％、較佳約丨〇重量％。牛磺膽酸 鈉之存在量為0.1重量％_2重量％、較佳約〇 5重量％，且阿 和克奋之存在量為1重量％_2〇重量％、較佳約1 〇重量％、 或約1〇重量％〇在-些實施例中，醫藥組合物另外包括第 二治療劑或第三治療劑。 在特定實施例中，阿利克崙之存在量小於33%、或小於 25/。或小於1 〇%、或小於1 %或小於〇. 1 %。固體形式可為 顆粒（例如，基本上由顆粒組成、或由顆粒組成）。顆粒可 藉由凍乾或藉由粒化或藉由喷霧乾燥製得。在一特定實施 例中，固體形式可為顆粒且可藉由凍乾或藉由粒化或喷霧 乾燥製得》 在所有上述調配物中，所述百分比係重量/重量，且固 體形式可為顆粒(例如，基本上由顆粒組成、或由顆粒組 成）顆粒可藉由凍乾或藉由粒化或藉由喷霧乾燥或藉由 其他方式製得。 投與至腸中後，治療劑可免受GI環境之損害，此乃因調 配物係以油為主。因此，可在腸中產生單獨之局部環境， 154767.doc -26· 201136582 其中治療劑含於油滴中，此會賦予活體内穩定性。 本發明之特定實施例包括含有醫藥組合物之口服劑型’ 特定而言係經腸溶包覆之口服劑型。本發明之其他實施例 包括含有本發明組合物之膠囊或錠劑，且在各個實施例 中，膠囊係硬質凝膠或軟質凝膠膠囊，且通常膠囊經腸溶 包覆。本發明其他實施例包括含有醫藥組合物之直腸劑 型，特定而言係栓n口腔劑型。亦設計包括說明書及 劑型之套組。 >。療劑《中鏈脂肪酸鹽或形成基質之聚合#、或表面活 性劑（例如膽鹽）或治療劑及其他組份（例如阿利克备穩定 劑^之任—組合可在混合物溶液t製得（例如，形成水溶液 或此σ物）’其可一起康乾且然後懸浮於疏水性介質中。 在重構固體材料期間’亦可視需要滚乾或添加組合物之笪 2組份U擇為，可以乾燥形式提供成份並在疏水性 "質中混合，由此形成懸浮液。 、：些實施例中，將治療劑溶於混合物(例如，包含一 :夕：額外組份，例如_鏈脂肪酸鹽、形成基質之聚合 :、穩定劑及/或表面活化劑(表面活性劑))中，且去除容 ^提供所得固體粉末（固體形式）並料於疏水性介質 或形中，可使治療劑及/或中鏈脂肪酸鹽及/ 疏水性介質如形成粒化顆粒’然後使該粒化顆粒與 介質進行塗幻:懸浮於疏水性介質中或使用疏水性 含「膜〜卞丨 般而言’本文所述之組合物實質上不 膜-化劑」’例如中鏈醇。 I54767.doc -27- 201136582 膜流化劑」定義為碳鏈長度為4至15個碳原子（例如， 匕35至15 5至12、6、7、8、9、10、或11個碳原子）之 中鍵醇。舉例而言，膜流化劑可為直鏈(例如，飽和或不 飽和）、具支鏈（例如，飽和或不飽和）、環狀（例如，飽和 或不飽和）或芳族醇。適宜直鏈醇之實例包含但不限於丁 醇、戊醇、己醇、庚醇、辛醇、壬醇、癸醇、十—醇、十 二醇'十三醇、十四醇、及十五醇。具支_之實例包含 但不限於香葉醇、法尼醇（farnesQl)、香茅醇、雄别董醇。 環狀醇之實例包含但不限於薄荷醇、⑪品醇 '桃金娘稀醇 及紫蘇子醇。適宜芳族醇之實例包含但不限於节基醇、4_ 故基桂皮酸、麝香草盼、苯乙烯二醇及_化合物。紛類 化合物之實例包含但不限於笨酚、間曱酚及間氣曱酚。 若期望，醫藥組合物亦可含有少量之非毒性輔助物質 (例如PH緩衝劑）、及其他物質（例如，乙酸鈉及三乙醇胺 油酸酯）。 在-些實施例中，製備醫藥組合物之方法包括如下過 程：製備包括治療有效量之至少一種治療劑(腎素抑制劑/ 阿利克备）、中鏈脂肪酸鹽及形成基質之聚合物之水溶性 組合物，乾燥該水溶性組合物以獲得固體粉末，且將=固 體粉末溶於基本上由辛酸組成之溶液中，由此製得醫藥組 合物’該醫藥組合物係具有所示固體濃度之懸浮液。獲得 固體濃度較低（低於飽和限值）之溶液。在一些實施例中， 固體形式可為顆粒(例 >，基本上由顆粒組成、或：顆粒 組成)。在一些實施例中，顆粒可藉由;東乾或藉由粒化製 I54767.doc -28- 201136582 得。在此方法之一些實施例中，辛酸在組合物中之存在量 為約50%至約90%或存在量為約55至約85%、較佳約58%。 在此方法之一些實施例中，脂肪酸鹽係辛酸鈉。在此方法 之其他實施例中，中鏈脂肪酸鹽在組合物中之存在量為約 11 %至約40重量％或存在量為約11%至約28重量％或存在量 為約15重量％。形成基質之聚合物可呈現為如上所述之形 式。組合物可另外包含如上所述之表面活性劑。該等方法 之醫藥產物係本發明之其他實施例。 膠囊及錠劑：較佳醫藥組合物係口服劑型或栓劑。實例性 劑型包含明膠或素食膠囊，例如經腸溶包覆且含有原料藥 產物之澱粉羥丙基-甲基纖維素（rHPMC」）膠囊。可用於 囊封本發明組合物之膠囊在業内已眾所周知且闡述於（例 如）Pharmaceutical Capsuies , p〇dczech 及 J〇nes 编輯，154767.doc -25- 201136582 Matrix polymer, and optionally surfactants and, if desired, aliskiren stabilizer. The hydrophobic medium contains at least one surfactant (preferably lecithin), preferably the surfactant is present in an amount of from about 3% by weight to about 9% by weight, preferably about 6% by weight. The medium chain fatty acid salt is sodium octanoate, the matrix forming polymer is PVP-12, and the surfactant is a bile salt (preferably sodium taurocholate). The aliskiren stabilizer is an amino acid or a metal salt or a combination thereof. Sodium octanoate is present in an amount of 10% by weight. /. _20 weight. / (), preferably about 5% by weight, and PVP is present in an amount of about 5 丨 5 wt%, preferably about 丨〇 wt%. The sodium taurocholate is present in an amount of 0.1% by weight to 2% by weight, preferably about 5% by weight, and the amount of the arsenic is 1% by weight, 2% by weight, preferably about 1% by weight, or About 1% by weight In some embodiments, the pharmaceutical composition additionally includes a second therapeutic agent or a third therapeutic agent. In a particular embodiment, aliskiren is present in an amount less than 33%, or less than 25/. Or less than 1 〇%, or less than 1% or less than 〇. 1%. The solid form can be a particle (e.g., consisting essentially of, or consisting of, particles). The granules can be obtained by lyophilization or by granulation or by spray drying. In a particular embodiment, the solid form can be a granule and can be prepared by lyophilization or by granulation or spray drying. In all of the above formulations, the percentage is weight/weight and the solid form can be Particles (e.g., consisting essentially of or consisting of particles) may be prepared by lyophilization or by granulation or by spray drying or by other means. After administration to the intestine, the therapeutic agent is protected from the GI environment, since the formulation is predominantly oil. Thus, a separate local environment can be created in the intestine, 154767.doc -26· 201136582 wherein the therapeutic agent is contained in the oil droplets, which confers stability in vivo. Particular embodiments of the invention include oral dosage forms containing a pharmaceutical composition, particularly an enteric coated oral dosage form. Other embodiments of the invention include capsules or lozenges containing the compositions of the invention, and in various embodiments, the capsules are hard gel or soft gel capsules, and typically the capsules are enteric coated. Other embodiments of the invention include rectal dosage forms containing a pharmaceutical composition, particularly a suppository oral dosage form. It also includes kits including instructions and dosage forms. >. The combination of the medium-chain fatty acid salt or the matrix-forming polymerization #, or the surfactant (such as bile salt) or the therapeutic agent and other components (for example, the Alec stabilizer) can be prepared in the mixture solution t ( For example, an aqueous solution or this sigma is formed, which can be dried together and then suspended in a hydrophobic medium. During the reconstitution of the solid material, it can also be selected as a component of the composition to be dried or added. The dry form provides the ingredients and is mixed in a hydrophobic "yellow, thereby forming a suspension. In some embodiments, the therapeutic agent is dissolved in the mixture (eg, comprising one: eve: additional components, such as _ chain fatty acid salts) Forming a polymerization of a matrix: a stabilizer and/or a surfactant (surfactant), and removing the resulting solid powder (solid form) and feeding it in a hydrophobic medium or form to provide a therapeutic agent and / or medium-chain fatty acid salts and / or hydrophobic media such as the formation of granulated particles 'and then the granulated particles and the medium are painted: suspended in a hydrophobic medium or using a hydrophobic "film ~ 卞丨 而言 '" Group The compound is substantially free of a membrane-forming agent such as a medium chain alcohol. I54767.doc -27- 201136582 Membrane fluidizing agent is defined as having a carbon chain length of 4 to 15 carbon atoms (for example, 匕35 to 15 5 to 12) a bond alcohol among 6, 6, 8, 9, 10, or 11 carbon atoms. For example, the film fluidizer can be linear (eg, saturated or unsaturated), branched (eg, saturated) Or unsaturated), cyclic (eg, saturated or unsaturated) or aromatic alcohol. Examples of suitable linear alcohols include, but are not limited to, butanol, pentanol, hexanol, heptanol, octanol, decyl alcohol, decyl alcohol , deca-alcohol, dodecanol tridecanol, tetradecanol, and pentadecyl alcohol. Examples of support include, but are not limited to, geraniol, farnesol (farnesQl), citronellol, and male alcohol Examples of cyclic alcohols include, but are not limited to, menthol, 11-sterol 'myramine dilute alcohol, and perillyl alcohol. Examples of suitable aromatic alcohols include, but are not limited to, benzyl alcohol, 4-base cinnamic acid, thyme expectant , styrene diols and _ compounds. Examples of singular compounds include, but are not limited to, phenols, m-nonyl phenols and meta-phenols. If desired, pharmaceutical compositions may also contain a small amount of a non-toxic auxiliary substance (such as a pH buffer), and other substances (for example, sodium acetate and triethanolamine oleate). In some embodiments, a method of preparing a pharmaceutical composition includes the following process: preparation includes therapeutically effective a water-soluble composition of at least one therapeutic agent (renin inhibitor/Alix), a medium chain fatty acid salt, and a matrix-forming polymer, the water-soluble composition is dried to obtain a solid powder, and the solid powder is dissolved In a solution consisting essentially of octanoic acid, a pharmaceutical composition is prepared from which the pharmaceutical composition has a suspension of the indicated solid concentration. A solution having a lower solids concentration (below the saturation limit) is obtained. In one embodiment, the solid form can be a particle (example > consisting essentially of particles, or: particles). In some embodiments, the granules can be obtained by lyophilization or by granulation, I54767.doc -28-201136582. In some embodiments of this method, the octanoic acid is present in the composition from about 50% to about 90% or from about 55 to about 85%, preferably about 58%. In some embodiments of this method, the fatty acid salt is sodium octanoate. In other embodiments of this method, the medium chain fatty acid salt is present in the composition from about 11% to about 40% by weight or from about 11% to about 28% by weight or from about 15% by weight. The polymer forming the matrix can be in the form as described above. The composition may additionally comprise a surfactant as described above. The pharmaceutical products of such methods are other embodiments of the invention. Capsules and Lozenges: Preferred pharmaceutical compositions are oral dosage forms or suppositories. Exemplary dosage forms comprise gelatin or vegetarian capsules, such as enteric coated starch hydroxypropyl-methylcellulose (rHPMC) capsules containing the drug product. Capsules useful for encapsulating compositions of the present invention are well known in the art and are described, for example, in Pharmaceutical Capsuies, p〇dczech and J〇nes.

Pharmaceutical Press (2004) ^ in Hard gelatin capsules today - and tomorr〇w，第 2版’ steggeman編輯，capsugeiPharmaceutical Press (2004) ^ in Hard gelatin capsules today - and tomorr〇w, 2nd edition ’ steggeman editor, capsugei

Library公開（2002)中。亦設計包括固體形式之原料藥產 物且使用業内已知之適宜賦形劑製錠的錠劑；錠劑應經 腸溶包覆。本發明之口服劑型包括適用於製備本發明之口 服劑型的添加劑或賦形劑，且可如本文所述製得。 本發明之其他實施例包括含有本發明組合物之膠囊或錠 劑且在各個實施例中，膠囊係硬質凝膠或軟質凝膠膠 囊’且膠囊或㈣通常經腸溶包覆。腸溶塗層可抵抗胃 酸’由此使完整膠囊或錠劑經過胃並到達腸中，該膠囊或 旋劑溶於腸中之酸性較小區域，由此釋放出治療劑。腸溶 154767.doc -29- 201136582 塗層之實例係Acryl-EZE™(C型甲基丙烯酸共聚物）、 Opadry™腸溶系列91(聚乙酸乙烯鄰苯二曱酸酯）、 Sureteric™ (亦係聚乙酸乙烯鄰苯二甲酸酯）、 溶系列94(甲基丙烯酸-曱基丙烯酸曱酯之1:1共聚物）、 Opadry™腸溶系列95(曱基丙烯酸-甲基丙烯酸甲酯之1:2共 聚物）-皆來自Colorcon ; Eudragit™系列（聚曱基丙烯酸 酉旨），來自 Evonik Rohm Gmbh ; Aquacoat CPD(乙酸鄰苯二 曱酸纖維素），來自 FMC Biopolymer，USA ; Eastman C-A-P 纖維素酯（乙酸鄰苯二甲酸纖維素），來自Eastman ; HPMCP-50(鄰苯二甲酸羥丙基曱基纖維素）及HPMCAS Shin-Etsu AQOAT(乙酸琥珀酸羥丙基曱基纖維素）-皆來自 Shin Etsu，曰本；及CMEC(羧曱基纖維素），來自 Freund，日本。 膠囊可經與錠劑相同之材料進行塗覆（有時需要用於更 好地黏著腸溶聚合物之子塗層或黏合劑）。亦設計包括說 明書及劑型之套組。發現經囊封阿利克崙之穩定性與非囊 封原料藥產物之穩定性相似。 額外調配物：本發明組合物可使用業内已知之額外方法進 行調配，如（例如）下列出版物中所述：Pharmaceutical Dosage Forms，第 1-3卷，Lieberman，Lachman及 Schwartz 編輯，Marcel Dekker 公司，紐約公開（1989) ; Water-insoluble Drug Formulation ， 第 2版， Liu編輯， CRC Press, Taylor and Francis Group公開（2008) ; Therapeutic Peptides and Proteins: Formulation, Processing and Delivery 154767.doc -30- 201136582Library is published (2002). Tablets comprising a solid form of the drug substance product and ingots prepared using suitable excipients known in the art are also contemplated; the tablet should be enteric coated. Oral dosage forms of the invention include additives or excipients suitable for use in preparing the oral dosage forms of the invention, and can be prepared as described herein. Other embodiments of the invention include capsules or lozenges containing the compositions of the invention and in various embodiments, the capsules are hard gel or soft gel capsules' and the capsules or (4) are typically enteric coated. The enteric coating is resistant to gastric acid' whereby a complete capsule or lozenge is passed through the stomach and into the intestine, which is dissolved in a less acidic area of the intestine, thereby releasing the therapeutic agent. Enteric 154767.doc -29- 201136582 Examples of coatings are Acryl-EZETM (C-type methacrylic acid copolymer), OpadryTM enteric series 91 (polyvinyl acetate phthalate), SuretericTM (also Polyvinyl acetate phthalate), solvent series 94 (1:1 copolymer of methacrylic acid-decyl methacrylate), OpadryTM enteric series 95 (methacrylic acid-methyl methacrylate) 1:2 copolymer) - all from Colorcon; EudragitTM series (polyacrylic acid) from Evonik Rohm Gmbh; Aquacoat CPD (cellulose phthalate acetate) from FMC Biopolymer, USA; Eastman CAP fiber Alkyl ester (cellulose acetate phthalate) from Eastman; HPMCP-50 (hydroxypropyl phthalocyanine phthalate) and HPMCAS Shin-Etsu AQOAT (hydroxypropyl thioglycolate acetate) - All from Shin Etsu, Sakamoto; and CMEC (carboxylated cellulose) from Freund, Japan. The capsules can be coated with the same material as the tablet (sometimes required for a sub-coat or adhesive to better adhere to the enteric polymer). It also includes kits including instructions and dosage forms. The stability of the encapsulated aliskiren was found to be similar to that of the non-encapsulated drug product. Additional Formulations: The compositions of the present invention can be formulated using additional methods known in the art, as described, for example, in the following publications: Pharmaceutical Dosage Forms, Volumes 1-3, edited by Lieberman, Lachman and Schwartz, Marcel Dekker , New York Public (1989); Water-insoluble Drug Formulation, 2nd Edition, edited by Liu, CRC Press, Taylor and Francis Group published (2008); Therapeutic Peptides and Proteins: Formulation, Processing and Delivery 154767.doc -30- 201136582

Systems，第 2 版，Ajay K. Banga(作者），CRC Press, Taylor and Francis Group公開（2006) ; Protein Formulation and Delivery，第 2 版，McNally 及 Hasted 編輯，Informa Healthcare USA 公司公開（2008);及 Advanced Drug Formulation to Optimize Therapeutic Outcomes，Williams 等人編輯，Informa Healthcare USA公開（2008)。 本發明組合物可使用微粒技術進行調配，如（例如）Systems, 2nd edition, Ajay K. Banga (author), CRC Press, Taylor and Francis Group published (2006); Protein Formulation and Delivery, 2nd edition, edited by McNally and Hasted, Informa Healthcare USA, published (2008); Advanced Drug Formulation to Optimize Therapeutic Outcomes, edited by Williams et al., published by Informa Healthcare USA (2008). The compositions of the invention can be formulated using microparticle technology, such as, for example,

