TW200533389A - Multilayer tablet - Google Patents
Multilayer tablet Download PDFInfo
- Publication number
- TW200533389A TW200533389A TW094104757A TW94104757A TW200533389A TW 200533389 A TW200533389 A TW 200533389A TW 094104757 A TW094104757 A TW 094104757A TW 94104757 A TW94104757 A TW 94104757A TW 200533389 A TW200533389 A TW 200533389A
- Authority
- TW
- Taiwan
- Prior art keywords
- layer
- tablet
- telmisartan
- lozenge
- ramipril
- Prior art date
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims abstract description 98
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 claims abstract description 59
- 229960003401 ramipril Drugs 0.000 claims abstract description 59
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims abstract description 49
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- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229960002003 hydrochlorothiazide Drugs 0.000 claims abstract description 22
- 239000011159 matrix material Substances 0.000 claims abstract description 19
- 230000001882 diuretic effect Effects 0.000 claims abstract description 17
- 239000007937 lozenge Substances 0.000 claims description 53
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- B30B11/08—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable
- B30B11/085—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable for multi-layer articles
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
200533389 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種醫藥錠劑，其包含血管緊張素π受體 拮抗劑替米沙坦在可溶性鍵劑基質中之第一層、血管緊張 素轉化酶（ACE)抑制劑雷米普利單獨或連同利尿劑在崩解 性錠劑基質中之第二層及視情況利尿劑如氫氯嗟嗪在快速 崩解性錠劑基質中之第三層。 【先前技術】
。如ΕΡ-Α-502314所揭示替米沙坦為經研製用於治療高血 壓或其它醫學適應症的血管緊張素Π受體拮抗劑。其化學 名為4,·[2_正丙基_4-曱基-6-(ι-曱基苯幷咪唑基）-苯幷^ 坐1基甲基]·聯笨基-2_羧酸且具有如下結構：