Microparticulate Oral Drug Delivery，Gerbre-Selassie 編 輯 ’ Marcel Dekker公司公開（1994)及Dey等人，]yiultiparticulate Drug Delivery Systems for Controlled Release, Tropical Journal of Pharmaceutical Research，2008 年 9 月；7(3): 1067-1075 中所述》 治療方法：本發明之阿利克崙調配物可用於治療高血壓、 伴有糖尿病之高血壓、充血性心臟衰竭、心絞痛、心肌梗 塞、動脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎 機能不全、白蛋白尿、周邊血管疾病、左心室肥大、認知 功能障礙、中風、頭疼及慢性心臟衰竭。 本發明一態樣係治療高血壓、伴有糖尿病之高血壓、充 血性心臟衰竭、心絞痛、心肌梗塞、動脈粥樣硬化、糖尿 病性腎病、糖尿病性心肌病、腎機能不全、白蛋白尿、周 邊血管疾病、左心室肥大、認知功能障礙、中風、頭疼及 慢性心臟衰竭之方法，該方法包括向有此需要之患者投與 治療有效量之本發明之口服劑型。 本發明另一態樣係本發明之阿利克崙調配物在製備用於 154767.doc •31 · 201136582 /台療尚血麼 '伴有糖尿病之高jk壓、充血性心臟衰竭、心 絞痛、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿病 性心肌病、腎機能不全、白蛋白尿、周邊血管疾病、左心 至肥大、通知功能障礙、中風、頭疼及慢性心臟衰竭之藥 劑中的用途。 本發明另一態樣係組合屬於本發明阿利克崙組合物/調 配物内之第二治療劑，其中該第二治療劑選自由以下組成 之群：AT〗受體拮抗劑、HMG-Co-A還原酶抑制劑、血管 緊縮素轉化酶（ACE)抑制劑、鈣通道阻斷劑、醛固酮合酶 抑制劑、醛固酮拮抗劑、雙重血管緊縮素轉化酶/中性内 肽酶（ACE/NEP)抑制劑、内皮素拮抗劑及利尿藥。 本發明另一態樣係組合屬於本發明阿利克崙組合物/調 配物内之第三治療劑，其中該第三治療劑選自由以下組成 之群· ATi受體拮抗劑、HMG-Co-A還原酶抑制劑、企管 緊縮素轉化酶（ACE)抑制劑、鈣通道阻斷劑、醛固酮合酶 抑制劑、醛固酮拮抗劑、雙重血管緊縮素轉化酶/中性内 肽S# (ACE/NEP)抑制劑、内皮素拮抗劑及利尿藥。 利用s亥等化合物之劑量方案係根據各種因素進行選擇， 包含患者之類型、物種、年齡、重量、性別及醫學狀況； 擬治療病狀之嚴重程度；投與途徑；患者之腎功能及肝功 月b，及所採用之特定化合物或其鹽。熟習此項技術之醫師 或獸醫可易於確定並開出㈣、抵抗或阻止病狀進展所需 之有效量藥物。 本發明化合物可以單次曰劑量投與，或總曰劑量可以每 I54767.doc -32- 201136582 日兩次、二次、四次、五次或六次之分次劑量投與。 本發明之代表性產品係以腸溶包覆膠囊形式經口投與之 阿利克崙基調配物：每一膠囊皆含有包括阿利克崙、 pvp、辛酸鈉、阿利克崙穩定劑及膽鹽（較佳係牛磺膽酸 鈉）之固體形式，該固體形式懸浮於包括（較佳）三辛酸甘油 酯及至少一種表面活性劑（較佳係卵磷脂）之疏水性（親脂 性）介質中。在本發明之另一代表性產品中，金屬鹽或胺 基酸或其組合存在於固體形式中作為阿利克崙穩定劑。 可將本文所述之組合物投與個體（亦即，人類或動物）以 使用藥理學或治療有效量之本文所述治療劑來心療該個 體。動物可為哺乳動物，例如小鼠m馬、牛或 :平。本文所用之術語「藥理學有效量」或「治療有效 量」或「有效量」意指藥物或醫藥藥劑（治療劑）之如下 量.^可對組織、系統、動物或人類引起研究者或臨床醫 師所哥求之生物或醫學反應，及/或該生物或醫學反應可 阻止或減小所治療病狀之進展或者另外完全或部分地治癒 該病狀或姑息性作用於該病狀。 ,本發明調配物使得可在阿利«沒有任何化學改變之情 屯下將阿利克备納人調配物中H本發明調配物使得 :克崙載里具有间度靈活性。最後，本發明調配物可防 止知物化合物在GI環境中失活。 兩種或更多種治療劑可彼此結合存在於相同劑型 或可單獨給予。「結合音 此 」思才日之刖、同時或之後。因 此—組合之個別組份可依序或同時自相同或單獨醫藥 154767.doc * 33 - 201136582 調配物投與。劑型可為具有—定生物利用度之σ服調配 物。特定而言，擬投與個體之劑型係本發明之口服劑型。 實施例概述：本發明醫藥組合物包括含有疏水性介質及固 體形式之混合物之懸浮液，其中該固體形式包括治療有效 量之阿利克备及視需要第二治療劑及視需要第三治療劑及 至少一種中鍵脂肪酸鹽；額外組份可選自由形成基質之聚 合物及糖組成之群；該固體形式包括顆粒；且該顆粒係藉 由康乾或藉由粒化或喷霧乾燥或藉由其他方式製得。醫藥 組合物中之水含量低於約6重量％、較佳低於約2重量。/。： 且固體形式中之水含量低於約6重量％、較佳低於2重量 %。中鏈脂肪酉免鹽具有約6至約14個碳原子之鍵長度，且 係己酸鈉、庚酸鈉、辛酸鈉、壬酸鈉、癸酸鈉、十一酸 鈉、十二酸鈉、十三酸鈉或十四酸鈉、或相應鉀鹽或鋰鹽 或錄鹽或其組合’特定而言係辛酸鈉。中鍵脂肪酸鹽在組 合物中之存在量為U重量％至4〇重量％、較佳12重量％至 18重量％、最佳約15重量％。中鏈脂肪酸鹽在固體形式_ 之存在量為50重量％至90重量％、較佳量為7〇重量％至 重量。/”形成基質之聚合物在組合物中之存在量為約〇5重 量％至15重量％、較佳約1重量％至10重量％，且選自由以 下組成之群：聚乙稀基0比略咬酮、卡波姆（例如卡波普聚 合物）、《乙稀醇、聚葡糖、海藻酸鹽、透明質酸鹽及聚 丙烯酸鹽及其組合’特定而言係聚乙稀基。比嘻咬綱、卡波 姆及聚乙稀醇及其組合。 聚乙烯基吡咯啶酮較佳係ρνρ_12，且較佳具有約3000之 154767.doc -34- 201136582 分子量，x其在組合物中之存在量為約2重量％至約2〇重 量％、較佳量為約5重量％至約15重量％、最佳量為約切重 量％。卡波姆較佳係卡波普934P，且係以約〇」重量％至約 6重量％之量、較佳以約G.5重量％至約4重量％之量、最佳 以約1重量％之量存在於組合物中。聚乙烯醇較佳係分子 量為約27000 Da之聚乙烯醇，且其在組合物中之存在量為 4重量％、最佳量為約u重量％。本發明醫藥組合物不含 中鏈醇且不含膜流化劑。 本發明醫藥組合物另外包括表面活性劑，該表面活性劑 係離子型表面活性劑或非離子型表面活性劑或其組合。在 一些實施例中，表面活性劑係卵磷脂或膽鹽（例如牛磺膽 酸鈉）或洗滌劑（例如Tween-80)或其組合；甘油單酯、克瑞 莫福、聚乙二醇脂肪醇醚、山梨醇酐脂肪酸酯、聚氧乙烯 山梨醇酐脂肪酸酯、色魯托HS15(12_羥基硬脂酸之聚氧乙 烯酯）、烷基糖（例如辛基糖苷、四癸基麥芽糖苷）或泊洛沙 姆或其組合。甘油單酯係單辛酸甘油酯（g丨 m〇nocaprylate)、單辛酸甘油酯（giyceryl m〇n〇〇ctan〇ate)、 單癸酸甘油酯、單月桂酸甘油酯、單肉豆蔻酸甘油酯、單 棕櫊酸甘油酯或單油酸甘油酯或單硬脂酸甘油酯或其組 合。山梨醇酐脂肪酸酯包括山梨醇酐單月桂酸酯、山梨醇 酐單油酸酯或山梨醇酐單棕櫚酸酯或其組合。聚氧乙烯山 梨醇酐脂肪酸酯包括聚氧乙烯山梨醇酐單油酸酯（丁^印 80)、聚氧乙烯山梨醇酐單硬脂酸酯或聚氧乙烯山梨醇酐 單棕櫚酸酯或其組合。在一些實施例中，表面活性劑係膽 154767.doc -35· 201136582 鹽’且膽鹽選自牛續膽酸納、脫氧膽酸納、甘膽酸鈉、我鳥 去氧膽酸鈉、膽酸鈉、石膽酸鈉及其組合，特定而言係牛 磺膽酸鈉。在一些實施例中，疏水性介質以重量計的主要 組份係三辛酸甘油酯。在一些實施例中，疏水性介質包括 脂肪族、烯系、環狀或芳族化合物；及/或疏水性介質包 括礦物油、石躐、脂肪酸（例如辛酸）、甘油單酯、甘油二 酸酯、甘油三酸酯、醚或酯（例如低分子量酯，較佳係異 戊酸乙醋或乙酸丁酯）或其組合。甘油三酸酯係長鏈甘油 三酸酯、或中鏈甘油三酸酯或短鏈甘油三酸酯或其組合。 在一些實施例中，醫藥組合物另外包括阿利克崙穩定劑 (例如胺基酸），且該胺基酸選自由甘胺酸、天門冬胺酸及 精胺酸及其組合組成之群，特定而言係精胺酸。在一些實 施例中，阿利克备穩定劑係金屬鹽且金屬鹽選自由鎂鹽、 鈣鹽及鋅鹽及其組合組成之群，或者金屬鹽選自由 MgCl2、ZnCl2、CaCl2、乙酸鋅、乙酸鎂及乙酸鈣組成之 群，特定而s金屬鹽係鋅鹽、較佳乙酸鋅。在一些實施例 中，阿利克崙穩定劑存於醫藥組合物之固體形式中。 在一些實施例中，醫藥組合物基本上由阿利克崙、中鏈 脂肪酸鹽及形成基質之聚合物及疏水性介質組成，及/或 固體粉末基本上由阿利克备、中鏈脂肪酸鹽及形成基質之 聚合物組成°在-些實施例中，疏水性介f基本上由三辛 酸甘油酯組成且疏水性介質另外含有表面活性劑。 在-些實她例中，醫藥組合物包括基本上由疏水性介質 及固體形式之混合物組成的懸浮液，纟中該固體形式包括 154767.doc •36· 201136582 m療有效#之阿利克备、至少—種中鏈脂肪酸鹽及形成基 質之聚合物；該疏水性介#包括甘油三酸喊甘油單醋或 其組合。在—些實施例中，醫藥組合物包括含有疏水性介 質及固體形式之混合物的懸浮液，其中該固體形式包括治 療有效量之阿利克I、至少—種中鏈脂肪酸鹽、形成基質 之聚CT物、及視需要表面活性劑及視需要阿利克崙穩定 劑。疏水性介質含有至少一種表面活性劑、較佳卵磷脂， 該表面活性劑之存在量較佳為約3重量％_9重量％、較佳約 6重量％ ;中鏈脂肪酸鹽係辛酸鈉，形成基質之聚合物係 PVP-12,且表面活性劑係膽鹽、較佳牛磺膽酸鈉；阿利克 崙穩定劑係胺基酸或金屬鹽或其組合；辛酸鈉之存在量為 10重量％-20重量％、較佳約15重量％，且pvp之存在為約 5-15重量％、較佳約10% ;牛磺膽酸鈉之存在量為〇 1重量 %-2重量％、較佳約〇·5重量阿利克崙之存在量為}重量 %-20重量％、較佳約5_10重量％、或約1〇重量％ ;阿利克 崙較佳係阿利克崙半富馬酸鹽。 在一些實施例中，醫藥組合物另外包括第二治療劑、及 視需要第三治療劑。在某些實施例中，水溶性組合物中之 中鏈脂肪酸鹽具有與中鏈甘油單酯或中鏈甘油三酸醋或其 組合相同之脂肪酸基團。在某些該等實施例中，中鏈脂肪 酸鹽係辛酸鈉（sodium Caprylate)(辛酸鈉（s〇dium 〇ctan〇ate》 且甘油單酯係單辛酸甘油酯’且甘油三酸酿係三辛酸甘油 酯。 本發明一實施例係製備醫藥組合物之方法，其包括：製 154767.doc -37- 201136582 備匕括/α療有效量之阿利克备及視需要第二治療劑、及視 需要第二治療劑、及中鏈脂肪酸鹽之水溶液，乾燥該水溶 液以獲得固體粉末，且將該固體粉末懸浮於疏水性介質中 乂製得3有固體形式之阿利克崙及中鏈脂肪酸鹽的懸浮 液由此製得醫藥組合物。在其他實施例中，該方法進一 步Ο括存於水，谷性溶液中之形成基質之聚合物；固體形式 匕括顆粒且乾燥係藉由凍乾或藉由粒化或藉由喷霧乾燥或 藉由其他方式來達成。 在-些方法實施例中’乾燥步驟可去除足量水從而使醫 樂組合物中之水含量低於約5重量％、較佳低於約2重量 /。及/或乾燥步驟可去除_定量之水從*使目體S末中之 水含量低於6重量％、較佳低於2重量％。在—些方法實施 例中，中鏈脂肪酸鹽具有約6至約14個碳原子之鏈長度， 及/或中鏈脂肪酸鹽係己酸鈉、庚酸鈉、辛酸鈉、壬酸 納、癸酸鈉、十_酸鈉、十二酸鈉、十三酸鈉或十四酸 納、或相應卸鹽或㈣或敍鹽或其組合、較佳辛酸納；且 中鏈脂肪酸鹽在組合物中之存在量為約η重量％至約重 量％、較佳U重量％至約28重量％、較佳約15重量%，及/ 或中鍵脂肪酸鹽在固體粉末中之存在量為30重量％至90重 量％、較佳40重量％至8〇重量％。 在-些方法實施例中，形成基質之聚合物選自由以下組 成之群：聚乙稀基料㈣、卡波姆（例如卡波普聚合 物）、聚乙烯醇、聚葡糖、海藻酸鹽、透明質酸鹽、及聚 丙稀酸鹽及其組合’特定而言係聚乙婦基料賴、卡波 154767.doc -38· 201136582 姆及聚乙烯醇及其組合。 PVP 眾乙烯基吡咯啶酮較佳係 ’且較佳分子量為約3000,且其在組合物 里為約2重量％至約20重量0/〇 子在 权1芏直為約5重量％至約j 重量，最佳量為約10重量％。在一 ^ —乃/无貫施例中，+ 波姆較佳係卡波普934p’且其在組合物 〇· 1重量％ i约6舌县。/ T你置#約 量/◦至靖量％，較佳量為約05重量％至約 二佳?:、里為約1重量％。在一些方法實施例中，聚乙烯醇 佳係t子量為約27000 Da之聚乙稀醇，且其在組合物中 之存在量為約(U重量％至約6重量％，較佳量為約〇 5重量 %至約4重量％’最佳量為約2重量％或1重量％。在該方法 中’組合物實質上不含中鍵醇及/或膜流化劑。在一此實 施例中，該方法另外包括表面活性劑；疏水性介質包括筵 麻油或三辛酸甘油醋或三丁酸甘油醋或辛酸或其組合；疏 水性介質以重量計之主要組份係莲麻油或三辛酸甘油醋或 辛I，疏水性介質包括脂肪族、烯系、環狀或芳族化合 物，特；t而言係脂肪族化合物；疏水性介質包括礦物油、 石犧、脂肪酸（例如辛酸）、甘油單酉旨、甘油二酸醋、甘油 三酸醋、醚或醋或其組合。在一些實施例中，疏水性介質 中之醋係低分子量酉旨，較佳係異戊酸乙醋或乙酸丁醋；甘 油三酸6旨係長鏈甘油三酸醋、中鏈甘油三酸醋或短鍵甘油 二酸醋或其混合物，或者長鏈甘油三酸醋係萬麻油或椰子 油或其組合。在一些實施例中，短鏈甘油三酸酯係三丁酸 甘油酯且中鏈甘油三酸酯係三辛酸甘油酯。 在一些實施例中，該方法另外包括至少一種表面活性 154767.doc -39- 201136582 劑，該表面活性杳丨丨你舱三Λ，丨± 系離子型表面活性劑或非離子型表面活 性劑或其組合。在-些方法實施例中，.表面活性劑係㈣ 脂或膽鹽(例如牛績膽酸納)或洗務劑或其組合；或者表面 活性劑係甘油單酯、克瑞苴 見知莫鈿、聚乙二醇脂肪醇醚、山梨 醇酐脂肪酸醋、聚氧乙稀山梨醇野脂肪酸醋、色魯托 肌5(12-經基硬脂酸之聚氧乙烯醋）、烧基糖（例如辛基糖 苦、四癸基麥芽糖芽）或泊洛沙姆或其組合。在一些實施 例中，甘*單醋係單辛酸甘油醋则_叩⑽⑷、 =辛酸甘油酯（glyceryl mon〇〇ctan〇ate)、單癸酸甘油酯、 早月桂酸甘油醋、單肉豆謹酸甘油酿、單掠櫚酸甘油醋或 單油酸甘油酯或單硬脂酸甘油酯或其組合；或者山梨醇酐 脂肪酸酿包括山梨醇酐單月桂酸酯、山梨醇肝單油酸醋或 山梨醇酐單棕櫚酸酯或其組合；或者聚氧乙烯山梨醇酐脂 肪酸酯包括聚氧乙烯山梨醇酐單油酸酯（Tween 8〇)、聚氧 乙烯山梨醇酐單硬脂酸酯或聚氧乙烯山梨醇酐單棕櫚酸酯 或其組合。表面活性劑存在於固體形式中或者其存在於疏 水性介質中或者其存在於固體形式及疏水性介質二者中。 在一些實施例中’表面活性劑係卵磷脂或膽鹽（例如牛磺 膽酸鈉）或洗滌劑（例如Tween-80)或其組合。在一些方法實 施例中，組合物基本上由阿利克崙、中鏈脂肪酸鹽及形成 基質之聚合物及疏水性介質組成，及/或固體粉末基本上 由阿利克崙、中鏈脂肪酸鹽及形成基質之聚合物組成。在 一些方法實施例中，疏水性介質基本上由三辛酸甘油酯組 成且視需要另外含有表面活性劑。 154767.doc •40· 201136582 在一些方法實施例中，固體粉末基本上由阿利克崙及t 鏈脂肪酸鹽及表面活性劑組成，且視需要疏水性介質基本 上由三辛酸甘油酯組成。在一些方法實施例中，組合物另 外包括阿利克崙穩定劑；阿利克崙穩定劑特定而言係胺基 酸或金屬鹽或其組合。胺基酸係甘胺酸或天門冬胺酸或精 胺酸或其組合’特定而言係精胺酸，且金屬鹽係鎮鹽、鈣 鹽或鋅鹽4其組合’ 4寺定而f，金屬鹽€自由以下組成之 群：叫^以心^丨厂乙酸辞义酸鎂及乙酸鈣。 -實施例係製備醫藥組合物之方法，其包括提供包括治 療有效量之利克I及視需要第二治療劑及視需要第三治 療劑、至少-種中鍵脂肪酸鹽的固體粉末；將該固體粉末 懸浮於疏水性介質中以製得含有固體形式治療劑及中鍵脂 肪酸鹽之懸浮液，由此製得醫藥組合物；且視需要在固體 粉末中提供形成基質之聚合物及阿利克备穩定劑，視需要 進-步包括在組合物中提供至少一種表面活性劑。中鏈脂 肪酸鹽、形成基質之聚合物、穩定劑及表面活性劑如上所 述。 實施例係藉由本發明任一實施例之方法製得的醫藥組 合物。-實施例係口服劑型’其包括本發明任一實施例之 組合物，該組合物另外經腸溶包覆。-實施例係包括說明 書及本發明劑型之套組。-實施例係含有本發明組合物之 膠囊，且該膠囊係硬質凝膠或軟質凝膠膠囊；該膠 2覆。㈣明之口服劑型係用於治療高血壓、伴有糖尿 血壓、充血心臟衰竭、心絞痛、心肌梗塞、動脈 154767.doc 201136582 粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不 全、白蛋白尿、周邊血管疾病、左心室肥大、認知功能障 礙、中風、頭疼及慢性心臟衰竭。 一實施例係用於治療以下疾病之方法：高血壓、伴有糖 尿病之高血壓、充血性心臟衰竭、心絞痛、心肌梗塞、動 脈粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不 全、白蛋白尿、周邊血管疾病、左心室肥大、認知功能障 礙、中風、頭疼及慢性心臟衰竭，該方法包括向有此需要 之患者投與治療有效量之本發明之固體口服劑型。一實施 例係本發明之口服劑型在製備用於治療高血壓、伴有糖尿 病之间血壓、充血性心臟衰竭、心絞痛、心肌梗塞、動脈 粥樣硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不 王白蛋白尿、周邊血管疾病、左心室肥大、認知功能障 礙、中風、頭疼及慢性心臟衰竭之藥劑中的用途。一實施 例係具有視需要第二治療劑及視需要第三治療劑之任一上 述，’且5物，其中該第二或第三治療劑選自由以下組成之 群：AT,受體拮抗劑、HMG_c〇_A還原酶抑制劑、血管緊 縮素轉化酶（ACE)抑制劑、鈣通道阻斷劑、醛固酮合酶抑 制劑、醛固酮拮抗劑、雙重血管緊縮素轉化酶/中性内肽 酶（ACE/NEP)抑制劑、内皮素拮抗劑及利尿藥。一實施例 係包括阿利克崙且用於經口傳遞之單位劑型，且阿利克崙 之存在量介於約5-75 mg/單位劑型、或約75_15〇 mg/單位 劑型、或約150-300 mg/單位劑型、或約3〇〇__ mg/單位 劑型之間…實施例係單位劑型，其中在經口投與單位劑 154767.doc -42- 201136582 型時阿利克崙之所得生物利用度大於3%、或大於4%、< 大於5%、或大於6%。 根據下列實例來更全面地理解該等及其他實施例之功能 及優點。該等實例意欲具有闡釋意義且並不視為限制本文 所述系統及方法之範圍。 實例 實例1:調配物之詳細製備方法 下文闡述兩種阿利克备調配物之製備。下列實例中所有 調配物之製備方法基本上如圖1及此實例1中所述。 A.包含PVP-12之阿利克崙調配物 親水性部分之製備 向含有100 mL水之燒杯中緩慢地逐份添加下列成份（在 每一成份之間混合2-3分鐘或直至獲得澄清溶液為止）： 10.08 g阿利克崙半富馬酸鹽（含量為99.2%)、10.00 g PVP-12 及1 5 ·00 g辛酸鈉。將溶液再混合5 min且然後轉移至不錄 鋼凍乾盤中。將盤在-80°C下冷凍1.5-2 h且然後凍乾約24 h。此程序可產生約3 5 g親水性部分。 疏水性介質之製備： 將2.2 g Tween 80、4.4 g單辛酸甘油醋、及64.0 g三辛酸 甘油醋混合至一起。此程序可產生約70 g疏水性（親脂性） 介質。 原料藥產物之製備： 使用研缽來混合親水性部分及疏水性介質。將57.8 g疏 水性介質傾倒至混合缽中。在混合下緩慢添加32 2 g親水 154767.doc •43· 201136582 性部分。添加全部親水性部分後，將懸浮潘 w哫合約1 h直 至獲得平滑之黏性懸浮液為止，將該懸浮液健存於25^以 下。此係實例4中表B中之調配物I。 B.包含PVA之阿利克崙調配物 自Aldrich獲得分子量為27000 Da之PVA。复奋贼L —入 昇實際上完全 發生水解（約98-99%)。 親水性部分之製備： 在攪拌下向含有100 mL水之燒杯中添加2·00 g PVA。將 混合物加熱至約60°C。在所有PVA溶解之後，將溶液冷卻 至室溫且在混合下添加15.00 g辛酸鈉。在辛酸鈉溶解之 後’在混合下添加10 · 0 8 g阿利克奋半富馬酸鹽（含量為 99.2%)。將盤在-80°C下冷;東1 ·5-2 h且然後滚乾約24 h。此 程序可產生約27 g親水性部分。 疏水性介質之製備：將2.2 g Tween 80、4.4 g單辛酸甘油 酯、及7 3.0 g三辛酸甘油酯混合至一起。此程序可產生約 80 g疏水性介質。 原料藥產物之製備：使用研缽混合親水性部分及疏水性介 質。將65.1 g疏水性介質傾倒至混合缽中且在混合下緩慢 添加24.9 g親水性部分。添加全部親水性部分之後，將懸 浮液混合約1 h直至獲得平滑黏性懸浮液/半固體為止，將 該懸浮液/半固體儲存在251以下。此係實例4中表B中之 調配物V。 實例2:用於測試含有不同活性成份之各種不同調配物之 生物利用度的動物模型 154767.doc •44- 201136582 為測試調配物平臺之能力，在下列動物模型中測試含有 不同貨物化合物或活性成份（API)之調配物的生物利用 度：空腸投與至清醒（未麻醉）大鼠。 為測試調配物在清醒大鼠之空腸中之生物利用度，建立 特定大鼠模型，其中將兩根不同插管藉由外科手術植入雄 性Sprague-Dowley大鼠中（亦可使用其他大鼠）： 1- 空腸插管，其用以繞過胃且使得能夠直接將調配物投與 至空腸；及 2- 頸靜脈插管，其用以測定在空腸投與之後所投與聚葡糖 之全身含量。 在研究之前使大鼠恢復4天且在開始研究之前禁食18小 時。 如上所述’將含有API之調配物投與清醒大鼠之空腸 中，且單獨地經靜脈内或皮下投與含有API之鹽水溶液作 為對照。在空腸投與後及靜脈内投與後（或皮下投與後）以 適當時間系列自頸靜脈抽取血樣，製備血漿且在每一試樣 中測疋活性成份之含量。如下所述來計算在空腸投與調配 物之後所達成之平均絕對生物利用度（aBA)。 自血清濃度對時間曲線下之面積（AUC)來計算暴露值 (AUC(O-T)) ’且測定空腸及靜脈内投與（或皮下投與）時之 暴露值。T=量測之最終時間。 根據下列等式來測定絕對生物利用度（aBA): &ΒΑ一（空腸AUC(〇-T))/(靜脈内AUC(0.T))*(靜脈内劑量/空腸 劑量） 154767.doc 45- 201136582 根據下列等式來測定相對生物利用度（rB A): rBA=(空腸AUC(〇.T) /皮下AUC(〇_T))*(皮下劑量/空腸劑量） 數據通常表示為平均值士 SD(在每組中，n25隻大鼠）。 實例3:聚葡糖調配物 基本上如實例1中所述製備含有FD4 (Sigma)之調配物， 只是使用下表A中所列之成份。卡波普（自Lubrizol獲得）必 須進行中和（與PVP-12及PVA不同）。FD4係經FITC標記之 聚葡糖且平均MW為4·4 kDa。Microparticulate Oral Drug Delivery, Gerbre-Selassie Editor's Marcel Dekker, Inc. (1994) and Dey et al., yiultiparticulate Drug Delivery Systems for Controlled Release, Tropical Journal of Pharmaceutical Research, September 2008; 7(3): 1067-1075 The treatment method: The aliskiren formulation of the invention can be used for treating hypertension, hypertension with diabetes, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic myocardium Disease, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure. One aspect of the invention is the treatment of hypertension, hypertension associated with diabetes, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, albuminuria, peripheral A method of vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure, the method comprising administering to a patient in need thereof a therapeutically effective amount of an oral dosage form of the invention. Another aspect of the present invention is the preparation of the aliskiren formulation of the present invention for use in 154767.doc • 31 · 201136582 / Taiwan treatment of bloody blood with high blood pressure jk pressure, congestive heart failure, angina pectoris, myocardial infarction Uses in atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, albuminuria, peripheral vascular disease, left heart to hypertrophy, notification of dysfunction, stroke, headache, and chronic heart failure. Another aspect of the invention is a combination of a second therapeutic agent within the aliskiren composition/formulation of the invention, wherein the second therapeutic agent is selected from the group consisting of AT receptor antagonists, HMG-Co- A reductase inhibitor, angiotensin converting enzyme (ACE) inhibitor, calcium channel blocker, aldosterone synthase inhibitor, aldosterone antagonist, dual angiotensin converting enzyme / neutral endopeptidase (ACE/NEP) Inhibitors, endothelin antagonists and diuretics. Another aspect of the invention is a combination of a third therapeutic agent within the aliskiren composition/formulation of the invention, wherein the third therapeutic agent is selected from the group consisting of: ATi receptor antagonists, HMG-Co-A Reductase inhibitors, vasopressin converting enzyme (ACE) inhibitors, calcium channel blockers, aldosterone synthase inhibitors, aldosterone antagonists, dual angiotensin converting enzyme/neutral endopeptide S# (ACE/NEP) Inhibitors, endothelin antagonists and diuretics. The dosage regimen using compounds such as shai is selected according to various factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal function and liver function of the patient Month b, and the particular compound or salt thereof employed. A physician or veterinarian familiar with the art can readily determine and prescribe (d) an effective amount of the drug required to resist or prevent progression of the condition. The compounds of the invention may be administered in a single dose, or the total dose may be administered in divided doses of two, two, four, five or six times per I54767.doc - 32 - 201136582. A representative product of the present invention is an allylicin-based formulation orally administered in the form of an enteric coated capsule: each capsule contains aliskiren, pvp, sodium octanoate, aliskiren stabilizer, and bile salts ( Preferably, it is a solid form of sodium taurocholate which is suspended in a hydrophobic (lipophilic) medium comprising (preferably) tricaprylin and at least one surfactant, preferably lecithin. In another representative product of the invention, a metal salt or an amino acid or a combination thereof is present in solid form as an aliskiren stabilizer. The compositions described herein can be administered to an individual (i.e., human or animal) to treat the subject with a pharmacologically or therapeutically effective amount of a therapeutic agent described herein. The animal can be a mammal, such as a mouse m horse, cow or: flat. The term "pharmacologically effective amount" or "therapeutically effective amount" or "effective amount" as used herein means the following amount of a drug or a pharmaceutical agent (therapeutic agent). It may cause a researcher or clinically to a tissue, system, animal or human. The biological or medical response sought by the physician, and/or the biological or medical response may prevent or reduce the progression of the condition being treated or otherwise completely or partially cure the condition or palliative action on the condition. The formulation of the present invention allows the formulation of the invention to be carried out in the Alix preparer formulation without any chemical change in the case of Ari's: the kelun load has moderate flexibility. Finally, the formulations of the present invention prevent the loss of the compound of interest in the GI environment. Two or more therapeutic agents may be present in the same dosage form in combination with one another or may be administered separately. "Combining the sound of this" is the day after, at the same time or after. Therefore, the individual components of the combination may be administered sequentially or simultaneously from the same or separate medicines 154767.doc * 33 - 201136582 Formulations are administered. The dosage form can be a sigma formulation with a defined bioavailability. In particular, the dosage form to be administered to an individual is an oral dosage form of the invention. Summary of the Invention: The pharmaceutical composition of the present invention comprises a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of alixone and optionally a second therapeutic agent and optionally a third therapeutic agent and At least one medium-bond fatty acid salt; the additional component may be selected from the group consisting of a polymer of a matrix and a sugar composition; the solid form comprises particles; and the particles are dried or dried by granulation or spray drying or by spraying Made in other ways. The water content of the pharmaceutical composition is less than about 6% by weight, preferably less than about 2% by weight. /. And the water content in the solid form is less than about 6% by weight, preferably less than 2% by weight. The medium chain fat bismuth salt has a bond length of about 6 to about 14 carbon atoms, and is sodium hexanoate, sodium heptanoate, sodium octanoate, sodium citrate, sodium citrate, sodium undecanoate, sodium dodecanoate, Sodium tridecanoate or sodium tetradecanoate, or the corresponding potassium or lithium salt or salt or combination thereof' is specifically sodium octanoate. The mid-bond fatty acid salt is present in the composition in an amount from U% by weight to 4% by weight, preferably from 12% by weight to 18% by weight, most preferably about 15% by weight. The medium chain fatty acid salt is present in the solid form in an amount of from 50% by weight to 90% by weight, preferably from 7% by weight to 3% by weight. /" The matrix-forming polymer is present in the composition in an amount of from about 5% to 15% by weight, preferably from about 1% to about 10% by weight, and is selected from the group consisting of: polyethylene-based ratio Slightly ketones, carbomers (such as carbopol polymers), "ethylene glycols, polyglucose, alginates, hyaluronates, and polyacrylates, and combinations thereof" are, in particular, polyethylene. More preferably, the polyvinylpyrrolidone is preferably ρνρ_12, and preferably has a molecular weight of about 1500767.doc-34-201136582, x which is in the composition. It is present in an amount of from about 2% by weight to about 2% by weight, preferably from about 5% by weight to about 15% by weight, most preferably in an amount of about 3% by weight. The carbomer is preferably carbopol 934P, and It is present in the composition in an amount of from about 8% by weight to about 6% by weight, preferably from about G.5% by weight to about 4% by weight, most preferably about 1% by weight. The polyvinyl alcohol is preferably a polyvinyl alcohol having a molecular weight of about 27,000 Da, and is present in the composition in an amount of 4% by weight, preferably in an amount of about 5% by weight. The pharmaceutical composition of the present invention does not contain a medium chain alcohol and does not contain a film fluidizing agent. The pharmaceutical composition of the present invention additionally includes a surfactant which is an ionic surfactant or a nonionic surfactant or a combination thereof. In some embodiments, the surfactant is lecithin or a bile salt (eg, sodium taurocholate) or a detergent (eg, Tween-80) or a combination thereof; monoglyceride, remimofo, polyethylene glycol fat Alcohol ether, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, color Ruto HS15 (polyoxyethylene ester of 12-hydroxystearic acid), alkyl sugar (such as octyl glycoside, tetradecyl) Maltoside) or poloxamer or a combination thereof. Monoglyceride monoglyceride (g丨m〇nocaprylate), monocaprylin (giyceryl m〇n〇〇ctan〇ate), glyceryl monocaprate, glycerol monolaurate, glyceryl monomyristate , glyceryl monopalmitate or glycerol monooleate or glyceryl monostearate or a combination thereof. The sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate or sorbitan monopalmitate or a combination thereof. Polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monooleate (Dingyin 80), polyoxyethylene sorbitan monostearate or polyoxyethylene sorbitan monopalmitate or Its combination. In some embodiments, the surfactant is biliary 154767.doc -35· 201136582 salt 'and the bile salt is selected from the group consisting of sodium nitrate, sodium deoxycholate, sodium glycocholate, sodium sodium sodium orodeoxycholate, gallium Sodium, sodium cholate, and combinations thereof, in particular, sodium taurocholate. In some embodiments, the hydrophobic component is the major component by weight of tricaprylin. In some embodiments, the hydrophobic medium comprises an aliphatic, olefinic, cyclic or aromatic compound; and/or the hydrophobic medium comprises mineral oil, sarcophagus, fatty acids (eg, octanoic acid), monoglycerides, diglycerides A triglyceride, an ether or an ester (eg, a low molecular weight ester, preferably isovalerate or butyl acetate) or a combination thereof. Triglyceride is a long chain triglyceride, or a medium chain triglyceride or a short chain triglyceride or a combination thereof. In some embodiments, the pharmaceutical composition additionally includes an aliskiren stabilizer (eg, an amino acid), and the amino acid is selected from the group consisting of glycine, aspartic acid, and arginine, and combinations thereof, specific In terms of arginine. In some embodiments, the Aleks Stabilizer is a metal salt and the metal salt is selected from the group consisting of magnesium salts, calcium salts, and zinc salts, and combinations thereof, or the metal salt is selected from the group consisting of MgCl 2 , ZnCl 2 , CaCl 2 , zinc acetate, and magnesium acetate. And a group consisting of calcium acetate, a specific s metal salt is a zinc salt, preferably zinc acetate. In some embodiments, the aliskiren stabilizer is present in a solid form of the pharmaceutical composition. In some embodiments, the pharmaceutical composition consists essentially of aliskiren, a medium chain fatty acid salt, and a matrix-forming polymer and a hydrophobic medium, and/or the solid powder is substantially formed from alex, medium chain fatty acid salts, and Polymer Composition of the Matrix ° In some embodiments, the hydrophobic interface f consists essentially of tricaprylin and the hydrophobic medium additionally contains a surfactant. In some examples, the pharmaceutical composition comprises a suspension consisting essentially of a mixture of a hydrophobic medium and a solid form, the solid form comprising 154767.doc • 36·201136582 m therapeutically effective #阿利克, At least one medium chain fatty acid salt and a matrix forming polymer; the hydrophobic medium #includes triglyceride glycerol monoacetate or a combination thereof. In some embodiments, the pharmaceutical composition comprises a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of alik I, at least a medium chain fatty acid salt, a matrix-forming poly CT Surfactants and, if desired, aliskiren stabilizers. The hydrophobic medium contains at least one surfactant, preferably lecithin, and the surfactant is preferably present in an amount of from about 3% by weight to about 9% by weight, preferably about 6% by weight; the medium chain fatty acid salt is sodium octoate, forming a matrix The polymer is PVP-12, and the surfactant is a bile salt, preferably sodium taurocholate; the aliskiren stabilizer is an amino acid or a metal salt or a combination thereof; sodium octanoate is present in an amount of 10% by weight - 20% by weight, preferably about 15% by weight, and pvp is present in an amount of from about 5 to 15% by weight, preferably about 10%; sodium taurocholate is present in an amount of from 1% by weight to 2% by weight, preferably about The 重量·5 weight of aliskiren is present in an amount of from 9% by weight to 20% by weight, preferably from about 5% by weight to about 10% by weight, or from about 1% by weight. The aliskiren is preferably aliskiren hemi-fumarate. In some embodiments, the pharmaceutical composition additionally includes a second therapeutic agent, and optionally a third therapeutic agent. In certain embodiments, the medium chain fatty acid salt in the water soluble composition has the same fatty acid group as the medium chain monoglyceride or medium chain triacetin or a combination thereof. In certain of these embodiments, the medium chain fatty acid salt is sodium caprylate (sodium 〇ctan〇ate and monoglyceride monocaprylin) and the triglyceride is triglyceride An embodiment of the present invention is a method of preparing a pharmaceutical composition comprising: 154767.doc -37-201136582 匕 / α α α α α α α α α α 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及a second therapeutic agent, and an aqueous solution of a medium-chain fatty acid salt, the aqueous solution is dried to obtain a solid powder, and the solid powder is suspended in a hydrophobic medium to prepare a suspension of 3 solid forms of aliskiren and medium-chain fatty acid salts. The pharmaceutical composition is thus prepared. In other embodiments, the method further comprises forming a matrix-forming polymer in water, a gluten solution; the solid form comprises particles and the drying is by lyophilization or by granules. Or by spray drying or by other means. In some method embodiments, the 'drying step can remove sufficient water to cause the water content of the medical composition to be less than about 5% by weight, preferably low. About 2 weights / / and / or drying step can remove _ quantitative water from * so that the water content in the end of the body S is less than 6% by weight, preferably less than 2% by weight. In some method examples, medium chain fatty acid salt a chain length of from about 6 to about 14 carbon atoms, and/or a medium chain fatty acid salt of sodium hexanoate, sodium heptanoate, sodium octanoate, sodium citrate, sodium citrate, sodium decanoate, sodium dodecanoate, Sodium tridecanoate or sodium tetradecanoate, or a corresponding unsalted salt or (d) or a salt or a combination thereof, preferably sodium octoate; and the medium chain fatty acid salt is present in the composition in an amount from about η% by weight to about 3% by weight, Preferably, U% by weight to about 28% by weight, preferably about 15% by weight, and/or the middle linkage fatty acid salt is present in the solid powder in an amount of from 30% by weight to 90% by weight, preferably from 40% by weight to 8% by weight. In some method embodiments, the matrix-forming polymer is selected from the group consisting of polyethylene (4), carbomer (eg, carbopol), polyvinyl alcohol, polyglucose, algae Acid salts, hyaluronate salts, and polyacrylic acid salts and combinations thereof are specifically poly-glycol base materials, Kappa 154767.doc -38· 20 1136582 and polyvinyl alcohol and combinations thereof. PVP vinylpyrrolidone is preferably 'and preferably has a molecular weight of about 3,000, and it is from about 2% by weight to about 20% by weight in the composition. 1芏 is from about 5% by weight to about j by weight, and the optimum amount is about 10% by weight. In a ^-/Non-application, +Bom is preferably carbop 934p' and it is in the composition 〇·1% by weight i about 6 tongue counts. / T you set #约量/◦至靖量%, the preferred amount is about 05% by weight to about two good?:, the inside is about 1% by weight. In some methods In the examples, the polyvinyl alcohol is preferably a polyethylene glycol of about 27,000 Da, and is present in the composition in an amount of from about 5% by weight to about 6% by weight, preferably about 5% by weight. The weight % to about 4% by weight 'optimal amount is about 2% by weight or 1% by weight. In this method the composition is substantially free of a medium linkage alcohol and/or a membrane fluidizer. In one embodiment, the method additionally comprises a surfactant; the hydrophobic medium comprises castor oil or tricaprylic glycerin or tributyrin or octanoic acid or a combination thereof; the hydrophobic medium is the main component of the lotus Sesame oil or tricapry glycerin or octyl I, hydrophobic medium includes aliphatic, olefinic, cyclic or aromatic compounds, especially; t; for aliphatic compounds; hydrophobic media including mineral oil, stone sacrifice, fatty acids (such as Caprylic acid, glycerol monoglyceride, glyceric acid vinegar, triacetin, ether or vinegar or a combination thereof. In some embodiments, the vinegar in the hydrophobic medium is of a low molecular weight, preferably isovaleric acid or butyl acetate; the triglyceride 6 is a long-chain triglyceride, medium-chain triglyceride or Short-chain diglyceride or a mixture thereof, or long-chain triacetin vinegar or coconut oil or a combination thereof. In some embodiments, the short chain triglyceride is tributyrin and the medium chain triglyceride is tricaprylin. In some embodiments, the method additionally comprises at least one surface active 154767.doc -39 - 201136582 agent, the surface active 杳丨丨 舱 舱 系 系 系 系 ionic surfactant or nonionic surfactant or Its combination. In some method embodiments, the surfactant is a (four) lipid or a bile salt (such as sodium borate) or a detergent or a combination thereof; or a surfactant is a monoglyceride, a gram is known. , polyethylene glycol fatty alcohol ether, sorbitan fatty acid vinegar, polyoxyethylene sorbitol wild fatty acid vinegar, color Rutto muscle 5 (12-based stearic acid polyoxyethylene vinegar), burnt sugar (for example An octylose, tetradecyl maltose bud) or a poloxamer or a combination thereof. In some embodiments, the glycerol monooleic monocaprylic glycerin vinegar is 叩10(4), = glyceryl mon 〇〇 〇 〇 、, glyceryl monoglyceride, lauric acid glycerol, single peas Acid glycerin, single glycerol or glycerol monooleate or glyceryl monostearate or a combination thereof; or sorbitan fatty acid including sorbitan monolaurate, sorbitol liver oleic acid or Sorbitan monopalmitate or a combination thereof; or polyoxyethylene sorbitan fatty acid esters including polyoxyethylene sorbitan monooleate (Tween 8®), polyoxyethylene sorbitan monostearate or Polyoxyethylene sorbitan monopalmitate or a combination thereof. The surfactant is present in the solid form or it is present in the hydrophobic medium or it is present in both the solid form and the hydrophobic medium. In some embodiments the surfactant is a lecithin or bile salt (e.g., sodium taurocholate) or a detergent (e.g., Tween-80) or a combination thereof. In some method embodiments, the composition consists essentially of aliskiren, a medium chain fatty acid salt, and a matrix-forming polymer and a hydrophobic medium, and/or the solid powder consists essentially of aliskiren, a medium chain fatty acid salt, and The polymer composition of the matrix. In some method embodiments, the hydrophobic medium consists essentially of tricaprylin and optionally contains a surfactant. 