替未沙坦係、以游離酸形式來製造及供應。其特徵為在pH 值介於1至7之門沾田 , 間的月腸道生理pH值範圍内之含水系統中具 有極差的溶解许 ，x 〃 、 唧度。如00/43370所揭示，晶狀替米沙坦 以1具有不同炫^對；4 兩個多晶形存在。在熱度與濕度之影響 下，較低炫：κ夕夕R /曰 ”’心夕日曰型物B不可逆地轉形為較高熔點之多 晶型物A。 99043.doc 200533389 EP-A-079022中所揭示之雷米普利為長效ace抑制劑，
其化學名為（28,3&8,6&8)-1[(8)-]^-[(8)-1-羧基_3-苯基丙基] 丙胺酸基]-八氫-環戊二烯幷[b]咣咯-2-羧酸，1-乙酯，其具 有如下結構：
其抑制血官緊張素〗轉化為血管緊張素π且破壞活性血 管擴張劑緩激肽。該等活性均導致血管擴張。雷米普利係 用於高血壓及充血性心臟衰竭之治療中且其活性代謝物為 游離酸雷米普利拉（ramiprilat)，其係經由投與雷米普利後 在活體内獲得。另夕卜，認為雷米普利在組織中實現顯著的
ACE抑制作用而導致諸如心臟、肺及腎之器官的保護性作 用。 利尿劑為在水腫及高血壓治療巾使用的治療劑。偶爾將 其與基於不同作用模式之抗高血壓劑組合以達成高血壓治 療之協同療功效。較佳的利尿劑為氫氯嗟嗪（HC丁Z)。 HCTZ之化學名稱為6_氯_3,4_二氫-2Η·1，2,4-苯幷噻二嗪_7-磺醯胺-l，l-二氧化物，其η具有如下結構： H^AC^so2nh2 〇 〇 99043.doc 200533389 【發明内容】 吾人認為替米沙坦與雷米普利之作用機制有利地配合了 諸如中風、心肌梗塞、短暫性腦缺血、心血m糖尿 病、認知衰退及癡呆之病症的治療或預防。隨著支持此假 設的臨床資料數量之增加，冑包含活性成份替米沙坦、雷 米普利及視情況諸如氫氯斜之利尿劑的固定劑量組合藥 物之需求漸增。然而，替米沙坦與雷米普利均為較難處理 之化合物。因，匕，組合了藥理功效、充分的藥物穩定性及 可靠與穩固的製造方法特徵之口服固定#j量組 克服大量技術問題。本發明之—目的為提供該固定劑量組 合藥物。 雖然可能得到各種類型的固定劑量之劑型，但不能預測 該等：型中何種劑型最佳地組合了產物穩定性、藥理功效 及可罪的製造方法。該等劑型之實例為 貝J馮口服渗透系統 〇s)、塗覆錠劑、基質錠劑、塗壓 夕層錠劑及 二頒似物。本發明係基於以下辨識：最佳地組合了充分的 藥物穩定性、兩種活性成份之最佳藥物釋放、藥理功二及 :米沙坦與雷米普利之組合的可靠製造之劑型為多層錠 一般而言，藉由製造粉末混合物或以必 而的賦形劑製造 -種活性成份之共顆粒來製備意欲用於 旦 _ 丨吋樟放之固定劑 里之樂物組合，其通常保持相應單藥物製 且僅 衣釗之鹼性調配物 :入第二藥物組份。具有替米沙坦與雷米普利之組合 式無可行性，此係由於雷米普利與習知的替米沙坦 99043.doc 200533389
組份之調配物不相纟。當組合物中包括組合的利尿劑 HCTZ或ACE抑制劑雷米普利時，可觀察到與來自崩解性 鍵劑之溶解性相比，來自可溶性基質之HCTZ溶解速率降 低。士流化床造粒機中以含有水溶性聚合物如經丙基纖維 素、經丙基甲基纖維素或聚乙料略㈣之聚合物溶液塗 覆H C T Z或雷米普利粒子以減少在混合及壓縮過程中H c τ z 粒子與替米沙坦或雷米普利調配物之接觸表面積，此舉不 能使在壓縮㈣巾H c T z與#米沙坦或雷米普利調配物之 ㈣面積減少至足以達成所要延長存放期之程度。此外， 歸因於聚合物之形成凝膠之特性，來自包含塗覆之 錠劑的HCTZ之溶解速率更顯著地降低。 另一種方式為生產用於替米沙坦、雷米普利及視情況 狀丁2之—疋尺寸與形狀之獨立的經薄膜塗覆之錠劑而使 一此夠填充至膠囊中。吾人發現藉由將替米沙坦、雷米普 利及視HCTZ之劑量分成小錠劑使得替米沙坦與雷米 晋利之樂物溶解速率與單—實體時相比降低，此係由於較 大膠囊外殼之延遲時間效應。此外，就患者·性而言， 視零長度膠囊為不可靠的。 根據本發明，可最佳藉助於多層醫藥錠劑來處理與包含 曰米"坦、雷米晋利及視情況利尿劑之固定劑量組合 有關的問題，該錠劑包含較佳為大體上非晶形的替米:少坦 在可溶性錠劑基質中之第一層與雷米普利單獨或雷米普利 連同利尿劑如HCTZ在崩解性錠劑基質中之第二層。或 者σ亥錠劑可含有包含利尿劑在崩解性錠劑基質中之第三 99043.doc 200533389 根據本發明，該錠劑提供具有較差水溶性之替米沙坦之 大體上非pH值依賴性溶解，由此促進藥物在生理？11值程 度上之溶解及t分的穩定性及雷米普利之藥物釋放。當該 錠劑與利尿劑組合時’其為利尿劑提供自快速崩解性基質 即時釋放。該錠劑結構亦克服了由利尿劑如hctz與替米 沙坦調配物之鹼性組成（constituent)所造成的穩定性問題 及由雷¥普利肖替米沙、坦之驗性組成所造成之穩定性問 題。 如本文所用，術語”大體上非晶系”係指如藉由乂射線粉 末繞射量測所判定包含至少90%(較佳至少95%)比例之非 晶系組成的產物。 術語，，可溶性鍵劑基質"係指具有即時釋放（快速溶解）特 徵之醫藥錠劑鹼性調配物，其在生理性水介質中易於溶 解。 術語"利尿劑”係指噻嗪及類似噻嗪之利尿劑如氫氯噻嗪 (HCTZ)、氯旅胺（clopamide)、氯磺水揚胺㈣_州或氯 他利酮（Chl〇rotalidone)及任何其它適用於高血壓治療之利 尿劑如吱喃苯胺酸及t各他尼（扣咖咖及其與胺氯吼脒 及胺苯蝶啶之組合。 ▲術語，，崩解性錠劑基質”係指具有即時釋放特徵之醫藥疑 劑鹼性調配物，其在生理性水介質中易於崩解。 根據本發明，固定劑量組合表示—種醫藥多層錠劑，其 包含以大體上非晶形存在之替米沙坦之第—層及雷米普利 99043.doc 200533389 單獨或雷米普利連㈣展劑在崩解性錠劑基質中之第二 層，或視情況在崩解性錠劑基質中利尿劑之第三層。 、雖然亦可使用醫藥學上可接受之鹽如納鹽，但：活性成 份替米沙坦一般以其游離酸形式供給。由於在隨後的加工 過程中通常將替米沙坦溶解且轉形為大體上非晶形，因而 其初始晶體形態及粒度對於所獲得之多層錠劑調配物之物 理及生物醫藥特性而言不是很重要。然而，最好（例如）藉 由筛分自起始材料中移除聚結物以促進在進—步加工過程 中之潤濕與溶解。 可藉由熟悉此項技術者所知的任何適用方法，例如，藉 由水/合液之♦束乾燥、流化床中載劑粒子之塗覆及糖丸粒 或其它载劑上之溶劑沉積生產大體上非晶系之替米沙坦。 然而，大體上非晶系替米沙坦較佳係藉由如w〇 〇3/〇59327 所述之特定喷霧乾燥方法製得。 如ΕΡ·Α_317878中所述雷米普利係以游離g旨形式供應或 經聚合物塗層穩定。適用於保護性塗覆之聚合物之實例為 纖維素衍生物，諸如，羥丙基纖維素、羥丙基曱基纖維 素、鄰苯二曱酸羥丙基甲基纖維素、羥乙基纖維素、乙基 纖維素、鄰苯二曱酸醋酸纖維素、醋酸纖維素、聚鄰苯二 甲酸醋酸乙烯酯、聚乙烯°比洛咬酮、陽離子及陰離子聚合 物、以聚（曱基）丙烯酸酯為主的中性共聚物（Eudragh(R) E，Eudragit(R) E 30 D)、曱基丙烯酸與甲基丙烯酸曱醋之 陰離子聚合物（Eudragit(R) L或 S，Eiuiragit(R) L 30 D)及明 膠0 99043.doc -10- 200533389 -般使用細晶粉末形式’視情況以細研磨、立軸研磨 (peg-milled)或微米化形式之利尿劑。例如，在乾燥分散系 統（Sympatec Helos/R〇d〇s，焦距1〇〇職）中藉由雷射光散 射之方法所測得氫氯畫嗪之粒度分佈較佳係如下所示： di〇 ·幺20 μηι，較佳為2至1〇叫 dso : 5至 50 μηι，較佳為 1〇至3〇 _ d9〇 · 20至1〇〇 μηι，較佳為4〇至㈣ 根據本發明，多層_ —般含有m16Gmg，較佳20至 8〇叫或4〇謂叫之替米沙坦；1至2()叫，較佳5至1〇呵 二：曰利’及6·25至5〇mg，較佳12.5至25邮之利尿劑 如HCTZ。 目前較佳形式為分別包含鳩mg、侧邮、觀〇呵、 20/5 mg、40/5 mg、80/5 mg、20/2 S ⑺,A/ g 20/2·5 mg、40/2.5 mg及 川/2.5 mg之替米沙扫及雷半並 及田米晋利之多層錠劑。利尿劑之較 佳量為12.5 mpt25mg。 剞惑竿乂 弟叙劑層含有分散於具有即時釋放（快速溶解）特徵之 可溶性錠劑基質中的大體上 ^ ^ „ 日日小之替未沙坦。雖然鹼性 、疋劑土貝較佳，但是可溶性鍵齊 ^ ^ d暴貝可具有中性或鹼性之 特性。 在該較佳實施例中，替米沙扭 1 τ 一層之可浴性基質包含鹼性 劑、水溶性利尿劑及視情況其它賦形劑與佐劑。 適合的鹼性劑之特定實例為驗金屬氫氧化物如NaOH及 職；驗性胺基酸如精胺酸及離胺酸； 其 小葡糖胺），Na0H及甲葡胺較佳。 1甲基- 99043.doc -11 - 200533389 適a的水溶性利尿劑之特 諸如葡_ 疋只例為碳水化合物，例如， 渚如匍甸糖之單醣類；諸如 a 寡醣,· R ^ 庶糖、媒水乳糖及單水乳糖之 养醣頒，及諸如山梨糖醇、 山± 甘^搪醇及木糖醇之糖醇類。 山木糖s子為較佳的稀釋劑。 其它賦形劑及/或佐劑係 、 、、自（例如）黏合劑、載劑、埴充 劑、潤滑劑、流動控制劑、姓曰 八 、、、口日日延遲劑、增溶劑、著奔 劑、pH值控制劑、界面活性 」 人物古μ a M及礼化劑，與第二錠劑層組