154767.doc • 40· 201136582 In some method embodiments, the solid powder consists essentially of aliskiren and t-chain fatty acid salts and surfactants, and optionally the hydrophobic medium consists essentially of tricaprylin. In some method embodiments, the composition additionally includes an aliskiren stabilizer; the aliskiren stabilizer is, in particular, an amino acid or a metal salt or a combination thereof. Amino acid glycine or asparagine or arginine or a combination thereof is specifically arginine, and the metal salt is a combination of a salt, a calcium salt or a zinc salt 4 Metal salt € free group of the following composition: called ^ heart ^ 丨 plant acetic acid word magnesium and calcium acetate. - the method of preparing a pharmaceutical composition comprising providing a solid powder comprising a therapeutically effective amount of a gram I and optionally a second therapeutic agent and optionally a third therapeutic agent, at least one of the intermediate fatty acid salts; The powder is suspended in a hydrophobic medium to prepare a suspension containing the solid form of the therapeutic agent and the middle bond fatty acid salt, thereby preparing a pharmaceutical composition; and if necessary, providing a matrix-forming polymer and alkib stability in the solid powder The agent, if desired, includes providing at least one surfactant in the composition. The medium chain fatty acid salt, the matrix forming polymer, the stabilizer, and the surfactant are as described above. The examples are pharmaceutical compositions prepared by the method of any of the embodiments of the present invention. - Examples are oral dosage forms' which comprise a composition according to any of the embodiments of the invention which is additionally enteric coated. - Examples include kits and sets of dosage forms of the invention. - The examples are capsules containing the composition of the invention, and the capsules are hard gel or soft gel capsules; the glue is coated. (4) Mingzhi oral dosage form for the treatment of hypertension, accompanied by diabetes, blood pressure, heart failure, angina pectoris, myocardial infarction, arteries 154767.doc 201136582 atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, albuminuria Peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure. One embodiment is a method for treating hypertension, hypertension associated with diabetes, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, Albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure, the method comprising administering to a patient in need thereof a therapeutically effective amount of a solid oral dosage form of the invention. An embodiment is an oral dosage form of the invention for use in the treatment of hypertension, diabetes, blood pressure, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal function Use in drugs such as albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure. An embodiment has any of the above-described second therapeutic agent and optionally a third therapeutic agent, wherein the second or third therapeutic agent is selected from the group consisting of AT, a receptor antagonist , HMG_c〇_A reductase inhibitor, angiotensin converting enzyme (ACE) inhibitor, calcium channel blocker, aldosterone synthase inhibitor, aldosterone antagonist, dual angiotensin converting enzyme / neutral endopeptidase ( ACE/NEP) inhibitors, endothelin antagonists, and diuretics. An embodiment is a unit dosage form comprising aliskiren for oral delivery, and aliskiren is present in an amount from about 5 to 75 mg per unit dosage form, or from about 75 to 15 mg per unit dosage form, or from about 150 to 300 Between mg/unit dosage form, or about 3 〇〇__mg/unit dosage form...Examples are unit dosage forms in which the bioavailability of aliskiren is obtained when the unit dose 154767.doc -42- 201136582 is administered orally. More than 3%, or more than 4%, < more than 5%, or more than 6%. The functions and advantages of these and other embodiments are more fully understood from the following examples. The examples are intended to be illustrative and not to limit the scope of the systems and methods described herein. EXAMPLES Example 1: Detailed Preparation of Formulations The preparation of two Alikidine formulations is set forth below. The preparation of all formulations in the following examples is essentially as described in Figure 1 and Example 1. A. Preparation of the hydrophilic portion of the aliquotene formulation containing PVP-12 Slowly add the following ingredients in portions to a beaker containing 100 mL of water (mix between each component for 2-3 minutes or until a clear solution is obtained) ): 10.08 g of aliskiren hemifumarate (content 99.2%), 10.00 g of PVP-12 and 1 5 ·00 g of sodium octanoate. The solution was mixed for an additional 5 min and then transferred to a non-recorded lyophilized pan. The plate was frozen at -80 °C for 1.5-2 h and then lyophilized for approximately 24 h. This procedure produces approximately 35 g of hydrophilic portion. Preparation of hydrophobic medium: 2.2 g of Tween 80, 4.4 g of monocaprylic glycerin, and 64.0 g of tricaprylic glycerin were mixed together. This procedure produces approximately 70 g of hydrophobic (lipophilic) medium. Preparation of the drug substance: A mortar is used to mix the hydrophilic portion and the hydrophobic medium. Pour 57.8 g of the hydrophobic medium into the mixing bowl. Slowly add 32 2 g of hydrophilic 154767.doc •43· 201136582 sex part under mixing. After all the hydrophilic fractions have been added, the suspension is suspended for 1 h until a smooth viscous suspension is obtained, and the suspension is stored under 25^. This is the formulation I in Table B of Example 4. B. Aleclon formulation containing PVA A PVA having a molecular weight of 27,000 Da was obtained from Aldrich. The thief L-increase actually undergoes complete hydrolysis (about 98-99%). Preparation of the hydrophilic portion: 20.00 g of PVA was added to a beaker containing 100 mL of water with stirring. The mixture was heated to about 60 °C. After all PVA was dissolved, the solution was cooled to room temperature and 15.00 g of sodium octoate was added with mixing. After dissolving sodium octanoate, 10·0 8 g of aliskifen hemifumarate (content 99.2%) was added under mixing. The plate was cooled at -80 ° C; East 1 · 5-2 h and then dried for about 24 h. This procedure produces approximately 27 g of hydrophilic fraction. Preparation of a hydrophobic medium: 2.2 g of Tween 80, 4.4 g of monocaprylin, and 73.0 g of tricaprylin were mixed together. This procedure produces approximately 80 g of hydrophobic media. Preparation of the drug substance product: The hydrophilic portion and the hydrophobic medium were mixed using a mortar. 65.1 g of the hydrophobic medium was poured into the mixed crucible and 24.9 g of the hydrophilic portion was slowly added with mixing. After all of the hydrophilic portion was added, the suspension was mixed for about 1 h until a smooth viscous suspension/semisolid was obtained, and the suspension/semisolid was stored below 251. This is the formulation V in Table B of Example 4. Example 2: Animal model for testing the bioavailability of various formulations containing different active ingredients 154767.doc • 44- 201136582 To test the ability of the formulation platform, test different animal compounds or active ingredients in the following animal models Bioavailability of the formulation of (API): jejunum administration to awake (unanesthetized) rats. To test the bioavailability of the formulation in the jejunum of conscious rats, a specific rat model was established in which two different cannulas were surgically implanted into male Sprague-Dowley rats (other rats could also be used) : 1- jejunal cannula for bypassing the stomach and enabling direct administration of the formulation to the jejunum; and 2-neck jugular cannula for measuring the body of polyglucose administered after jejunal administration content. Rats were allowed to recover for 4 days prior to study and fasted for 18 hours prior to starting the study. The formulation containing the API was administered to the jejunum of the conscious rat as described above, and the saline solution containing the API was administered intravenously or subcutaneously as a control alone. Blood samples were taken from the jugular vein at the appropriate time series after administration of the jejunum and after intravenous administration (or after subcutaneous administration), and plasma was prepared and the content of the active ingredient was measured in each sample. The average absolute bioavailability (aBA) achieved after administration of the formulation in the jejunum was calculated as follows. The exposure value (AUC(O-T))' was calculated from the area under the serum concentration versus time curve (AUC) and the exposure values when jejunal and intravenous administration (or subcutaneous administration) were measured. T = the final time of the measurement. Absolute bioavailability (aBA) was determined according to the following equation: & ΒΑ (jejunum AUC (〇-T)) / (intravenous AUC (0.T)) * (intravenous dose / jejunal dose) 154767.doc 45- 201136582 Relative bioavailability (rB A) is determined according to the following equation: rBA = (jejunum AUC (〇.T) / subcutaneous AUC (〇_T))* (subcutaneous dose / jejunal dose) data is usually expressed as average Value SD (in each group, n25 rats). Example 3: Polyglucoside formulation A formulation containing FD4 (Sigma) was prepared essentially as described in Example 1, except that the ingredients listed in Table A below were used. Carpop (obtained from Lubrizol) must be neutralized (unlike PVP-12 and PVA). FD4 is a FITC-labeled polyglucose with an average MW of 4·4 kDa.

表A 成份 (%w/w) 親水性 部分 FD4 0.545 卡波普934P 1.000 NaOH 15.000 辛酸鈉 0.360 水 1.033 疏水性 介質(親脂性部分） Tween 80 2.000 單辛酸甘油醋 4.000 三辛酸甘油酯 76.062 結果 BA, % 12.5 SD 5.7 N 10 如實例2中所述來測試含有FD4之調配物，且如上表所 示FD4之絕對BA為12.5%。來自相同批次之與調配物I相似 且含有FD4的調配物（參見實例1及實例4中之表B)可得到 12.0%±7.2%之 BA (N=6)。 實例4 :阿利克崙調配物 如下表B中所述來設計各種阿利克崙（Novartis)調配物， 且製備所有5種調配物。基本上如實例1中所述來製備調配 154767.doc -46- 201136582 物，其中每一調配物之親水性部分及疏水性介質中之成份 如表B中所列示。僅卡波普調配物（調配物II)使用中和步驟 且其他調配物則省去中和步驟。每一調配物皆含有10%之 阿利克崙游離鹼。Table A Ingredients (%w/w) Hydrophilic part FD4 0.545 Carbopol 934P 1.000 NaOH 15.000 Sodium octanoate 0.360 Water 1.033 Hydrophobic medium (lipophilic part) Tween 80 2.000 Monocaprylic glycerin 4.000 Tricaprylate 76.062 Result BA, % 12.5 SD 5.7 N 10 The formulation containing FD4 was tested as described in Example 2, and the absolute BA of FD4 as shown in the above table was 12.5%. Formulations similar to Formulation I and containing FD4 from the same batch (see Table B in Examples 1 and 4) gave 12.0% ± 7.2% BA (N = 6). Example 4: Aleclon Formulation Various Novartis formulations were designed as described in Table B below, and all five formulations were prepared. Formulations 154767.doc-46-201136582 were prepared essentially as described in Example 1, wherein the hydrophilic portion of each formulation and the components of the hydrophobic medium are as listed in Table B. Only the Carbopol formulation (Formulation II) uses the neutralization step and the other formulation eliminates the neutralization step. Each formulation contained 10% aliskiren free base.

表B 調配物 PVP12 (I) 1%卡波普 934P (II) 基本 (III) 辛酸 (IV) 1%PVA 27000 Da (V) 成份 (%w/w) (%w/w) (%w/w) (%w/w) (%w/w) 阿利克崙 10.0 10.0 10.0 10.0 10.0 PVP 12 10.0 0 2.75 10.0 0 親水性 PVA (M.W 27,000) 0 0 0 0 1.0 部分 卡波普934P 0 1.0 0 0 0 NaOH 0 0.384 0 0 0 辛酸鈉 15.0 15.0 12.0 15.0 15.0 水 0.711 0.538 0.506 0.702 0.522 Tween 80 2.0 2.0 0 0 2.0 單辛酸甘油酯 (GMC) 4.0 4.0 0 0 4.0 三辛酸甘油酯 (GTC) 58.2 67.00 0 0 67.4 疏水性 (親脂性） 介質 Span40 0 0 1.2 0 0 Lutrol F-68 6.0 卵磷脂 0 0 2.4 0 0 異戍酸乙酯 0 0 10.0 0 0 單油酸甘油酉旨 0 0 2.3 0 0 三丁酸甘油酯 0 0 19.6 0 0 蓖麻油 0 0 39.2 0 0 辛酸 0 0 0 58.2 0 AUC(〇-24Qmiiy 劑量 (ng*min/mL)/ (mg/kg) 2188 1429 1938 2182 1667 結果 CV, % 65 63 39 49 68 N 10 10 9 10 10 自阿利克崙口服 溶液之倍數 2.2 1.4 2.0 2.2 1.7 154767.doc • 47· 201136582 在凋配物i中，親水性部分之主要組份係pvp。藉由使用 不同形成基質之聚合物代替pvp(亦即，分別係卡波普及聚 乙烯醇（27 kDa PVA)及調配物1；1及¥)來檢驗pvp作為構成 要素之重要性。如針對其他4種調配物所述來製備基於辛 酸之調配物IV(參見例如圖1}且其似乎係半透明液體但仍 為懸浮液》 測試表B中之上述調配物在實例2中所述動物模型中的生 物利用度，亦即，藉由空腸投與至清醒（未麻醉）大鼠。使 用LC/MS/MS量測阿利克崙且如本文所述來測定每一調配 物之生物利用度。然後將此生物利用度與藉由管飼法給予 之未調配口服阿利克崙溶液的生物利用度進行比較，得到 下列結果.AUC(〇.24Qmin)/劑量/kg=99〇，cv=53%，N=l〇 該等結果示於上表B中。所測試之所有調配物皆顯示阿 利克崙生物利用度與阿利克崙之未調配口服溶液相比有所 增加。除外，以兩種形式來製備1〇% pvp調配物（調配物 I).上述凍乾形式及非凍乾形式丨（調配物〗_NL),此得到下 列結果： AUC(0.240min) /劑量/1^=^654 ’ cV=1220/〇，N=9，自阿利克 奋口服溶液之倍數= 1.7 穩定性數據：藉由在25〇c下培育2個月來測試表B中之3種 調配物、以及調配物穩定性。使用HpL(：來確定個 別雜質及降解物。總1]〇〇結果（雜質及降解物測定）如下： 調配物1=4.57%，調配物ΠΙ=7.29%，調配物IV=35.37%， 且調配物I-NL在2週之後失去同質性且不能進行量測。 154767.doc -48- 201136582 基於穩定性及生物利用度之數據，選擇調配物i作為未 來研發之基本候選者。 實例5:滲透性增強劑及PVP量之變化 滲透性增強劑：中鏈脂肪酸鹽係用於增加本發明調配物之 吸收之主要賦形劑，且特定而言使用辛酸鈉（sodium octanoate)(辛酸鈉（sodium caprylate))。由發明者實施之早 期調配作業顯示，生物利用度隨辛酸鈉濃度以線性關係增 加（3至12%)。在測試辛酸鈉濃度之進一步增加時（12、15 及1 8%之辛酸鈉），結果清晰地顯示在1 5%之辛酸鈉濃度時 具有最高生物利用度。使用不同API實施所有該等實驗， 其中需要顯著較低之載量（約0.05-0.1 %相對於約10%之阿 利克崙）。假設該等載量值很可能需要較高滲透性增強劑 濃度。 為證實此假設，製備調配物IA，其具有增加之辛酸鈉濃 度（20%)及減小之PVP濃度（2.75%)以為辛酸鈉「騰出空間 (to make room)」；此調配物可使得與調配物I相比生物利用 度減小約30%，如表C中所示。Table B Formulation PVP12 (I) 1% Carbopol 934P (II) Basic (III) Octanoic acid (IV) 1% PVA 27000 Da (V) Ingredient (%w/w) (%w/w) (%w/ w) (%w/w) (%w/w) Aleclon 10.0 10.0 10.0 10.0 10.0 PVP 12 10.0 0 2.75 10.0 0 Hydrophilic PVA (MW 27,000) 0 0 0 0 1.0 Part of Kapoor 934P 0 1.0 0 0 0 NaOH 0 0.384 0 0 0 Sodium octanoate 15.0 15.0 12.0 15.0 15.0 Water 0.711 0.538 0.506 0.702 0.522 Tween 80 2.0 2.0 0 0 2.0 Monocaprylin (GMC) 4.0 4.0 0 0 4.0 Tricaprylin (GTC) 58.2 67.00 0 0 67.4 Hydrophobic (lipophilic) Medium Span40 0 0 1.2 0 0 Lutrol F-68 6.0 Lecithin 0 0 2.4 0 0 Ethyl isodecanoate 0 0 10.0 0 0 Monooleic acid glycerol 0 0 0 2.3 0 0 Tributyric acid Glyceride 0 0 19.6 0 0 Castor oil 0 0 39.2 0 0 Octanoic acid 0 0 0 58.2 0 AUC (〇-24Qmiiy dose (ng*min/mL) / (mg/kg) 2188 1429 1938 2182 1667 Result CV, % 65 63 39 49 68 N 10 10 9 10 10 Multiples from the oral solution of Alikron 2.2 1.4 2.0 2.2 1.7 154767.doc • 47· 201136582 In the ligand i, the main component of the hydrophilic part is pvp. The importance of pvp as a constituent element was examined by replacing pvp with different matrix-forming polymers (i.e., respectively, Kappa universal polyvinyl alcohol (27 kDa PVA) and formulations 1; 1 and ¥). Formulations to prepare octanoic acid-based formulation IV (see, eg, Figure 1} and appear to be a translucent liquid but still a suspension.) The above formulation in Table B is tested in the animal model described in Example 2. Bioavailability, ie, administration to awake (non-anesthetized) rats by jejunum. Alikron was measured using LC/MS/MS and the bioavailability of each formulation was determined as described herein. This bioavailability was compared with the bioavailability of unallocated oral aliskiren solution administered by gavage to obtain the following results. AUC (〇.24Qmin)/dose/kg=99〇, cv=53%, N =l〇 These results are shown in Table B above. All formulations tested showed an increase in aliquots bioavailability compared to the unaltered oral solution of aliskiren. Except, the 1% pvp formulation (Formulation I) was prepared in two forms. The above lyophilized form and the non-lyophilized form 丨 (Formulation _NL) gave the following results: AUC (0.240 min) / dose / 1^=^654 ' cV=1220/〇, N=9, multiples from Alikrefen oral solution = 1.7 Stability data: Test 3 types in Table B by incubation at 25 °c for 2 months And the stability of the formulation. HpL (: to determine individual impurities and degradants. Total 1) 〇〇 results (measured by impurities and degradants) are as follows: Formulation 1 = 4.57%, formulation ΠΙ = 7.29%, formulation IV = 35.37%, and blending I-NL lost homogeneity after 2 weeks and could not be measured. 154767.doc -48- 201136582 Based on stability and bioavailability data, formulation i was chosen as a basic candidate for future R&D. Example 5: Infiltration Changes in Sex Enhancer and PVP Amount Permeability Enhancers: Medium chain fatty acid salts are the primary excipients used to increase the absorption of the formulations of the present invention, and in particular sodium octanoate (sodium caprylate) )). Early deployments performed by the inventors showed that bioavailability increased linearly with sodium octanoate concentration (3 to 12%). When testing for further increase in sodium octanoate concentration (12, 15 and 1.8% octanoic acid) Sodium), the results clearly show the highest bioavailability at a concentration of 1% sodium octanoate. All of these experiments were performed using different APIs, where a significantly lower loading was required (approximately 0.05-0.1% vs. approximately 10%) Alek Assuming that these loading values are likely to require higher permeability enhancer concentrations. To confirm this hypothesis, formulation IA was prepared with increased sodium octanoate concentration (20%) and reduced PVP concentration (2.75%). It is thought that sodium octanoate "to make room"; this formulation can reduce bioavailability by about 30% compared to Formulation I, as shown in Table C.