a物有關的該等物質之特定 ^ 打疋声、例係在下文中給出。用於 一錠劑層組合物之賦形劑 、 ^及/或佐劑較佳係經選定以 得非酸性快速溶解之錠劑基質。 又 一第—錠劑層組合物—般包含3至50重量％，較佳5至_ 量％之活性成份；0.25至20重量％，較佳〇 4〇至15重量％之 驗性劑；及30至95重量％，較佳6〇至8〇重量％之水溶性利 尿劑（填充劑）。 例如，其它（可選的）組成可選自一或多種具有所示量之 下列賦形劑及/或佐劑： 里 10至30重量％，較佳15至25重量％之黏合劑、载劑及填 充劑，以便置換水溶性利尿劑； 、 0.1至5重量％，較佳〇·5至3重量％之潤滑劑； 〇·1至5重量％，較佳〇·3至2重量％之流動控制劑； 1至10重量％，較佳2至8重量％之結晶延遲劑； 1至10重量％，較佳2至8重量％之增溶劑； 0.05至1.5重量°/〇，較佳〇.1至〇.8重量％之著色劑； 〇·5至1〇重量°/〇，較佳2至8重量％之？11值控制齊j ; 99043.doc 200533389 〇·〇1至5重量％，較佳〇· 劑 1室里/〇之界面活性劑及乳化 〇 合物包含分散於具有即時釋放(快速溶解) 解性錠劑基質中的雷米普利。其視情況包含雷米 =㈣該崩解性錠劑基質可具有弱酸性、"生 或弱鹼性，中性錠劑基質較佳。 在一較佳實施例中，崩解 朋解性基質包含一或多種填充劑、 黏合劑或聚合物、崩解南丨 朋解』肩滑劑及視情況其它賦形劑與 佐劑0 、 較佳的填充劑係選自由預凝膠化殿粉、微晶纖維素、低 取代之經丙基纖維素、纖維素、 ^ I 甘路糖S子、赤澡糖醇、乳 糖 庶糖、酸氮；^丐、山刹4古35含Ί2 » :、 牛夂XL灼山木糖醇及木糖醇組成之群。預凝 勝化;殿粉、微晶_维杳 斗+ 纖、准素甘路糖醇及乳糖單水合物尤其較 ik ° 一 」交佳的崩解劑係選自由墙甲纖維素鈉鹽(經交聯之 纖維素羧甲基乙醚鈉鹽)、羥基乙酸澱粉鈉、經交聯之聚 ^稀料㈣（交聯聚乙烯吼㈣）、玉米殿粉及低取代之 經丙基纖維素組成之群。經基乙酸殿粉納及交聯叛甲纖維 素納鹽尤其較佳。 —佐的钻5劑係遥自由聚乙烯基吡咯啶酮（聚乙烯吡咯 、乙烯吨定酮與其它乙烯基衍生物（共$乙烯吨嘻酉同） 之共聚物、羥丙基甲基纖維素、甲基纖維素、羥丙基纖維 素及低取代之羥丙基纖維素組成之群。羥丙基甲基纖維素 及共聚乙烯吡咯酮尤其較佳。 99043.doc 200533389 =的潤滑劑為硬脂酸反丁烯二酸納及硬脂酸鎂。 弟一叙劑層組合物—般包含0.5至25重量％，較佳ul5 =量^雷米普利及5()至95重量％，較佳75至9()重量％之 、充劑。利尿劑之可選的含量為2至15重量％。 2 β M、流動控制劑、結晶延遲劑、增溶劑、著色 ^物^控制劑、界面活性劑及乳化劑，與第三鍵劑層組 一 4寸疋貝例係在下文中給出。用於第 -叙劑層組合物之職形劑及/或佐劑 得中性崩解性錠劑基質………疋的以便獲 預凝膠化殿粉、乳^ 糖醇' 早水合物及諸如低取代經丙基纖維素 <纖維素衍生物。 可選的第三錠劑層組合物含有在快速崩解性錠劑基質中 ^尿^ °在—較佳實施例中’該崩解性錠劍基質包含填 μ黏合劑及視情況其它賦形劑與佐劑。
时^剩較佳係選自無水乳糖、經喷霧乾燥之乳糖及乳糖 早水合物。 、阳:所選出的用於第二旋劑層之製造過程而定，黏合劑係 :由乾燥黏合劑組成之群及/或由濕式造粒黏合劑組成 手°適合的乾燥黏合劑為（例如）纖維素粉末及微晶纖維 二。_濕式造粒黏合劑之特定實例為玉米殿粉、聚乙烯吼咯 乙細°比ΰ各綱）、乙婦対11定剩-乙婦醋酸醋共聚物 乙烯比略_)及纖維素衍生物如經V基纖雉素、經乙 土’截維素、經丙基纖維素及㈣基甲基纖維素。 99043.doc -14- 200533389 適合的崩解劑為(例如)羥基乙酸澱粉鈉、交聯 =、，«甲纖維素、Μ基纖維素減乾玉米凝粉， 經基乙酸殿粉納較佳。