表C 調配物 AUC(〇.240 min)/ 劑量/kg(CV) N 自管飼法之倍數 阿利克崙口服溶液 (管飼法） 990 (53%) 10 1 調配物I (參見表B) 2188 (65%) 10 2.2 調配物IA-含有 20%辛酸鈉、2.75% PVP 1427 (63%) 9 1.4 154767.doc -49- 201136582 PVP :另一考慮因素涉及PVP之含量。API載量必須維持於 相對較高值以達成治療性阿利克崙血液濃度。因此，其可 有助於試圖減小形成基質之聚合物之含量以獲得更大API 載量能力並減小調配物黏度。此係使用調配物I之非凍乾 (NL)形式（調配物I-NL)來實施，如表d中所示。調配物I-NL-3% PVP與調配物I-NL相似，只是將PVP量減小至3%。Table C Formulation AUC (〇.240 min) / dose / kg (CV) N Self-administration multiples of aliskiren oral solution (gavage) 990 (53%) 10 1 Formulation I (see Table B) 2188 (65%) 10 2.2 Formulation IA-containing 20% sodium octanoate, 2.75% PVP 1427 (63%) 9 1.4 154767.doc -49- 201136582 PVP: Another consideration relates to the PVP content. The API loading must be maintained at a relatively high value to achieve a therapeutic aliskiren blood concentration. Thus, it can be helpful to attempt to reduce the amount of polymer forming the matrix to achieve greater API loading capacity and to reduce formulation viscosity. This was carried out using the non-lyophilized (NL) form of Formulation I (Formulation I-NL) as shown in Table d. Formulation I-NL-3% PVP is similar to Formulation I-NL except that the amount of PVP is reduced to 3%.

表D 調配物 AUC(〇.240 min)/ 劑量/kg(CV) N 自管飼法之倍數 阿利克崙口服溶液 (管飼法） 990 (53%) 10 1 調配物I-NL 1654 (122%) 9 1.7 調配物 I-NL^/o PVP 1195 (51%) 9 1.2 如表D中所示’減小PVP量會導致生物利用度略有降低 且因此並不在未來調配物中實施。 實例6:使用極性化合物來代替辛酸之研究。 如上所述’辛酸基調配物（表B中之調配物IV)顯示具有 良好生物利用度及延長之PK特徵（較佳），但亦在25°C下培 育2個月之後總共產生35.37%之降解物。 為試圖保持生物利用度優點並改良穩定性，檢查不同之 極性親脂性化合物，該等極性親脂性化合物之酸性及極性 小於辛酸。該等親脂性化合物係單辛酸甘油酯（GMC)、辛 酸乙酯、Captex 200(丙二醇二辛酸酯/二癸酸酯）及泊洛沙 姆123、124及181。根據表B中之調配物I來製備調配物， 154767.doc •50- 201136582 其中親脂（疏水）相由上述化合物中之一者代替。檢查調配 物之穩定性及/或生物利用度。結果示於下表E中。Table D Formulation AUC (〇.240 min) / dose / kg (CV) N Self-administration multiples of Alikron oral solution (gavage) 990 (53%) 10 1 Formulation I-NL 1654 (122 %) 9 1.7 Formulation I-NL^/o PVP 1195 (51%) 9 1.2 As shown in Table D, decreasing the amount of PVP results in a slight decrease in bioavailability and is therefore not implemented in future formulations. Example 6: Study using a polar compound instead of caprylic acid. As described above, the 'octanoate-based formulation (Formulation IV in Table B) showed good bioavailability and prolonged PK characteristics (preferred), but also produced a total of 35.37% after 2 months of incubation at 25 °C. Degradation. In an attempt to maintain bioavailability advantages and improve stability, different polar lipophilic compounds are examined which are less acidic and less polar than octanoic acid. The lipophilic compounds are monocaprylin (GMC), ethyl octoate, Captex 200 (propylene glycol dicaprylate/dicaprate) and poloxamers 123, 124 and 181. Formulations were prepared according to Formulation I in Table B, 154767.doc • 50-201136582 wherein the lipophilic (hydrophobic) phase was replaced by one of the above compounds. Check the stability and/or bioavailability of the formulation. The results are shown in Table E below.

表E 調配物 AUC(〇_240 min/ 劑量/kg(CV) N 自管飼法之倍數 阿利克备口服溶液 (管飼法） 990 (53%) 10 1 調配物I 2188 (65%) 10 2.2 調配物IV 2182 (49%) 10 2.2 調配物IV-NL，具有GMC 作為脂質相 3855 (126%) 19 3.9 調配物I， 具有 Captex 200 (0.5%NaTC、6%卵磷脂） 1515 (101%) 10 1.5 該等結果顯示使用GMC作為脂質相可得到良好生物利用 度。並不檢查含有其他極性親脂性化合物之調配物之生物 利用度，此乃因其缺乏穩定性改良（辛酸乙酯、泊洛沙姆 124)或因調配物對大鼠具有毒性（泊洛沙姆1 23及1 8 1)。極 性親脂性LFP方式論述於實例9中。 實例7 :不同表面活性劑對調配物之生物利用度及穩定性 的影響 大部分本發明調配物係親水性顆粒存在於親脂性（疏水 性）介質中之懸浮液。在將調配物放置於GI環境中時，其 會暴露於水性介質且可能將形成乳液。乳液性質（包含吸 收能力）應與表面活性劑摻和物之性質密切相關。設計若 干實驗以優化表面活性劑，從而產生較高生物利用度/穩 154767.doc -51 - 201136582 定性。 HLB方式。使用不同比率之親脂性及親水性表面活性劑來 實施實驗以優化表面活性劑摻和物之HLB。使用Labrafil (HLB 4)及Lutrol F-68 (HLB 29)之組合（總表面活性劑濃度 為6%)且涵蓋之HLB範圍為5.3至27.8。該等實驗所產生之 調配物黏性過大且生物利用度較小。 膽汁模擬。根據調配物1(表B中）製備一系列調配物，其中 使用6°/。卵磷脂作為疏水性介質中之單一表面活性劑（代替 GMC及Tween 80)並向固體（親水性）相中添加不同量之磺膽 酸鈉（Na-TC)。檢查調配物之生物利用度，如下表F中所 示。 調配物 AUC(〇_240 min/ 劑量/kg(CV) N 自管飼法之倍數 阿利克崙口服溶液 (管飼法)對照 990 (53%) 10 1 調配物I 2188 (65%) 10 2.2 調配物I，包含 6%卵磷脂 2497 (45%) 9 2.5 調配物I，包含 0.1% Na-TC、6%卵磷脂 3347 (150%) 9 3.4 調配物I，包含 0.5% Na-TC、6%卵磷脂 (此處稱為調配物ΫΙ) 6897 (78%) 10 7.0 調配物I，包含 1% Na-TC、6%卵磷脂 2217 (62) 10 2.2 調配物I，包含 3% Na-TC、6%卵磷脂 2813 (91) 10 2.8 -52- 154767.doc 201136582 表F展示牛績膽酸鈉（稱為Na-TC)之劑量-反應結果，且 顯示在調配物中納入膽汁組份（牛磺膽酸鈉）會改良生物利 用度且在0.5%牛磺膽酸鈉時具有最大效應。在固體（親水 性）相中具有0.5% Na-TC且具有6%卵磷脂作為單一表面活 性劑之調配物I稱為調配物VI ;其詳細組成可參見實例1〇 中之表J。在不含卵磷脂之相似系列調配物中，使用2〇/〇阿 利克崙實施相似牛磺膽酸鈉劑量-反應實驗；此實驗亦顯 示在固體（親水性）相中包括0.5% Na-TC之調配物可得到最 高生物利用度’在此情形下最高生物利用度較管飼法增加 5 ·6 倍。 然後研究表F中之兩種調配物-調配物I及調配物VI(具有 〇·5°/。Na_TC、6°/。卵磷脂）的穩定性。將調配物在25°c下維 持4週並在40°C下維持4週且分析降解物；參見實例8。兩 種調配物之結果極其相似且顯示納入卵磷脂及牛磺膽酸鈉 對穩定性並無顯著影響。 其他表面活性劑：研究包含若干組份之摻和物且基於pEG 之表面活性劑（例如辛酸癸酸聚乙二醇甘油酯）。發現調配 物並不穩定。納入Lutrols (F-68, F-127)可產生與納入6%卵 磷脂時相比具有較差生物利用度之調配物。 因此’具有最佳生物利用度之調配物係改良之調配物 I ’其在固體形式中含有〇.5%牛磺膽酸鈉且在疏水性介質 中含有6%㈣脂作為表面活性劑，且此調配物稱為調配 物VI’·此調配物之詳細組成可參見實例1〇中之表卜使用 調配物VI作為進一步研發之基礎。 154767.doc -53· 201136582 實例8 :阿利克崙調配物之穩定性 阿利克崙之穩定性係調配物研發之主要關注點之一。 研究降解物形成之3個最可能原因：甸賦形劑中之殘餘 水含量；b)賦形劑中之殘餘酸含量；及勹金屬催化： a) 殘餘水.控制調配物中親水性部分（HFp)之水含量且並 不超過2%。在調配物中具有額外殘餘水之唯一可能係脂 類賦形劑之水含量。藉由KF滴定檢查若干賦形劑（GMC、 GTC、Tween-80及辛酸）之水含量，且在25<t&4〇t：下以 長達2個月之間隔量測每一賦形劑中阿利克崙之穩定性。 發現賦形劑中之水含量與相應賦形劑中之阿利克崙穩定性 之間並無關聯。 b) 殘餘酸度：檢驗若干賦形劑之酸值與穩定性結果之間之 關聯。在25°C及4〇t下，將阿利克崙與具有較低酸值之4 種賦形劑（辛酸、GMC、Tween-80及GTC)中的一者一起分 別單獨培育長達兩個月，且量測雜質及降解物之量。發現 賦形劑酸度與由賦形劑產生之去穩定作用之間實際上具有 正相關聯。換言之，最多之酸性介黉辛酸會產生最多之雜 質及降解物，而最少之酸性介質GTC會產生最少之雜質及 降解物。 為研究此問題’製備兩種基於GTC之調配物。此係不含 表面活性劑且添加/不添加2%乙酸之調配物I。4週内在 2 5 C下之穩定性結果顯示，增加調配物之酸度會導致降解 顯著增加。人們試圖藉由緩衝系統來解決此問題，且將不 同鹼（有機胺）添加至GMC中之阿利克崙分散液中（咪唑、菸 154767.doc •54· 201136582 酿胺及N，N-二異丙基乙基胺）或添加至調配物i中（菸醯胺或 於酸乙醋’添加至親水性部分或親脂性介質或二者中）’ 其中並無任何可察覺之穩定作用。顯而易見，在此類調配 物中’殘餘酸度並非主要之降解源。 c)金屬觸媒。研究殘餘金屬對阿利克崙穩定性之影響。為 檢查殘餘重金屬之量，對調配物〗中之成份實施感應耦合 電浆（ICP)分析，該等成份係辛酸鈉、PVP-12、Tween 80、GMC及GTC。在辛酸鈉中發現之唯一可疑發現係高硼 含量。因此’將硼作為可能之阿利克崙去穩定劑進行研 九。然而’發現不同pH值下之硼酸鹽並不影響溶液中之阿 利克崙穩定性* 實例9:獲得阿利克备調配物穩定性之額外方式 在上述研究（實例8)未能成功之後，本發明者試圖以下 列方式來解決穩定性問題： 0)抗氧化劑。在GMC基調配物之早期研發階段中，嘗試若 干抗氧化劑。納入親水性部分（〇〇25% Tori〇x)或分散於親 脂性介質（0.03% α-生育酚、〇 〇2% BHA)中之抗氧化劑並 無穩定作用。 (11)由GTC代替GMC »基於GMC之調配物顯示具有最佳生 物利用度但具有受限之穩定性。製備含有GTC作為唯一親 脂性相成份之GTC基調配物，且藉由在25。(：及40°C下培育 兩週來測試穩定性。 使用HPLC確定個別雜質及降解物。總IDE)結果（雜質及 降解物測定）如下： 154767.doc -55- 201136582 在25 C下培育兩週之後，含有GTC作為唯一親脂性相之 調配物I的IDD=1.12%，且含有GMC作為唯一親脂性相之 調配物I的IDD=1.74%。 在40°C下培育兩週之後，含有GTC作為唯一親脂性相之 調配物I的IDD=3.04%，且含有GMC作為唯一親脂性相之 調配物I的IDD=7.01% » (iii) 用於親脂性（疏水性）介質中之GTC之極性無羥基替代 物。本發明之GMC基調配物顯示具有最佳生物利用度但具 有受限之穩定性，此可能係由高含量之氫氧化物所致。因 此’人們試圖識別具有相似生物利用度但不危害穩定性之 極性連續相。辛酸乙醋' Captex 200(丙二醇二辛酸g旨/二 癸酸酯）及泊洛沙姆123及181皆作為本發明調配物之脂質 相進行研究。所有3種調配物中之穩定性結果皆未得到改 良。另外，生物利用度亦未得到改良，亦即，生物利用度 小於使用GMC之相應調配物（參見例如上表E)。 (iv) 金屬鹽。將二價陽離子之不同鹽（鎂、鈣及鋅化合物） 納入調配物I之親水性部分（僅親脂性介質GTC)及調配物VI 之親水性部分中；測試不同鹽濃度（1:1或1:2莫耳比率之阿 利克崙：穩定劑）。然後藉由在25°下培育四週並在40。下培 育兩週來測試其穩定性。使用HPLC確定個別雜質及降解 物。25°及40°下之總IDD結果（雜質及降解物測定）分別如 下：僅調配物1=2.00%及2.80% ;調配物I加3.0%乙酸鋅 = 0.74%及 1.95% ;調配物 I加 1.6%氣化鎂=1.30%及 4.76% ; 調配物VI加1.6%氣化鎂=0.9%及6.12% ;調配物VI加2.23% 154767.doc •56· 201136582 氣化鋅=1.1 7%及5.59% ;調配物VI加4.47%氣化鋅=0.90% 及2.71% ;調配物VI加1.82%氣化鈣=1.23%及4.96% ;調配 物VI加3.0%乙酸辞=0_ 50%及2.21% ;且調配物VI加6.0%乙 酸辞=0.3 0%及 1.92%。 亦在添加下列鹽時進行檢驗：乙酸亞鐵、檸檬酸鐵及乙 酸鈉。穩定性並無改良。因此，含有乙酸辞之調配物顯示 最佳穩定性。在獲得令人鼓舞之穩定性結果之後，檢查上 述調配物中若干調配物之生物利用度，且一些結果示於下 表G中。Table E Formulation AUC (〇_240 min/dose/kg(CV) N Multiple from self-administration method Alec oral solution (gavage) 990 (53%) 10 1 Formulation I 2188 (65%) 10 2.2 Formulation IV 2182 (49%) 10 2.2 Formulation IV-NL with GMC as lipid phase 3855 (126%) 19 3.9 Formulation I with Captex 200 (0.5% NaTC, 6% lecithin) 1515 (101% 10 1.5 These results show that good bioavailability can be obtained with GMC as the lipid phase. The bioavailability of formulations containing other polar lipophilic compounds is not checked, due to its lack of stability improvement (ethyl octanoate, mooring) Losham 124) or because the formulation is toxic to rats (poloxamers 1 23 and 181). The polar lipophilic LFP mode is discussed in Example 9. Example 7: Different surfactants versus formulation organisms Effects of Utilization and Stability Most of the formulations of the present invention are suspensions of hydrophilic particles present in a lipophilic (hydrophobic) medium. When the formulation is placed in a GI environment, it is exposed to an aqueous medium and may Will form an emulsion. The properties of the emulsion (including absorption capacity) should be compatible with the surface. The nature of the active agent blend is closely related. Several experiments were designed to optimize the surfactant to produce a higher bioavailability/stability 154767.doc -51 - 201136582 Qualitative. HLB method. Use different ratios of lipophilic and hydrophilic surfaces The active agent was used to perform experiments to optimize the HLB of the surfactant blend. A combination of Labrafil (HLB 4) and Lutrol F-68 (HLB 29) (total surfactant concentration of 6%) was used and the HLB range was 5.3. To 27.8. The formulations produced in these experiments were too viscous and less bioavailable. Bile simulation. A series of formulations were prepared according to Formulation 1 (in Table B) using 6 ° / lecithin as hydrophobic A single surfactant in the medium (instead of GMC and Tween 80) and a different amount of sodium sulfonate (Na-TC) added to the solid (hydrophilic) phase. Check the bioavailability of the formulation as shown in Table F below. Formulation AUC (〇 _240 min / dose / kg (CV) N multiple of self-administration method Alikron oral solution (gavage) control 990 (53%) 10 1 Formulation I 2188 (65%) 10 2.2 Formulation I, containing 6% lecithin 2497 (45%) 9 2.5 Formulation I, containing 0.1% Na-TC, 6% lecithin 3347 (150%) 9 3.4 Formulation I, containing 0.5% Na-TC, 6% lecithin (herein referred to as formulation ΫΙ) 6897 (78% 10 7.0 Formulation I, containing 1% Na-TC, 6% lecithin 2217 (62) 10 2.2 Formulation I, containing 3% Na-TC, 6% lecithin 2813 (91) 10 2.8 -52- 154767. Doc 201136582 Table F shows the dose-response results for sodium cholic acid sodium (called Na-TC) and shows that inclusion of the bile component (sodium taurocholate) in the formulation improves bioavailability and is 0.5% cattle Sodium sulfate has the greatest effect. Formulation I having 0.5% Na-TC in a solid (hydrophilic) phase and having 6% lecithin as a single surfactant is referred to as Formulation VI; the detailed composition can be found in Table J of Example 1A. In a similar series of formulations containing no lecithin, a similar dose of taurocholate dose-response was performed using 2 〇/〇 aliskiren; this experiment also showed 0.5% Na-TC in the solid (hydrophilic) phase. The highest bioavailability is obtained for the formulation'. In this case, the highest bioavailability is increased by 5.6 times compared to the tube feeding method. The stability of the two formulations in Table F, Formulation I and Formulation VI (having 〇·5°/.Na_TC, 6°/. lecithin), was then investigated. The formulation was maintained at 25 ° C for 4 weeks and at 40 ° C for 4 weeks and analyzed for degradation products; see Example 8. The results of the two formulations were extremely similar and showed no significant effect on the stability of the inclusion of lecithin and sodium taurocholate. Other Surfactants: Surfactants containing several components and based on pEG (eg, octadecyl phthalate). The formulation was found to be unstable. Inclusion of Lutrols (F-68, F-127) resulted in formulations with poor bioavailability compared to when 6% lecithin was included. Thus, the formulation with improved optimum bioavailability I's contained 〇.5% sodium taurocholate in a solid form and 6% (tetra) lipid as a surfactant in a hydrophobic medium, and This formulation is referred to as Formulation VI'. The detailed composition of this formulation can be found in Table 1 of Table 1 using Formulation VI as a basis for further development. 154767.doc -53· 201136582 Example 8: Stability of aliskiren formulations One of the main concerns of the development of formulations is the stability of aliskiren. Study the three most likely causes of degradant formation: residual water content in the excipient; b) residual acid content in the excipient; and ruthenium metal catalysis: a) residual water. Control the hydrophilic portion of the formulation ( The water content of HFp) does not exceed 2%. The only possible water content of the lipid excipient with additional residual water in the formulation. The water content of several excipients (GMC, GTC, Tween-80 and octanoic acid) was checked by KF titration and each excipient was measured at 25<t&4〇t: for up to 2 months intervals The stability of Aleclon. There was no correlation between the water content of the excipients and the stability of aliskiren in the corresponding excipients. b) Residual acidity: The correlation between the acid value of several excipients and the stability results is examined. Acrylol was separately incubated with one of the four excipients with lower acid value (octanoic acid, GMC, Tween-80 and GTC) for up to two months at 25 ° C and 4 °t And measure the amount of impurities and degradants. It was found that there is actually a positive correlation between the acidity of the excipient and the destabilizing effect produced by the excipient. In other words, the most acidic octanoic acid will produce the most impurities and degradants, while the least acidic medium GTC will produce the least impurities and degradants. To study this problem, two GTC-based formulations were prepared. This is a formulation I which does not contain a surfactant and is added/not added with 2% acetic acid. Stability results at 2 5 C over 4 weeks showed that increasing the acidity of the formulation resulted in a significant increase in degradation. Attempts have been made to solve this problem by buffering systems, and different bases (organic amines) have been added to the aliskiren dispersion in GMC (imidazole, smoke 154767.doc •54· 201136582 amine and N,N-di Propylethylamine) or added to Formulation i (smokimin or in the addition of a fatty acid or a lipophilic medium or both) to which there is no appreciable stabilizing effect. It is apparent that residual acidity is not a major source of degradation in such formulations. c) Metal catalyst. Study the effect of residual metals on the stability of aliskiren. In order to check the amount of residual heavy metals, inductively coupled plasma (ICP) analysis was performed on the components in the formulation, which were sodium octoate, PVP-12, Tween 80, GMC and GTC. The only suspicious finding found in sodium octanoate is the high boron content. Therefore, boron was studied as a possible aliskiren destabilizer. However, 'the discovery of borate at different pH values does not affect the stability of aliskiren in the solution* Example 9: Additional way to obtain stability of the Alikort formulation After the above study (Example 8) failed, the invention Try to solve the stability problem in the following ways: 0) Antioxidant. Try several antioxidants in the early stages of development of GMC-based formulations. The antioxidants contained in the hydrophilic fraction (〇〇25% Tori〇x) or dispersed in the lipophilic medium (0.03% α-tocopherol, 〇 2% BHA) did not have a stabilizing effect. (11) Replacement of GMC by GTC » GMC-based formulations show optimal bioavailability but limited stability. A GTC-based formulation containing GTC as the sole lipophilic phase component was prepared and was at 25. (: and two weeks of incubation at 40 ° C to test stability. Determination of individual impurities and degradants using HPLC. Total IDE) results (measured by impurities and degradation products) are as follows: 154767.doc -55- 201136582 Incubate two at 25 C After week, IDD = 1.12% of Formulation I containing GTC as the only lipophilic phase, and IDD = 1.74% of Formulation I containing GMC as the only lipophilic phase. After incubation for two weeks at 40 ° C, IDD = 3.04% of Formulation I containing GTC as the only lipophilic phase, and IDD = 7.01% of Formulation I containing GMC as the only lipophilic phase » (iii) The polarity of GTC in a lipophilic (hydrophobic) medium is free of hydroxy substitutions. The GMC-based formulations of the present invention exhibit optimum bioavailability but have limited stability, which may be caused by high levels of hydroxide. Therefore, people try to identify polar continuous phases that have similar bioavailability but do not compromise stability. Capitol 200 (propylene glycol dioctanoic acid g/dicaprate) and poloxamers 123 and 181 were studied as lipid phases of the formulations of the present invention. The stability results in all three formulations were not improved. In addition, bioavailability has not been improved, i.e., bioavailability is less than the corresponding formulation using GMC (see, for example, Table E above). (iv) Metal salts. Different salts of divalent cations (magnesium, calcium and zinc compounds) are incorporated into the hydrophilic portion of formulation I (Gophilic medium only) and the hydrophilic portion of formulation VI; different salt concentrations are tested (1:1 or 1) : 2 molar ratio of aliskiren: stabilizer). It is then incubated at 25° and at 40°. The culture was tested for two weeks to test its stability. Individual impurities and degradants were determined using HPLC. The total IDD results (measured by impurities and degradants) at 25° and 40° were as follows: Formulation 1 = 2.00% and 2.80%, respectively, Formulation I plus 3.0% zinc acetate = 0.74% and 1.95%; Formulation I plus 1.6% magnesium oxide = 1.30% and 4.76%; Formulation VI plus 1.6% magnesium oxide = 0.9% and 6.12%; Formulation VI plus 2.23% 154767.doc • 56· 201136582 Zinc oxide = 1.1 7% and 5.59 %; Formulation VI plus 4.47% zinc oxide = 0.90% and 2.71%; Formulation VI plus 1.82% Calcium Calcium = 1.23% and 4.96%; Formulation VI plus 3.0% acetic acid = 0_50% and 2.21%; And Formulation VI plus 6.0% acetic acid = 0.30% and 1.92%. It was also tested when the following salts were added: ferrous acetate, ferric citrate and sodium acetate. Stability has not improved. Therefore, the formulation containing the acetic acid showed the best stability. After obtaining encouraging stability results, the bioavailability of several formulations in the above formulations was examined and some results are shown in Table G below.