若使用其它賦形劑及佐劑，則其較佳係選自稀釋劑 d例如、纖維素粉末、微晶纖維素、諸如經甲基纖維 素罗工乙基纖維素、經丙基纖維素及經丙基甲基纖維素之 纖維素何生物、碟酸氫與、玉米殿粉、預凝膠化凝粉、聚 乙烯吼口各欠酮（聚乙烯❸各酮）等；潤滑劑，例如硬脂酸、 硬脂酸鎂、硬脂醯反丁烯二酸鈉、三山窬酸甘油酯等；流 體控制劑，例如謂、滑石#·，結晶延遲劑，例如聚^ 吼略二等；增溶劑，例如，泊洛尼克（pl則㈣）、聚乙烯口比 各綱:’包括染料及顏料之著色劑，例如，氧化鐵紅或氧 化鐵二氧化鈦、滑石等；ΡΗ值控制劑，例如檸檬酸、 =石酸、反丁烯二酸、檸檬酸鈉、磷酸氫鈉、磷酸氫鈣 等’界面活性劑及乳化冑，例如，泊洛尼克、％乙二醇、 羧甲基纖維素鈉、聚乙氧基化及氫化議由等；及兩種或 兩種以上該等賦形劑及/或佐劑之混合物。 在尤其較佳實施例中，第三層係位於第一與第二層之 間以避免替米沙坦與雷米普利之間相互接觸。可藉由使用 不同顏色來區分此三層。 该第三錠劑層組合物一般包含1.5至35重量％，較佳2至 15重里％之活性成份；25至75重量％，較佳35至65重量〇/〇 、充刈’ 10至40重量Q/❽，較佳1 5至35重量％之乾燥黏合 ^ ’ 〇·5至5重量％，較佳1至4重量％之濕式造粒黏合劑； 99043.doc -15 - 200533389 〇重里較佳2至8重量％之崩解劑。一般使用與第 叙劑層組合物相同量之其它賦形劑及佐劑。 根據本發明，就製備雙層錠劑而言，可以一般方式在雙 層製錠機（例如，雙層製錠模式之高速輪轉壓力機）中壓縮 第一及第二錠劑層組合物。然而，應注意不要對第一錠劑 層鈀加過多壓縮力。在第一錠劑層壓縮過程中所施加之壓 縮力與在第一及第二錠劑層之壓縮過程中所施加之壓縮力 之比例較佳係在1 ·· 1〇至丨：2之範圍内。舉例言之，可在4 至8 kN之中等力下壓縮第一錠劑層，而第一層加上第二層 的主要壓縮係在1 〇至2〇 kN的力下進行。 在雙層錠劑壓縮過程中，藉助於粒子間的距離吸引力 (分子間力）及機械聯鎖在兩層間達成足夠的鍵形成。 所獲得的多層旋劑快速釋放活性成份且為大體上非阳值 ，賴性方式，在少於60分鐘内發生完全釋放且在少於。分 鐘内發生主要部分的釋放。可以不同方式控制多層鍵劑之 溶解/-崩解動力學。舉例言之，該等層可同時溶解/崩解。 然而’較佳為含有雷米普利之第二層及含有利尿劑之第三 錠劑層首先崩解’而含有替米沙坦之第一層隨後溶解。 根據本發明，達成活性成份且詳言之替米沙坦之大體上 增加的溶解速率。-般而言，3〇分鐘後溶解至少7〇%且通 常至少90%之藥物負荷。 本發明之多層錠劑趨向於輕微吸濕且因此較佳使用抗濕 包裝材料如銘猪發泡包裝或聚丙稀管及較佳含有乾燥劑之 高密度聚乙烯（HDPE)瓶來包裝。 99043.doc -16 - 200533389 根據本發明，生產雙層錠劑之較佳方法包含· ⑴藉由下列步驟提供第一錠劑層組人物· a)製備替米沙坦水溶液、至少— 劑及/或結晶延遲劑； 種鹼性劑及視情況增 溶 b) 喷霧乾燥該水溶液以獲 c) 混合該經喷霧乾燥之顆 合料； 得經噴霧乾燥之顆粒； 粒與水溶性稀釋劑以獲得預混
混合該預混合料與潤滑劑以獲得用 物； 於第一層之終摻合 項中添加其它賦形劑及 e)視情況，在步驟a)至d)之任_ /或佐劑； ⑼ 長:供包含雷米普利早獨或連同刺 人疋I口J利尿劑之第二錠劑層 合物 (iii) 視情況提供包含利尿劑之第三錠劑層 之各組合物以
(iv) 壓縮第一、第二及第三錠劑層組合胃物中 形成錠劑層；及 ⑺壓縮獨立的錠劑層以形成多層錠劑。 入了提供第一錠劑層組合物，藉由藉助於一或多種驗性 劑：氫氧化鈉及葡甲胺將活性成份溶解在純水中來製備替 ；； 之鹼丨生水'谷液。視情况，可添加增溶劑及/或結晶 =遲劑。起始水溶液之乾燥物質含量—般為1〇至4〇重量 % ’較佳為20至30重量％。 接者，在室溫下或較佳在介於50至100它之間的增高溫 度下在（例如）1至4 bar之壓力下於平行流或反向流喷霧乾 99043.doc 200533389 秌裔中賀務乾煉水溶液。一般而言，喷霧乾燥條件係以此 方式較佳地選擇以使得在分離旋風中獲得殘留濕度重量 %，較佳幻·5重量％之經喷霧乾燥之顆粒。為此，喷霧乾 秌為之出口氣體溫度較佳保持在介於約8〇至9〇它之間的 值而相應地调整其它過程參數如噴霧壓力、喷射率、進 口氣體溫度等。 