表G 調配物 AUC{〇.240 min)/ 劑量/kg(CV) N 自管飼法之倍數 阿利克崙口服溶液 (管飼法)對照 990 (53%) 10 1 調配物I 2188 (65%) 10 2.2 調配物VI 6897 (78%) 10 7.0 調配物VI加2.59% CaCl2 1051 (69%) 10 1.1 調配物VI加3.0% ZnAc2 1925 (62%) 10 2.0 (v)胺基酸。本發明者假定胺基酸（例如甘胺酸、天門冬胺 酸及精胺酸）可用作穩定劑。將甘胺酸（1.23%)、精胺酸 (2.86%)及天門冬胺酸（2.2%)各自單獨添加至調配物VI之親 水性部分中。藉由在25°C下培育一週並在40°C下培育一週 來測試該等調配物以及不含胺基酸之調配物VI的穩定性。 使用HPLC確定個別雜質及降解物。25°及40°下之總IDD結 154767.doc -57- 201136582 果（雜質及降解物測定）分別如下：僅調配物VI = 0.62%及 3.5 5% ;調配物VI加甘胺酸=0·44%及2.93% ;調配物VI加 精胺酸=0.36%及1.59% ;且調配物VI加天門冬胺酸=0.66% 及5.02%。亦測試胍，但其對穩定性並無顯著影響。 基於該等結果，研究調配物VI中較高精胺酸濃度下之穩 定性。在25°C下培育4週及在40°C下培育兩週之總IDD結果 分別如下：僅調配物VI = 0.90%及6.12% ;調配物VI加 2.86%精胺酸=1.07%及3.57% ;調配物VI加5.72%精胺酸 =1.00%及3.27%。然後測試含有精胺酸之本發明調配物的 生物利用度，且結果示於表Η中。 表Η 調配物 AUC(〇-240 min)/ 劑量/kg(CV) N 自管飼法之倍數 阿利克崙口服溶液 (管飼法)對照 990 (53%) 10 1 調配物I 2188 (65%) 10 2.2 調配物VI 6897 (78%) 10 7.0 調配物VI加2.86% Arg 4448 (69%) 10 4.5 調配物VI加5.72% Arg 2985 (23%) 10 3.0 上表Η中之結果顯示，含有精胺酸之調配物具有生物利 用度。 (vi)組合調配物。組合調配物係包含金屬鹽及胺基酸二者 之調配物。因含有精胺酸之調配物及含有ZnAc2之調配物 (如上所述）顯示降解物形成顯著降低，故人們試圖製備組 154767.doc -58 - 201136582 合調配物。發現難以製備包含乙酸辞及精胺酸二者之親水 性部分’此乃因在製備期間會形成黏性沉澱物。最後，製 備含有3 %乙酸辞/ 2 · 8 6 %精胺酸之組合乙酸辞/精胺酸調配 物，且使用兩種不同親水性部分進行製備： •第1親水性部分：將一半量之阿利克崙、一半量之牛 石黃膽酸鈉、所有PVP及所有乙酸鋅溶於—半量之水 中，冷凍並凍乾。 •第2親水性部分：將一半量之阿利克崙、一半量之牛 磺膽酸鈉、所有辛酸鈉及所有精胺酸溶於一半量之水 中，冷凍並凍乾。 /東乾之後，將兩種親水性部分一起混合至親脂性介質中 以製得一種原料藥產物。 穩定性結果如下：在25°C下培育3個月時， IDD=0.40% ;在 40°C 下培育 4週時，lDD=〇.79% ;在 下 培育2個月時，IDD=0.08%。 因此，此組合調配物極其穩定，但在動物模型中測試 時，發現此調配物具有較低生物利用度，且顯示相比於管 飼法並無改良。 使用精胺酸：乙酸鎂（使用兩種不同濃度之精胺酸及乙 酸鎂）、及乙酸鈣來製備其他組合❶其他金屬鹽並不形成 使用鋅鹽時所看到之沉澱且可以常規方式（製備一種親水 性部分）製得，但其他金屬鹽與精胺酸之組合不能如乙酸 鋅/精胺酸之組合調配物一般顯著改良穩定性。 ㈣其他測試方式。嘗試奸額外方式以改良調配物之穩 154767.doc •59- 201136582 定性。該等方式包含；I用乾式粒化代替床乾（以減小阿 利克崙在水中之暴露）及使用甘油（作為穩定劑添加至 或LFP中，或者在與LFp混合之前使用甘油塗覆HpF粉 末）。所有該等努力皆不能獲得任何可察覺之穩定作用。 (iix)溫度影響。在穩定性程式期間，注意到4〇t>c下之降解 程度並不與25 C下之穩定性結果一致。似乎4〇艽下之降解 遠问於可能之預期。因此，研究若干調配物以探究2_8。〔 下培月之影響。結果清晰地顯示，在冰箱溫度（2 8。匚）下測 試之每一單一調配物中，即使在儲存2個月之後亦未形成 顯著降解物。4°C下之穩定性實驗結果如下： 對於調配物VI而言，4週後之IDD=0.150/。 對於調配物VI-Zri(具有3.0%乙酸鋅之調配物vi)而言，2 個月後之IDD=0.10% 對於調配物VI-Arg(具有5.72%精胺酸之調配物vi)而 言，2個月後之IDD=0.67% 實例10 : 3種阿利克崙調配物 基於生物利用度及穩定性結果之組合，應注意3種主要 調配物： •調配物VI :此源自調配物I，其中在親水性部分中具 有0.5%牛磺膽酸鈉且在親脂性介質中具有6%卵磷脂 代替 Tween/GMC。Table G Formulation AUC {〇.240 min) / Dosage / kg (CV) N Self-administration multiples of Alikron oral solution (gavage) control 990 (53%) 10 1 Formulation I 2188 (65% 10 2.2 Formulation VI 6897 (78%) 10 7.0 Formulation VI plus 2.59% CaCl2 1051 (69%) 10 1.1 Formulation VI plus 3.0% ZnAc2 1925 (62%) 10 2.0 (v) Amino acid. The inventors have assumed that amino acids such as glycine, asparagine and arginine can be used as stabilizers. Glycine (1.23%), arginine (2.86%) and asparagine (2.2%) were each added separately to the hydrophilic portion of Formulation VI. The stability of the formulations and the amino acid-free formulation VI was tested by incubation at 25 ° C for one week and at 40 ° C for one week. Individual impurities and degradants were determined using HPLC. The total IDD junction at 25° and 40° 154767.doc -57- 201136582 (measured by impurities and degradation products) are as follows: only formulation VI = 0.62% and 3.5 5%; formulation VI plus glycine = 0 44% and 2.93%; Formulation VI plus arginine = 0.36% and 1.59%; and Formulation VI plus aspartic acid = 0.66% and 5.02%. Helium was also tested, but it did not have a significant effect on stability. Based on these results, the stability of the higher arginine concentration in the formulation VI was investigated. The total IDD results of incubation at 25 ° C for 4 weeks and incubation at 40 ° C for two weeks were as follows: only formulation VI = 0.90% and 6.12%; formulation VI plus 2.86% arginine = 1.07% and 3.57% Formulation VI plus 5.72% arginine = 1.00% and 3.27%. The bioavailability of the formulations of the invention containing arginine was then tested and the results are shown in the table. Table 调 Formulation AUC (〇-240 min) / dose / kg (CV) N Self-administration method Alikron oral solution (gavage) control 990 (53%) 10 1 Formulation I 2188 (65% 10 2.2 Formulation VI 6897 (78%) 10 7.0 Formulation VI plus 2.86% Arg 4448 (69%) 10 4.5 Formulation VI plus 5.72% Arg 2985 (23%) 10 3.0 The results in the above table show that The formulation of arginine has bioavailability. (vi) Combination formulation. The combination formulation comprises a formulation of both a metal salt and an amino acid. Since the formulation containing arginine and the formulation containing ZnAc2 (described above) showed a significant decrease in the formation of degradants, attempts were made to prepare a formulation of the group 154767.doc -58 - 201136582. It has been found to be difficult to prepare a hydrophilic portion comprising both acetic acid and arginine. This is due to the formation of viscous precipitates during preparation. Finally, a combination acetic acid/arginine formulation containing 3% acetic acid / 2 · 680 % arginine was prepared and prepared using two different hydrophilic moieties: • 1 hydrophilic portion: half the amount Alikron, half the amount of sodium citrate, all PVP and all zinc acetate dissolved in half the amount of water, frozen and lyophilized. • The second hydrophilic fraction: half of the amount of aliskiren, half of the amount of sodium sulphocholate, all sodium octanoate and all arginine is dissolved in half the amount of water, frozen and lyophilized. After the East Dry, the two hydrophilic portions are mixed together into a lipophilic medium to prepare a drug substance product. The stability results were as follows: IDD = 0.40% at 3 months of incubation at 25 °C, lDD = 〇.79% at 4 weeks of incubation at 40 °C, and IDD = 0.08% at 2 months of incubation. Therefore, this combination formulation is extremely stable, but when tested in animal models, this formulation was found to have lower bioavailability and showed no improvement over tube feeding. The use of arginine: magnesium acetate (using two different concentrations of arginine and magnesium acetate), and calcium acetate to prepare other combinations of other metal salts does not form the precipitate seen when zinc salts are used and can be used in a conventional manner ( Preparation of a hydrophilic moiety) is made, but the combination of other metal salts with arginine does not generally improve stability as a combination of zinc acetate/arginine. (4) Other test methods. Try to sneak extra ways to improve the stability of the formula 154767.doc •59- 201136582 Qualitative. These include: I use dry granulation instead of bed dry (to reduce exposure of aliskiren in water) and use glycerin (added to LFP as a stabilizer, or glycerin coated HpF powder before mixing with LFp) ). None of these efforts can achieve any appreciable stabilization. (iix) Temperature effects. During the stability program, it was noted that the degree of degradation under 4〇t>c was not consistent with the stability results at 25 C. It seems that the degradation of 4 远 is far from what is expected. Therefore, several formulations were studied to explore 2_8. [The impact of the next month. The results clearly show that in each of the single formulations tested at the refrigerator temperature (2 8 Torr), no significant degradation products were formed even after storage for 2 months. The stability test results at 4 ° C are as follows: For Formulation VI, IDD = 0.150 / after 4 weeks. For the formulation VI-Zri (mixture vi with 3.0% zinc acetate), IDD = 0.10% after 2 months for the formulation VI-Arg (with 5.72% arginine formulation vi) IDD = 0.67% after 2 months Example 10: Combination of three aliquotene formulations based on bioavailability and stability results, three major formulations should be noted: • Formulation VI: This is derived from Formulation I, There is 0.5% sodium taurocholate in the hydrophilic portion and 6% lecithin in the lipophilic medium instead of Tween/GMC.

•調配物VI-Ζη :具有3.0%乙酸辞作為穩定劑之調配物 VI •調配物VI-Arg :具有5·72°/〇精胺酸作為穩定劑之調配 154767.doc -60· 201136582 物VI。 清晰起見，該3種調配物之組成如表J中所示：• Formulation VI-Ζη: Formulation with 3.0% acetic acid as stabilizer VI • Formulation VI-Arg: with 5·72°/〇 arginine as stabilizer Stabilizer 154767.doc -60· 201136582 . For clarity, the composition of the three formulations is shown in Table J:

表J 調配物編號 成伤 VI TCL VI-Ζη 3% Zn VI-Arg 5.72Arg % (%w/w) (%w/w) (%w/w) 親水性 部分 阿利克崙，呈半富馬 酸鹽形式 10 10 10 PVP 12 10 10 10 辛酸鈉 15 15 15 牛磺膽酸鈉 0.5 0.5 0.5 乙酸鋅 - 3.0 - 精胺酸 - - 5.72 殘餘水（假設佔HFP之 2%) 0.7 0.8 0.8 疏水性 (親脂性） 介質 卵磷脂 6.0 6.0 6.0 三辛酸甘油酯(GTC) 57.7 54.6 51.9 結果 AUC (〇-240min)/劑量 / kg b.w 6897 1925 2985 cv 78 62 23 N 10 10 10 自管飼法之倍數 7.0 2.0 3.0 在達成該等主要調配物之方法中，製備140種完整之本 發明調配物（不包含在針對不同賦形劑測試阿利克崙穩定 性時之預調配作業）。在大鼠中測試該等調配物中之65 種。 如此闡述至少一實施例之若干態樣後，應瞭解，彼等熟 習此項技術者可易於作出各種改變、修改及改良。該等改 變、修改及改良意欲作為本揭示内容之一部分且意欲屬於 本發明範圍内。因此，前文之闡述及圖式僅具有例示意 義，且本發明範圍應藉由合理構造隨附申請專利範圍及其 -61 - 154767.doc 201136582 等效内容來確定。 【圖式簡單說明】 下文參照附圖1來論述至少—實施例之各個態樣。提供 該圖式以用於闡述及闡釋目的且並不意欲界定本發明之界 限。圖1顯示根據一或多個實施例參照隨附實例來製備本 發明組合物之調配物的—般方法。 I54767.doc •62-Table J Formulation number is injured VI TCL VI-Ζη 3% Zn VI-Arg 5.72Arg % (%w/w) (%w/w) (%w/w) Hydrophilic part of aliskiren, semi-rich horse Acid form 10 10 10 PVP 12 10 10 10 Sodium octanoate 15 15 15 Sodium taurocholate 0.5 0.5 0.5 Zinc acetate - 3.0 - arginine - - 5.72 Residual water (assuming 2% of HFP) 0.7 0.8 0.8 Hydrophobicity (lipophilic) Medium Lecithin 6.0 6.0 6.0 Tricaprylin (GTC) 57.7 54.6 51.9 Result AUC (〇-240min) / dose / kg bw 6897 1925 2985 cv 78 62 23 N 10 10 10 Multiples from the tube feeding method 7.0 2.0 3.0 In a method of achieving these primary formulations, 140 complete formulations of the invention were prepared (not included in the pre-mixing operation when testing the stability of aliskiren for different excipients). 65 of the formulations were tested in rats. Having thus described a number of aspects of at least one embodiment, it will be appreciated that those skilled in the art can readily make various changes, modifications and improvements. Such changes, modifications, and improvements are intended to be part of this disclosure and are intended to be within the scope of the invention. Therefore, the foregoing description and drawings are intended to be illustrative only, and the scope of the invention should be BRIEF DESCRIPTION OF THE DRAWINGS At least the various aspects of the embodiments are discussed below with reference to FIG. The drawings are provided for purposes of illustration and description and are not intended to limit the scope of the invention. 1 shows a general method of preparing a formulation of a composition of the present invention with reference to the accompanying examples, in accordance with one or more embodiments. I54767.doc •62-

Claims (1)

201136582 七、申請專利範圍： 1· 一種醫藥組合物，其包括含有疏水性介質及固體形式之 混合物的懸浮液，其中該固體形式包括治療有效量之阿 利克崙（aliskiren)及視需要第二治療劑及視需要第三治療 劑及至少一種中鏈脂肪酸鹽。 2. 如請求項丨之醫藥組合物，其包括選自由形成基質之聚 合物及糖組成之群的額外組份。 3. 如明求項1及2之醫藥組合物，其中該固體形式包括顆 粒。 4. 如清求項3之醫藥組合物，其中該顆粒係藉由凍乾或粒 化或喷霧乾燥製得。 5. 如凊求項i至5中任一項之醫藥組合物，其中該醫藥組合 物中之水含量低於約6重量％、較佳低於約2重量％。 月求項1至5中任一項之醫藥組合物，其中該固體形式 中之水含量低於約6重量％、較佳低於約2重量％。 7_如請求項…中任一項之醫藥組合物，其中該中鏈脂肪 酸鹽具有約6至約14個碳原子之鏈長度。 士明求項7之醫藥組合物，其中該中鏈脂肪酸鹽係己酸 鈉、庚酸鈉、辛酸鈉、壬酸鈉、癸酸鈉、十一酸鈉、十 酸鈉十二酸鈉或十四酸鈉、或相應鉀鹽或鋰鹽或銨 鹽或其組合。 9.如”月求項8之醫藥組合物，其中該脂肪酸鹽係辛酸納。 1〇·如明求項1至9中任一項之醫藥組合物，其中該中鏈脂肪 酸鹽以11重量％至40重量％、較佳12重量％至18重量％、 154767.doc 201136582 最佳約15重量％之量存在於該組合物中。 U·如請求項H0中卜項之醫藥組合物，其中該中鍵脂 肪酸鹽以50重量％至90重量％之量、較佳7〇重量％至8〇重 量％之量存在於該固體形式中。 12·如請求項！至μ任—項之醫藥組合物，其中該形成基 質之聚合物以約0.5重量％至15重量％、較佳約！重量％至 10重量％之量存在於該組合物中。 13·如請求項1至12中任一項之醫藥組合物，其中該形成基 質之聚合物選自由以下組成之群：聚乙烯基吡咯啶酮、 卡波姆（carbomer)(例如卡波普（Carb〇p〇i)聚合物）、聚乙 烯醇、聚葡糖、海藻酸鹽、透明質酸鹽及聚丙烯酸鹽或 其組合。 14.如請求項13之醫藥組合物，其中該形成基質之聚合物選 自由以下組成之群：聚乙稀基°比略咬酮、卡波姆及聚乙 烯醇或其組合。 15_如請求項14之醫藥組合物’其中該聚乙烯基D比咯啶酮較 佳係PVP-12，且較值具有約3000之分子量，且係以約2 重量％至約20重量％之量、較佳約5重量％至約15重量％ 之量、最佳約10重量°/。之量存在於該組合物中。 16.如請求項14之醫藥組合物’其中該卡波姆較佳係卡波普 934P ’且係以約0.1重量％至約6重量％之量、較佳約〇.5 重量％至約4重量％之量、最佳約1重量°/。之量存在於該組 合物中。 1 7.如請求項14之醫藥組合物，其中該聚乙烯醇較佳係分子 154767.doc 201136582 量為約27000 Da之聚乙烯醇，且係以4重量％之量最佳 約1重量％至2重量％之量存在於該組合物中。 18·如請求項1至17之醫藥組合物’其中該組合物不含中鏈 醇〇 19·如請求項1至17中任-項之醫藥組合物，其中該組合物 - 不含膜流化劑。 .2G.如請求項1至19中任-項之醫藥組合物，其另外包括表 面活性齊I。 21.如請求項2〇之醫藥組合物，其中該表面活性劑包括離子 型表面活性劑或非離子型表面活性劑或其組合。 月长項20之醫藥組合物’纟中該表面活性劑係印填脂 或膽鹽（例如牛磺膽酸鈉）或洗滌劑或其組合。 23.如請求項2〇之醫藥組合物，其中該表面活性劑係甘油單 酯、克瑞莫福(cremophore)、聚乙二醇脂肪醇醚、山梨 醇酐脂肪酸醋、聚氧乙烯山梨醇酐脂肪酸酯、色魯托 (S〇lutol)HS15(12_經基硬脂酸之聚氧乙烯⑹、院基糖⑽ 如辛基糖苦、四癸基麥芽糖苦）或泊洛沙姆（p〇i〇xa而）或 其組合。 24·如請求項23之醫藥組合物，其中該甘油單酿係單辛酸甘 油酯（glyceryl m〇n〇caprylate)、單辛酸甘油酯⑽叫！ m〇n〇OCtanoate)、單癸酸甘油酯、單月桂酸甘油酯、單 肉旦謹酸甘油0旨、單棕櫚酸甘油醋或單油酸甘油醋或單 硬脂酸甘油S旨或其組合。 25_如請求項23之醫藥組合物，其中該山梨醇酐脂肪酸酯包 154767.doc 201136582 山梨醇酐單油酸酯或山梨醇酐 括山梨醇酐單月桂酸醋、 單棕櫚酸酯或其組合。 26.如請禾項23之 八f该聚氧乙烯山梨醇脂 肪酸醋包括聚氧乙稀山梨料單油酸醋（Tween8〇)、聚 氧乙烯山梨醇肝單硬脂酸醋或聚氧乙婦山梨醇野單掠櫚 酸酯或其組合。 其中該表面活性劑存在 其中該表面活性劑存在 27.如請求項20至26之醫藥組合物 於該固體形式中。 28.如請求項20至26之醫藥組合物， 於該疏水性介質中。 29. 如請求項20至26之醫藥組合物，丨中該表面活性劑存在 於該固體形式及該疏水性介質二者中。 30. 如請求項27至29之醫藥組合物，其中該表面活性劑係卵 磷脂或膽鹽（例如牛續膽酸納）或洗務劑（例如Tw 或其組合。 31.如凊求項30之醫藥組合物’纟中該膽鹽選自牛磺膽酸 鈉、去氧膽酸鈉、甘膽酸鈉、鵝去氧膽酸鈉、膽酸鈉、 石膽酸鈉或其組合。 3 2 ·如凊求項1至3 1中任一頂之醫藥细人此 孭之朁樂組合物，其中該疏水性 介質以重量計之主要組份係三辛酸甘油酯。 33. 如請求項^中任_項之醫藥組合物，其中該疏水性 介質包括脂肪族、烯系、環狀或芳族化合物。 34. 如請求項1至33中任-項之醫藥組合物，其中該疏水性 介質包括礦物油、石躐、諸如辛酸等脂肪酸、甘油單 154767.doc 201136582 酉曰甘油二酸酯、甘油三酸酯、醚或酯（例如低分子量 醋’較佳異戊酸乙酯或乙酸丁酯）或其組合。 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 如凊求項34之醫藥組合物，其中該甘油三酸酯係長鏈甘 油三酸酯、或中鏈甘油三酸酯或短鏈甘油三酸酯或其組 合。 如請求項1至35中任一項之醫藥組合物，其另外包括阿 利克奋穩定劑。 如請求項36之醫藥組合物，其中該阿利克崙穩定劑係胺 基酸。 如請求項37之醫藥組合物，其中該胺基酸選自由甘胺 酸、天門冬胺酸及精胺酸或其組合組成之群。 如請求項38之醫藥組合物，其中該胺基酸係精胺酸。 如請求項36之醫藥組合物，其中該阿利克崙穩定劑係金 屬鹽。 如請求項40之醫藥組合物，其中該金屬鹽選自由鎂鹽、 鈣鹽及鋅鹽或其組合組成之群。 如請求項41之醫藥組合物，其中該金屬鹽選自由以下組 成之群.MgCl2、ZnCl2、CaCl2、乙酸辞、乙酸鎂及乙酸 鈣。 如請求項42之醫藥組合物，其中該金屬鹽係鋅鹽、較佳 乙酸辞。 如請求項36至43中任一項之醫藥組合物，其中該阿利克 崙穩定劑存在於該固體形式中。 如請求項1至44中任一項之醫藥組合物，其中該組合物 154767.doc 201136582 基本上由阿利克崙、中鏈脂肪酸鹽及形成基質之聚合物 及疏水性介質組成。 46. 如請求項i至44中任一項之醫藥組合物，其中該固體粉 末基本上由阿利克崙、中鏈脂肪酸鹽及形成基質之聚合 物組成。 47. 如請求項！至45中任一項之醫藥組合物，其中該疏水性 介質基本上由三辛酸甘油酯組成。 48. 如請求項47之醫藥組合物，其中該疏水性介質另外含有 表面活性劑。 49. 一種醫藥組合物，其包括基本上由疏水性介質及固體形 式之混合物組成的懸浮液，其中該固體形式包括治療有 效量之阿利克崙'至少一種中鏈脂肪酸鹽及形成基質之 聚合物^ 50. 如請求項49之醫藥組合物，其中該疏水性介質包括甘油 三酸酯或甘油單酯或其組合。 5 1. —種醫藥組合物，其包括含有疏水性介質及固體形式之 混合物的懸浮液，其中該固體形式包括治療有效量之阿 利克崙、至少一種中鏈脂肪酸鹽、形成基質之聚合物、 及視需要表面活性劑及視需要阿利克崙穩定劑。 52.如请求項5 1之醫藥組合物，其中該疏水性介質含有至少 一種表面活性劑、較佳卵磷脂，該表面活性劑較佳以約 3重量％至9重量％、較佳約6重量％存在。 53·如請求項5M52H组合物’其中該中鏈脂肪酸鹽係 辛酸鈉，該形成基質之聚合物係PVP_12，且該表面活性 154767.doc -6 - 201136582 劑係膽鹽、較佳牛續膽酸鈉。 54.如請求項5 1至53之醫藥組合物，其中該阿利克崙穩定劑 係胺基酸或金屬鹽或其組合。 5 5.如請求項5 3至5 4之醫藥組合物，其中該辛酸納係以1 〇重 量％至20重量％、較佳約1 5重量％之量存在，且該pvp係 以約5重量％至15重量％、較佳約1 〇重量％之量存在。 56.如請求項53至55之醫藥組合物，其中該牛磺膽酸鈉係以 〇. 1重量。/。至2重量％、較佳約〇.5重量％之量存在。 5 7.如請求項5 1至5 6之醫藥組合物’其中該阿利克崙係以i 重量°/。至20重量％、較佳約5重量％至1 〇重量％、或約丄〇 重量％之量存在。 58·如請求項5 1至57之醫藥組合物，其中該阿利克崙係阿利 克奋半富馬酸鹽。 59. 如請求項5 1至58之醫藥組合物’其另外包括第二治療 劑。 60. 如請求項59之醫藥組合物，其另外包括第三治療劑。 61. —種製備醫藥組合物之方法，其包括：製備包括治療有 效量之阿利克崙及視需要第二治療劑、及視需要第三治 療劑、及中鏈脂肪酸鹽之水溶液，乾燥該水溶液以獲得 固體粉末，及將該固體粉末懸浮於疏水性介質中，以製 得含有固體形式之該阿利克崙及該中鏈脂肪酸鹽的懸浮 液’由此製得該醫藥組合物。 62. 如請求項61之方法’其進一步包括存在於水溶性溶液中 之形成基質之聚合物。 I54767.doc 201136582 63. 如請求項61之方法，其中該固體形式包括顆粒。 64. 如請求項61至63之方法，其. 、中該乾知係藉由凍乾或粒化 或喷霧乾燥來達成》 65. 如請求顿至64中任-項之方法，其中該乾燥步驟去除 足量水’以使該醫藥組合物中之水含量低於約5重量％、 較佳低於約2重量％。 66·如請求項61至64中任-項之方法，其中該乾燥步驟去除 一定量的水，以使該固體粉末中之水含量低於6重量％、 較佳低於2重量％。 67.如請求項61至66中任一ϋ夕士 i ^ , T1項之方法，其中該中鏈脂肪酸鹽 具有約6至約14個碳原子之鏈長度。 6 8 ·如清求項61至6 6中任一夕士〇+ I γ1負之方法，其中該中鏈脂肪酸鹽 係己酸鈉、庚酸鈉、辛酸鈉、壬酸鈉、癸酸鈉、十一酸 鈉、十一酸鈉、十二酸鈉或十四酸鈉或相應鉀鹽或鋰鹽 或銨鹽或其組合，較佳係辛酸鈉。 69. 如請求項61至68中任一項之方法，其中該中鏈脂肪酸鹽 係以約11重量％至約40重量％、較佳丨丨重量％至約28重量 %、較佳約15重量％之量存在於該組合物中。 70. 如請求項61至68中任一項之方法，其中該中鏈脂肪酸鹽 係以3 0重量％至90重量％、較佳4〇重量％至8〇重量％之量 存在於該固體粉末中。 71. 如請求項62至70中任一項之方法，其中該形成基質之聚 合物選自由以下組成之群：聚乙烯基吡咯啶酮、卡波姆 (例如卡波普聚合物）、聚乙烯醇、聚葡糖、海藻酸鹽、 154767.doc 201136582 透明質酸鹽及聚丙烯酸鹽或其組合。 72. 73. 74. 75. 76. 77. 78. 79. 如4求項71之方法，其中該形成基質之聚合物選自由以 下組成之群：聚乙烯基吡咯啶酮、卡波姆及聚乙烯醇或 其組合。 月长項7 2之方法’其中該聚乙婦基η比略咬嗣較佳係 PVP-12 ’且較佳具有約3〇〇〇之分子量，且係以約2重量0/〇 至約20重量％之量、較佳約5重量％至約15重量％之量、 最佳約10重量％之量存在於該組合物中。 如凊求項72之方法，其中該卡波姆較佳係卡波普934ρ , 且係以約〇·1重量％至約6重量％之量、較佳約〇 5重量％至 約4重量％之量、最佳約1重量％之量存在於該組合物 中。 如请求項72之方法，其中該聚乙烯醇較佳係分子量為約 27000 Da之聚乙烯醇，且係以約〇1重量％至約6重量。/〇之 里、較佳約0.5重量y。至約4重量％之量、最佳約2重量％ 或1重量％之量存在於該組合物中。 如明求項61至75中任一項之方法，其中該組合物實質上 不含中鏈醇及/或膜流化劑。 如凊求項61至76中任一項之方法，其另外包括表面活性 劑。 如4求項61至77中任—項之方法’其中該疏水性介質包 括藥麻油或三辛酸甘油s旨或三丁酸甘油醋或辛酸或其組 合。 如请求項61至78中任一項之方法’其中該疏水性介質以 I54767.doc 201136582 十之主要組份係蓖麻油或三辛酸甘油酯或辛酸。 8〇·如：求項61至78中任-項之方法，其中該疏水性介質包 括脂肪族、烯系、環狀或芳族化合物。 81_如味求項8〇之方法’其中該疏水性介質包括脂肪族化合 物。 82·如請求項61至78中任-項之方法，其中該疏水性介質包 括礦物油、石蠟、諸如辛酸等脂肪酸、甘油單醋、甘油 二酸酯、甘油三酸酯、醚或酯或其組合。 83·如^項82之方法，其中該疏水性介質令之該醋係低分 子:S日’較佳係異戊酸乙g旨或乙酸丁酉旨，或者其中該甘 油^酸S旨係長鏈甘油三_、巾鏈甘油三㈣或短鏈甘 油二酸1¾其混合物’或者其中該長鏈甘油三酸醋係藥 麻油或椰子油或其組合。 月长項82之方法’其中該短鏈甘油三酸醋係三丁酸甘 油S曰且該中鏈甘油三酸酯係三辛酸甘油酯。 85. 如請求項61至84中任-項之方法，其另外包括至少-種 表面活性齊|J。 86. 如請求項85之方法，Α 〃中5亥表面活性劑包括離子型表面 活性劑或非離子型表面活性劑或其•且合。 ”·如請求項85之方法’其中該表面活性劑雜脂或膽鹽 (例如牛磺膽酸鈉）或洗滌劑或其組合。 青长項85之方法’其中該表面活性劑係甘油單醋、克 瑞莫福、聚乙二醇脂肪醇鍵、山梨醇肝脂肪酸醋、聚氧 乙稀山梨醇肝脂肪酸西旨、色魯托則15(12_經基硬脂酸之 154767.doc 201136582 聚氧乙稀s旨）、烧基糖（例如辛基糖苦、四癸基麥芽糖们 或泊洛沙姆或其組合。 89. 如請求項88之方法，其中該甘油單自旨料辛酸甘油醋 (glyceryl m〇nocaprylate)、單辛酸甘油醋（giyc一 m〇n〇〇ctanoate)、單癸酸甘油酯、單月桂酸甘油酯、單 肉豆蔬酸甘油醋、單棕櫚酸甘油酿或單油酸甘油酷或單 硬脂酸甘油m组合；或者其中該山梨料脂肪酸醋 包括山梨醇酐單月桂酸酯、山梨醇酐單油酸酯或山梨醇 酐單棕櫚酸醋或其組合；或者其中該聚氧乙烯山梨醇針 脂肪酸酯包括聚氧乙烯山梨醇酐單油酸酯（Tween 80)、 聚氧乙烯山梨醇酐單硬脂酸酯或聚氧乙烯山梨醇酐單棕 櫚酸酯或其組合。 90. 如請求項85至89之方法，其中該表面活性劑存在於該固 體形式中。 91. 如請求項85至89之方法，其令該表面活性劑存在於該疏 水性介質中。 92. 如請求項85至89之方法，其中該表面活性劑存在於該固 體形式及該疏水性介質二者中。 93. 如研求項85至92之方法’其中該表面活性劑係卵鱗脂或 膽鹽（例如牛磺膽酸鈉）或洗滌劑（例如Tween-80)或其組 合〇 94. 如請求項61至93中任一項之方法，其中該組合物基本上 由阿利克崙、中鏈脂肪酸鹽及形成基質之聚合物及疏水 性介質組成。 154767.doc 201136582 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 如哨求項61至93中任一項之方法，其中該固體粉末基本 上由阿利克崙、中鏈脂肪酸鹽及形成基質之聚合物組 成。 如明求項61至93中任一項之方法，其中該疏水性介質基 本上由三辛酸甘油酯組成。 如咕求項61至93中任一項之方法，其中該疏水性介質另 外含有表面活性劑β 如請求項61至93中任一項之方法，其中該固體粉末基本 上由阿利克崙及中鏈脂肪酸鹽及表面活性劑組成。 如請求項61至98中任一項之方法，其中該疏水性介質基 本上由三辛酸甘油酯組成。 如凊求項61至99中任一項之方法，其另外包括阿利克崙 穩定劑。 如凊求項100之方法，其中該阿利克崙穩定劑係胺基酸 或金屬鹽或其組合。 如請求項101之方法，其中該胺基酸係甘胺酸或天門冬 胺酸或精胺酸或其組合，且其中該金屬鹽係鎂鹽、鈣鹽 或辞鹽或其組合。 如請求項101之方法，其中該胺基酸係精胺酸。 如請求項101之方法，其中該金屬鹽選自由以下組成之 群：MgCl2、ZnCl2、CaCl2、乙酸鋅、乙酸鎂及乙酸鈣。 種製備醫藥組合物之方法’其包括：提供包括以下之 固體粉末： 治療有效量之阿利克崙及視需要第二治療劑及視需要第 154767.doc •12· 201136582 二治療劑、至少一種中鏈脂肪酸鹽；將該固體粉末懸浮 ；欠〖生介質中，以製得含有固體形式之該治療劑及該 中鏈脂肪酸鹽的懸浮液，由此製得該醫藥組合物。 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 如靖求項105之方法，其進一步包括在該固體粉末中提 供形成基質之聚合物及阿利克崙穩定劑。 如明求項105至106之方法，其進一步包括在該組合物中 長:供至少一種表面活性劑。 一種醫藥組合物，其係藉由如請求項6 1至1 〇7中任一項 之方法製得。 一種口服劑型，其包括如請求項1至5〇及91中任一項之 組合物。 如請求項109之口服劑型，其另外經腸溶包覆。 種套組’其包括說明書及如請求項1 09至丨丨〇中任—項 之劑型。 一種膠囊，其含有如請求項1至6〇及1〇8中任一項之組人 物0 如請求項112之膠囊，其中該膠囊係硬質凝膠或軟質凝 膠膠囊。 如請求項112或113之膠囊，其中該膠囊經腸溶包覆。 如請求項109至110中任一項之口服劑型，其用於治療言 血壓、伴有糖尿病之高血壓、充血性心臟衰竭、、、上 痛、心肌梗塞、動脈粥樣硬化、糖尿病性腎病、糖尿疒 性心肌病、腎機能不全、白蛋白尿、周邊血管疾病、左 心室肥大、§忍知功能障礙、中風、頭疼及料 、 H II心臟衰 154767.doc -13· 201136582 竭0 116. —種治療以下疾病之方法：高血壓、伴有糖尿病之高血 壓、充血性心臟衰竭、心絞痛、心肌梗塞、動脈粥樣硬 化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、白 蛋白尿、周邊血管疾病、左心室肥大、認知功能障礙、 中風、頭疼及慢性心臟衰竭，該方法包括向有此需要之 患者投與治療有效量之如請求項109至110中任一項之固 體口服劑型。 117. —種如請求項109至11〇中任一項之口服劑型用於製備藥 劑之用途’該藥劑係用於治療高血壓、伴有糖尿病之高 血壓、充血性心臟衰竭' 心絞痛、心肌梗塞、動脈粥樣 硬化、糖尿病性腎病、糖尿病性心肌病、腎機能不全、 白蛋白尿、周邊血管疾病、左心室肥大、認知功能障 礙、中風、頭疼及慢性心臟衰竭。 H8.如s青求項1至60及108中任一項之組合物，其中該第二或 第三治療劑選自由以下組成之群：AT丨受體拮抗劑、 HMG-Co-A還原酶抑制劑、血管緊縮素轉化酶（ACE)抑制 劑、妈通道阻斷劑、酿固酮合酶抑制劑、醛固酮括抗 劑、雙重血管緊縮素轉化酶/中性内肽酶（ACE/NEp)抑制 劑、内皮素拮抗劑或利尿藥。 154767.doc -14-201136582 VII. Scope of Application: 1. A pharmaceutical composition comprising a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of aliskiren and optionally a second treatment And a third therapeutic agent and at least one medium chain fatty acid salt, as desired. 2. A pharmaceutical composition as claimed in claim 1, which comprises an additional component selected from the group consisting of a polymer forming a matrix and a sugar. 3. The pharmaceutical composition according to any of claims 1 and 2, wherein the solid form comprises granules. 4. The pharmaceutical composition according to claim 3, wherein the granule is obtained by lyophilization or granulation or spray drying. 5. The pharmaceutical composition of any one of clauses 1 to 5, wherein the pharmaceutical composition has a water content of less than about 6% by weight, preferably less than about 2% by weight. The pharmaceutical composition of any one of items 1 to 5, wherein the solid form has a water content of less than about 6% by weight, preferably less than about 2% by weight. The pharmaceutical composition according to any one of the preceding claims, wherein the medium chain fatty acid salt has a chain length of from about 6 to about 14 carbon atoms. The pharmaceutical composition of claim 7, wherein the medium chain fatty acid salt is sodium hexanoate, sodium heptanoate, sodium octoate, sodium citrate, sodium citrate, sodium undecanoate, sodium decanoate, sodium or sodium Sodium tetrasulphate, or the corresponding potassium or lithium or ammonium salt or a combination thereof. The pharmaceutical composition according to any one of claims 1 to 9, wherein the medium chain fatty acid salt is 11% by weight. An amount of up to 40% by weight, preferably 12% to 18% by weight, 154767.doc 201136582, preferably about 15% by weight, is present in the composition. U. The pharmaceutical composition of claim H0, wherein The mid-bond fatty acid salt is present in the solid form in an amount of from 50% by weight to 90% by weight, preferably from 7% by weight to 8% by weight. 12. The pharmaceutical composition of the present invention Wherein the matrix-forming polymer is present in the composition in an amount of from about 0.5% to about 15% by weight, preferably from about 3% by weight to about 10% by weight, according to any one of claims 1 to 12. A pharmaceutical composition wherein the matrix-forming polymer is selected from the group consisting of polyvinylpyrrolidone, carbomer (e.g., Carb〇p〇i polymer), polyvinyl alcohol , polyglucose, alginate, hyaluronate and polyacrylate or a combination thereof. 4. The pharmaceutical composition of claim 13, wherein the matrix-forming polymer is selected from the group consisting of polyethylene glycol, ketone, carbomer, and polyvinyl alcohol, or a combination thereof. The pharmaceutical composition of item 14 wherein the polyvinyl D is more preferably a PVP-12 than the bromo ketone, and the comparative value has a molecular weight of about 3,000, and is preferably from about 2% by weight to about 20% by weight, preferably An amount of from about 5% by weight to about 15% by weight, most preferably about 10% by weight, is present in the composition. 16. The pharmaceutical composition of claim 14 wherein the carbomer is preferred 134P 'and is present in the composition in an amount of from about 0.1% by weight to about 6% by weight, preferably from about 5% by weight to about 4% by weight, optimally about 1% by weight. The pharmaceutical composition according to claim 14, wherein the polyvinyl alcohol is preferably a molecular weight of 154767.doc 201136582 of polyvinyl alcohol of about 27,000 Da, and is preferably about 1% by weight in an amount of 4% by weight. An amount of up to 2% by weight is present in the composition. 18. The pharmaceutical composition of claims 1 to 17 wherein the composition does not contain a medium chain alcohol The pharmaceutical composition according to any one of claims 1 to 17, wherein the composition contains no film fluidizing agent. The pharmaceutical composition of any one of claims 1 to 19, which additionally comprises 21. The pharmaceutical composition according to claim 2, wherein the surfactant comprises an ionic surfactant or a nonionic surfactant or a combination thereof. The pharmaceutical composition of the Moon 20 is in the middle The surfactant is a printing fat or a bile salt (such as sodium taurocholate) or a detergent or a combination thereof. 23. The pharmaceutical composition according to claim 2, wherein the surfactant is a monoglyceride or a Cray. Cremophore, polyethylene glycol fatty alcohol ether, sorbitan fatty acid vinegar, polyoxyethylene sorbitan fatty acid ester, S〇lutol HS15 (12_base stearic acid polyoxygen) Ethylene (6), yard sugar (10) such as octylose, tetradecyl maltose or poloxamer (p〇i〇xa) or a combination thereof. 24. The pharmaceutical composition of claim 23, wherein the glycerol monoglyceride (glyceryl m〇n〇caprylate), monocaprylin (10) is called! M〇n〇OCtanoate), glycerol monocaprate, glycerol monolaurate, glycerol monoglyceride, glycerol monopalmitate or glycerol monooleate or glyceryl monostearate or combination thereof . The pharmaceutical composition of claim 23, wherein the sorbitan fatty acid ester package 154767.doc 201136582 sorbitan monooleate or sorbitan sorbitan monolaurate, monopalmitate or combination. 26. For example, please note that the polyoxyethylene sorbitol fatty acid vinegar includes polyoxyethylene sorbitan monooleate (Tween8〇), polyoxyethylene sorbitol liver monostearate or polyoxymethylene Sorbitol wild succinate or a combination thereof. Wherein the surfactant is present wherein the surfactant is present 27. The pharmaceutical composition of claims 20 to 26 is in the solid form. 28. The pharmaceutical composition of claims 20 to 26 in the hydrophobic medium. 