所獲得的經喷霧乾燥之顆粒較佳為具有下列粒度分佈之 精細粉末： d10 :幺20 μπι，較佳為 <1〇 μιη d50 : <80 μηι，較佳為 2〇至 55 μιη d90 : S350 μηι，較佳為 5〇至15〇 _ 噴務乾無後’活性成份替米沙坦連同包含於經喷霧乾燥 之顆粒中之賦形劑為具有可偵測之無結晶度的大體上非晶 系狀態。自物理學角度來看’經喷霧乾燥之顆粒為固化溶 液或玻璃，其具有較佳>5(rc，更佳赠之玻璃轉移溫度 (Tg)。 經喷霧乾燥之顆粒較佳含有以每⑽份活性成份替米沙 士-之重里汁5至200重置份之鹼性劑及視情況增溶劑及/或 結晶延遲劑。 -般使用以第-錠劑層組合物之重量計3〇至％重量％(較 佳60至80重量％)之量的水溶性稀釋劑。 一般將以第一錠劑層組合物重量計〇1至5重量％(較佳 0.3至2重量％)之量的潤滑劑添加至預混合料中。 混合分兩階段進行，意即在第一混合步驟中使用（例 99〇43.doc -18 - 200533389 高剪切混合器或自由下落摻合器將經喷霧乾燥之顆粒與稀 釋劑混合，且在第二混合步驟中較佳亦在高剪切條件下將 潤滑劑與預混合料摻合。但是本發明之方法不受限於該等 混合程序，且一般而言，可在步驟c)、d)亦及隨後的步驟 f)及g)中使用替代混合程序，例如，與中間篩網混合之容 器0
為了提供單獨包含雷米普利之第二錠劑層組合物，使用 流化床造粒機將雷米普利與黏合劑溶液預混合且造粒。部 分賦形劑可與雷米普利一起在流化床造粒機中預混合且造 粒。視情況，可將雷米普利溶解或懸浮於黏合劑溶液中以 改良雷米普利在終產物中之含量均一度。將經乾燥之顆粒 經由適當的篩子篩分。在添加其它賦形劑之後，於自由下 落摻合器中混合該混合物。用於雷米普利及賦形劑與黏合 劑溶液造粒之替代方法為高剪切造粒法或單槽造粒法，接 著為顆粒之濕式師分、乾無及乾式師分。 可使用適當的製錠機將上述第一及第二錠劑層組合物壓 縮成具有適當尺寸及抗壓強度之目標錠劑重量的雙層錠 劑。在製造錠劑過程中可使用用於沖模及衝壓之可選的適 當外用潤滑喷霧系統以改良潤滑度。 為了提供包含雷米普利連同利尿劑如氫氯噻嗪（HCTZ) 之替代的第二錠劑層組合物，如上所述將雷米普利及氫氯 噻嗪連同部分於黏合劑溶液中之賦形劑在流化床造粒機中 預混合且造粒。視情況，可將活性成份溶解或懸浮於黏合 劑溶液中以改良在終產物中之含量均一度。在添加其它賦 99043.doc -19- 200533389 I劑之後’在自由下落摻合器中混合該混合物。 可使用適當的製錠機將上述第一及替代的第二層組合物 壓縮成具有適當尺寸及抗壓強度之雙層錠劑。在製造錠劑 過程中可使用用於沖模及衝壓之可選的適當外用潤滑噴霧 系統以改良潤滑度。
在另一貫施例中，可藉由乾燥混合組成組份製備包含利 尿d之第二錠劑層組合物，例如藉助於高強度混合器或自 由下洛摻合器。或者較佳地使用濕式造粒法技術製備第三 錠劑層組合物，其中將濕式造粒黏合劑水溶液加入預混合 料中且後（例如）在流化床乾燥器或乾燥室中乾燥所得的 :顆粒命j如’使用轉筒混合器或自由下落摻合器將經乾 燥之混合物篩分，且接著與潤滑劑混合。 ^使用適當的製錠機將上述第_、第二及第三層組合物 壓縮成具有適當尺寸及抗壓強度之3層錠劑。 根據本發明，就生產雙層錠劑而言，可以上述方式在雔 =定Γ(例如，為雙層錠劑化模式之 錠劑層組合物。為避免_層⑶㈣的交又污 Γ 致雷米普利或HCTZ降解)，在藉由模台之強烈抽 氣succtlon)來錠劑化的過程中必須將製 餘物小心移除。 貞H至内任何顆粒殘 給出以下非限制性實例。 為進一步說明本發明 【實施方式】 調配物實例 99043.doc 20- 200533389
實例1 ··替米沙坦80 mg /雷米普利10 mg 2層錠劑 組成 mg/錠劑 替米沙坦層 之百分比 雷米 <普利層 之百分比 替米沙坦 80.000 16.667 氫氧化納 6.720 1.400 聚乙烯°比洛酮 24.000 5.000 葡曱胺 24.000 5.000 純水* 槪000 山梨糖醇 337.280 70.267 硬脂酸鎂 8.000 1.667 總替米沙坦層 480.000 100.000 雷米普利 10.000 5.000 微晶纖維素 60.000 30.000 乳糖單水合物 110.000 55.000 羥丙基甲基纖維素 6.000 3.000 純水* 70.000 羥基乙酸澱粉鈉 8.000 4.000 硬脂醯反丁烯二酸鈉 6.000 3.000 總雷米普利層 200.000 100.000 總2層錠劑 680.000 *揮發性組份，其在終產物中無殘留 99043.doc -21 200533389
實例2 :替米沙坦80 mg/雷米普利10 mg 2層錠劑 組成 mg/錠劑 替米沙坦層 之百分比 雷米普利層 分比 替米沙坦 80.000 ------ 16.667 氫氧化鈉 6.720 1.400 聚乙烯π比嘻_ 24.000 5.000 葡甲胺 24.000 5.000 純水* 400.000 山梨糖醇 337.280 70.267 硬脂酸鎮 8.000 1.667 總替米沙坦層 480.000 100.000 雷米普利 10.000 5.000 微晶纖維素 80.000 40.000 甘露糖醇 85.670 42.835 羥丙基曱基纖維素 10.000 5.000 純水* 70.000 羥基乙酸澱粉鈉 8.000 4.000 氧化鐵紅 0.330 0.165 硬脂醯反丁稀二酸納 6.000 3.000 總雷米普利層 200.000 100,000 總2層錠劑 680.000 揮杂性組伤，其在終產物中無殘留 99043.doc -22- 200533389
實例3 :替米沙坦80mg/雷米普利5 mg 2層錠劑 組成 mg/錠劑 替米沙坦層 之百分比 雷米普利層 之百分比 替米沙坦 80.000 16.667 氫氧化納 6.720 1.400 聚乙浠啦17各酮 24扁 5.000 葡曱胺 24.000 5.000 純水* 400.000 山梨糖醇 337.280 70.267 硬脂酸鎂 8.000 1.667 總替米沙坦層 480.000 100.000 雷米普利 5.000 2.500 微晶纖維素 60.000 30.000 乳糖 115.000 57.500 羥丙基甲基纖維素 6.000 3.000 純水* 70.000 羥基乙酸澱粉鈉 8.000 4.000 硬脂醯反丁烯二酸鈉 6.000 3.000 總雷米普利層 200.000 100.000 總2層錠劑 680.000 揮發性組份，其在終產物中無殘留 99043.doc -23- 200533389 貝例4 ·替米沙坦80 mg/雷米普利2·5 mg 2層 錠劑 組成 —-—_ mg/錠劑 替米沙坦層 之百分比 雷米普利層 之百分比 替米沙坦 80.000 16.667 —-----~__ 氫氧化鈉 6.720 1.400 聚乙稀各酉同 24.000 5.000 葡甲胺 24.000 5.000 純水* 400.000 山梨糖醇 337.280 70.267 硬脂酸鎂 8.000 1.667 總替米沙垣層 480.000 100.000 雷米普利 2.500 1.250 微晶纖維素 60.000 30.000 乳糖 117.500 58.750 备丙基甲基纖維素 6.000 3.000 純水* 70.000 輕基乙酸殿粉納 8.000 4.000 硬脂酸反丁烯二酸鈉 ------ 6.000 3.000 總雷米普利層 200.000 100.000 總2層錠劑 680.000 揮發性組份，其在終產物中無殘留 99043.doc -24 - 200533389
實例5 :替米沙坦40 mg /雷米普利5 mg 2層錠劑 組成 mg/錠劑 替米沙坦層 之百分比 雷米普利層 之百分比 替米沙坦 40.000 16.667 氫氧化鈉 3.360 1.400 聚乙烯0比洛酮 12.000 5.000 葡甲胺 12.000 5.000 純水* 200.000 山梨糖醇 168.640 70.267 硬脂酸鎂 4.000 1.667 總替米沙坦層 240.000 100.000 雷米普利 5.000 2.500 微晶纖維素 60.000 30.000 乳糖 115.000 57.500 羥丙基甲基纖維素 6.000 3.000 純水* 70.000 羥基乙酸澱粉鈉 8.000 4.000 硬脂醯反丁烯二酸鈉 6.000 3.000 總雷米普利層 