29. The pharmaceutical composition of claims 20 to 26, wherein the surfactant is present in both the solid form and the hydrophobic medium. The pharmaceutical composition according to any one of claims 27 to 29, wherein the surfactant is lecithin or a bile salt (for example, bovine sodium thionate) or a detergent (for example, Tw or a combination thereof). The pharmaceutical composition 'the bile salt is selected from the group consisting of sodium taurocholate, sodium deoxycholate, sodium glycocholate, sodium chenodeoxycholate, sodium cholate, sodium lithate or a combination thereof. 3 2 In the case of the pharmaceutical composition of any of the items 1 to 3, the main component of the hydrophobic medium is tricaprylin. 33. The pharmaceutical composition of any one of claims 1 to 33, wherein the hydrophobic medium comprises an aliphatic, an olefinic, a cyclic or an aromatic compound, wherein the hydrophobic medium comprises Mineral oil, Dendrobium, fatty acids such as octanoic acid, glycerol 154767.doc 201136582 酉曰 diglyceride, triglyceride, ether or ester (eg low molecular weight vinegar 'preferably ethyl isovalerate or butyl acetate) Or a combination thereof 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. The triglyceride is a long-chain triglyceride, or a medium-chain triglyceride or a short-chain triglyceride or a combination thereof. The pharmaceutical composition according to any one of claims 1 to 35, which additionally comprises A pharmaceutical composition according to claim 36, wherein the aliskiren stabilizer is an amino acid. The pharmaceutical composition according to claim 37, wherein the amino acid is selected from the group consisting of glycine and asparagine The pharmaceutical composition of claim 38, wherein the amino acid is arginine. The pharmaceutical composition of claim 36, wherein the aliskiren stabilizer metal salt The pharmaceutical composition of claim 40, wherein the metal salt is selected from the group consisting of magnesium salts, calcium salts, and zinc salts, or a combination thereof. The pharmaceutical composition of claim 41, wherein the metal salt is selected from the group consisting of .MgCl2, ZnCl2, CaCl2, acetic acid, magnesium acetate, and calcium acetate. The pharmaceutical composition according to claim 42, wherein the metal salt is a zinc salt, preferably a acetic acid. The medicine according to any one of claims 36 to 43 Composition, wherein the Ali The pharmaceutical composition of any one of claims 1 to 44, wherein the composition 154767.doc 201136582 is substantially polymerized from aliskiren, a medium chain fatty acid salt, and a matrix-forming substrate. The pharmaceutical composition according to any one of claims 1 to 44, wherein the solid powder consists essentially of aliskiren, a medium chain fatty acid salt, and a matrix-forming polymer. The pharmaceutical composition of any one of the preceding claims, wherein the hydrophobic medium consists essentially of tricaprylin. 48. The pharmaceutical composition of claim 47, wherein the hydrophobic medium additionally comprises a surfactant. 49. A pharmaceutical composition comprising a suspension consisting essentially of a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of aliskiren' at least one medium chain fatty acid salt and a matrix forming polymer The pharmaceutical composition of claim 49, wherein the hydrophobic medium comprises a triglyceride or a monoglyceride or a combination thereof. 5 1. A pharmaceutical composition comprising a suspension comprising a mixture of a hydrophobic medium and a solid form, wherein the solid form comprises a therapeutically effective amount of aliskiren, at least one medium chain fatty acid salt, a matrix forming polymer, Surfactants and aliskiren stabilizers as needed. The pharmaceutical composition according to claim 51, wherein the hydrophobic medium contains at least one surfactant, preferably lecithin, and the surfactant is preferably from about 3% by weight to 9% by weight, preferably about 6 parts by weight. %presence. 53. The composition of claim 5M52H wherein the medium chain fatty acid salt is sodium octanoate, the matrix forming polymer is PVP_12, and the surface active 154767.doc -6 - 201136582 agent is a bile salt, preferably bovine cholesteric acid sodium. 54. The pharmaceutical composition of claim 5 to 53 wherein the aliskiren stabilizer is an amino acid or a metal salt or a combination thereof. 5. The pharmaceutical composition of claim 5 to 5, wherein the sodium octanoate is present in an amount from 1% by weight to 20% by weight, preferably about 15% by weight, and the pvp is about 5 weight percent It is present in an amount of from 0.01 to 15% by weight, preferably about 1% by weight. The pharmaceutical composition according to claim 53 to 55, wherein the sodium taurocholate is 〇.1 by weight. /. It is present in an amount of up to 2% by weight, preferably about 5% by weight. 5. The pharmaceutical composition of claim 5 to 5 wherein the aliskiren is at a weight of i. It is present in an amount of up to 20% by weight, preferably from about 5% by weight to about 1% by weight, or about 3% by weight. 58. The pharmaceutical composition of claim 5 to 57, wherein the aliskiren is aliprofen fumarate. 59. The pharmaceutical composition of claim 5 to 58 which additionally comprises a second therapeutic agent. 60. The pharmaceutical composition of claim 59, which additionally comprises a third therapeutic agent. 61. A method of preparing a pharmaceutical composition, comprising: preparing an aqueous solution comprising a therapeutically effective amount of aliskiren and optionally a second therapeutic agent, and optionally a third therapeutic agent, and a medium chain fatty acid salt, drying the aqueous solution A solid powder is obtained, and the solid powder is suspended in a hydrophobic medium to prepare a suspension containing the aliskiren and the medium chain fatty acid salt in a solid form. Thus, the pharmaceutical composition is prepared. 62. The method of claim 61, which further comprises forming a matrix-forming polymer present in the water soluble solution. The method of claim 61, wherein the solid form comprises particles. 64. The method of claim 61 to 63, wherein the dry understanding is achieved by lyophilization or granulation or spray drying. 65. The method of claiming to 64, wherein the drying The step removes sufficient water 'to make the water content of the pharmaceutical composition less than about 5% by weight, preferably less than about 2% by weight. The method of any one of claims 61 to 64, wherein the drying step removes a quantity of water such that the water content of the solid powder is less than 6% by weight, preferably less than 2% by weight. 67. The method of any one of clauses 61 to 66, wherein the medium chain fatty acid salt has a chain length of from about 6 to about 14 carbon atoms. 6 8 · A method according to any one of claims 61 to 6 6 wherein the medium chain fatty acid salt is sodium hexanoate, sodium heptanoate, sodium octoate, sodium citrate, sodium citrate, Sodium undecanoate, sodium undecanoate, sodium or sodium dodecanoate or the corresponding potassium or lithium or ammonium salt or a combination thereof is preferably sodium octanoate. The method of any one of claims 61 to 68, wherein the medium chain fatty acid salt is from about 11% by weight to about 40% by weight, preferably from about 8% by weight to about 28% by weight, preferably about 15% by weight. An amount of % is present in the composition. The method of any one of claims 61 to 68, wherein the medium chain fatty acid salt is present in the solid powder in an amount of from 30% by weight to 90% by weight, preferably from 4% by weight to 8% by weight. in. The method of any one of claims 62 to 70, wherein the matrix-forming polymer is selected from the group consisting of polyvinylpyrrolidone, carbomer (e.g., carbopol polymer), polyethylene Alcohol, polydextrose, alginate, 154767.doc 201136582 Hyaluronate and polyacrylate or a combination thereof. 72. The method of claim 71, wherein the matrix-forming polymer is selected from the group consisting of polyvinylpyrrolidone, carbomer, and poly Vinyl alcohol or a combination thereof. The method of the month length item 7 2 wherein the poly-glycol group η is preferably a PVP-12′ and preferably has a molecular weight of about 3 Å, and is about 2 weights/〇 to about 20 An amount of the amount by weight, preferably from about 5% by weight to about 15% by weight, most preferably about 10% by weight, is present in the composition. The method of claim 72, wherein the carbomer is preferably carbopol 934p and is present in an amount of from about 1% by weight to about 6% by weight, preferably from about 5% by weight to about 4% by weight. An amount, preferably about 1% by weight, is present in the composition. The method of claim 72, wherein the polyvinyl alcohol is preferably a polyvinyl alcohol having a molecular weight of about 27,000 Da and is from about 1% by weight to about 6 parts by weight. Preferably, it is about 0.5 weight y. An amount of up to about 4% by weight, optimally about 2% by weight or 1% by weight, is present in the composition. The method of any one of clauses 61 to 75, wherein the composition is substantially free of medium chain alcohol and/or membrane fluidizing agent. The method of any one of clauses 61 to 76, which additionally comprises a surfactant. The method of any one of the items 61 to 77 wherein the hydrophobic medium comprises sesame oil or tricapry glycerol or tributyrin or octanoic acid or a combination thereof. The method of any one of claims 61 to 78 wherein the hydrophobic medium is a major component of I54767.doc 201136582 ten is castor oil or tricaprylin or octanoic acid. The method of any one of clauses 61 to 78, wherein the hydrophobic medium comprises an aliphatic, olefinic, cyclic or aromatic compound. 81_ The method of claim 8 wherein the hydrophobic medium comprises an aliphatic compound. The method of any one of claims 61 to 78, wherein the hydrophobic medium comprises mineral oil, paraffin wax, a fatty acid such as caprylic acid, glycerol monoacetate, diglyceride, triglyceride, ether or ester or combination. 83. The method of claim 82, wherein the hydrophobic medium causes the vinegar to be a low molecular: S-day is preferably a isovaleric acid or a butyl acetate, or wherein the glycerin is a long-chain glycerol A mixture of three or four, or a mixture of short-chain diglycerides, or a long-chain triglyceride-based sesame or coconut oil or a combination thereof. The method of the month length item 82 wherein the short-chain triglyceride succinate succinic acid S 曰 and the medium chain triglyceride is tricaprylin. 85. The method of any of clauses 61 to 84, which additionally comprises at least one type of surface activity. 86. The method of claim 85, wherein the 亥 〃 中 5 surfactant comprises an ionic surfactant or a nonionic surfactant or a combination thereof. The method of claim 85, wherein the surfactant is a heterotrophic or bile salt (such as sodium taurocholate) or a detergent or a combination thereof. The method of 青长项85, wherein the surfactant is glycerin monooleic , Kremmofu, polyethylene glycol fatty alcohol bond, sorbitol liver fatty acid vinegar, polyoxyethylene sorbitol liver fatty acid West, color Ruto 15 (12_ sulphate 154767.doc 201136582 Oxyethylene sulphate), a sucrose (for example, octylose, tetradecyl maltose or poloxamer or a combination thereof. 89. The method of claim 88, wherein the glycerol is a single octyl vinegar (glyceryl m〇nocaprylate), giyc-m〇n〇〇ctanoate, glyceryl monocaprate, glycerol monolaurate, glycerol mono-glycolic acid, glycerin monopalmitate or single oil a combination of acid glycerin or glyceryl monostearate; or wherein the sorbitan fatty acid vinegar comprises sorbitan monolaurate, sorbitan monooleate or sorbitan monopalmitate or a combination thereof; or Polyoxyethylene sorbitol needle fatty acid esters including polyoxyethylene sorbitan Monooleate (Tween 80), polyoxyethylene sorbitan monostearate or polyoxyethylene sorbitan monopalmitate or a combination thereof. 90. The method of claim 85 to 89, wherein the surface active The agent is present in the solid form. 91. The method of claim 85 to 89, wherein the surfactant is present in the hydrophobic medium. 92. The method of claim 85 to 89, wherein the surfactant is present In both the solid form and the hydrophobic medium. 93. The method of claim 85 to 92 wherein the surfactant is a squama or bile salt (such as sodium taurocholate) or a detergent (eg The method of any one of claims 61 to 93, wherein the composition consists essentially of aliskiren, a medium chain fatty acid salt, and a matrix-forming polymer and a hydrophobic medium. The method of any one of the items 61 to 93, wherein the solid powder consists essentially of aliskiren. a medium chain fatty acid salt and a polymer forming a matrix. The method of any one of the preceding claims, wherein the hydrophobic medium consists essentially of tricaprylin. The method of any one of clauses 61 to 93, wherein the hydrophobic medium additionally comprises a surfactant β as claimed The method of any one of clauses 61 to 93, wherein the solid powder consists essentially of aliskiren and a medium chain fatty acid salt and a surfactant, the method of any one of claims 61 to 98, wherein the hydrophobic medium It consists essentially of tricaprylin. The method of any one of items 61 to 99, which additionally comprises an aliskiren stabilizer. The method of claim 100, wherein the aliskiren stabilizer is an amino acid or a metal salt or a combination thereof. The method of claim 101, wherein the amino acid is glycine or aspartic acid or arginine or a combination thereof, and wherein the metal salt is a magnesium salt, a calcium salt or a salt or a combination thereof. The method of claim 101, wherein the amino acid is arginine. The method of claim 101, wherein the metal salt is selected from the group consisting of MgCl2, ZnCl2, CaCl2, zinc acetate, magnesium acetate, and calcium acetate. A method of preparing a pharmaceutical composition comprising: providing a solid powder comprising: a therapeutically effective amount of aliskiren and optionally a second therapeutic agent and, if desired, 154767.doc • 12·201136582 two therapeutic agents, at least one A chain fatty acid salt; the solid powder is suspended; the suspension is immersed in a medium to prepare a suspension containing the therapeutic agent in solid form and the medium chain fatty acid salt, thereby preparing the pharmaceutical composition. 106. The method of claim 105, further comprising providing a matrix-forming polymer and an aliskiren stabilizer in the solid powder. The method of any of claims 105 to 106, further comprising: growing in the composition: providing at least one surfactant. A pharmaceutical composition obtained by the method of any one of claims 6 to 1 to 7. An oral dosage form comprising the composition of any one of claims 1 to 5 and 91. The oral dosage form of claim 109, which is additionally enteric coated. The kit includes 'the instructions and the dosage form as claimed in claim 109 to 丨丨〇. A capsule comprising the capsule of any one of claims 1 to 6 and 1 to 8, such as claim capsule 112, wherein the capsule is a hard gel or a soft gelatin capsule. The capsule of claim 112 or 113, wherein the capsule is enteric coated. An oral dosage form according to any one of claims 109 to 110 for use in the treatment of blood pressure, hypertension associated with diabetes, congestive heart failure, upper pain, myocardial infarction, atherosclerosis, diabetic nephropathy, Diabetes cardiomyopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, § forbearance dysfunction, stroke, headache and material, H II heart failure 154767.doc -13· 201136582 exhaust 0 116. — Methods for treating the following diseases: hypertension, hypertension associated with diabetes, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, albuminuria, peripheral Vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure, the method comprising administering to a patient in need thereof a therapeutically effective amount of a solid oral dosage form according to any one of claims 109 to 110. 117. Use of an oral dosage form according to any one of claims 109 to 11 for the preparation of a medicament for treating hypertension, hypertension associated with diabetes, congestive heart failure, angina pectoris, myocardial infarction Atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, albuminuria, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, headache, and chronic heart failure. The composition of any one of claims 1 to 60 and 108, wherein the second or third therapeutic agent is selected from the group consisting of an AT丨 receptor antagonist, HMG-Co-A reductase Inhibitors, angiotensin-converting enzyme (ACE) inhibitors, mother channel blockers, tyrosine synthase inhibitors, aldosterone inhibitors, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEp) Inhibitor, endothelin antagonist or diuretic. 154767.doc -14-
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