200.000 100.000 總2層錠劑 440.000 揮發性組份，其在終產物中無殘留 99043.doc -25- 200533389 實例6 :替米沙坦80mg/雷米普^J1〇mg/HCTZ125mg2層錠劑 組成 mg/錠劑 替米 之百分比 雷米普利層 j百分比 替米沙坦 80,000 — 16,667 氫氧化納 6,720 -~~-——__ 1，40〇 聚乙烯外[^各酉同 24,000 ----- 5,000 葡甲胺 24,000 5,000 純水* 400,000 山梨糖醇 337,280 70,267 硬脂酸鎂 8,000 1，667 總替米沙坦層 480,000 100,000 雷米普利 10,000 5,000 氫氣噻嗪(HCTZ) 12,500 6,250 微晶纖維素 64,000 32,000 甘露糖醇 93,170 46,585 羥丙基曱基纖維素 6,000 3,000 純水* 70,000 羥基乙酸澱粉鈉 8,000 4,000 氧化鐵紅 0,330 0，165 硬脂酸反丁稀二酸納 6,000 3,000 總雷米普利+HCTZ層 200,000 100,000 總2層錠劑 680,000 *揮發性組份，其在終產物中無殘留
99043.doc -26- 200533389 鱗
實例7 :替米沙坦8〇11^/雷米普利1〇11^/11012 12.511^3層錠劑 組成 mg/錠劑 替米沙坦層 之百分比 HCTZ層之 百分比 雷米普利層 之百分比 替米沙坦 80,000 16,667 氫氧化納 6,720 1，400 聚乙烯°比略酉同 24,000 5,000 葡曱胺 24,000 5,000 純水* 400,000 山梨糖醇 337,280 70,267 硬脂酸鎂 8,000 1,667 總替米沙坦層 480,000 100,000 氫氯噻嗪(HCTZ) 12,500 8,333 微晶纖維素 64,000 42,667 乳糖單水合物 59,670 39J80 玉米澱粉 6,000 4,000 純水* 適量 羥基乙酸澱粉鈉 6,000 4,000 氧化鐵紅 0,330 0,220 硬脂酸鎂 1，500 1，000 總HCTZ層 150,000 100,000 雷米普利 10,000 6,667 微晶纖維素 64,000 42,667 甘露糖醇 59,170 39,447 羥丙基曱基纖維素 6,000 4,000 純水* 適量 氧化鐵黃 0,330 0,220 羥基乙酸澱粉鈉 6,000 4,000 硬脂酿反丁烯二酸納 4,500 3,000 總雷米普利層 0tbt t 150,000 100,000 780,000 揮發性瓦 99043.doc -27>
Claims (1)
- 200533389 十、申請專利範圍： 種W樂錠劑’其包含一替米沙坦（telmisartan)在可溶性 旋』基貝中之第一層及一雷米普利（ramipril)在崩解性錠 劑基質中之第二層。 月求項1之錠劑，其另外在該第二層中或在一具有崩 解性錠劑基質之獨立第三層中包含利尿劑。 3·=明求項2之錠劑，其中該第三層係位於該第一層與該 第層之間且該等層係藉由使用不同顏色來區分。 4·如2求項1之錠劑，其中替米沙坦為大體上非晶形。 5·如明求項1之錠劑，#中該可溶性錠劑基質具有即時釋 放特徵。 守字 2明求項1之錠劑，其中該可/分，丨土狄评j/土、貝e 7 d &水'谷性稀釋劑及視情況其它賦形劑及佐劑。 '求項6之錠劑，其中該驗性劑係選自驗金屬氫氧化 物、驗性胺基酸及葡甲胺。 飞乳化8 iri:6之錠劑，其中該水溶性稀釋劑係選自單醣類 醇寡釀類如嚴糖及乳糖；及糖醇類如山梨糖 路糖醇及木糖醇。 9.如請求項6之錠劑， 黏合劑 、中化、匕賦形劑及佐劑係選自 遲禹丨 彳、填充劑、潤滑劑、流動控制劑、处曰延 遲制、增溶劑、著色劑、_ 〜曰延 化劑。 P ^^、界面活性劑及乳 10·如請求項i ^ 、、疋鈉，其中藉由以下# # γ ^ 4 坦之第一岸.A兩# 私作T衣侍该替米沙 曰.貝務乾躁包含替米沙坦及驗性劑之水溶液 99043doc.doc 200533389 以專又得經噴霧乾燥之顆粒、混合該經噴霧乾燥之顆粒與 水溶性稀釋劑以獲得預混合料、混合該預混合料與潤滑 劑以獲得終摻合物且㈣該終摻合物以形成該第―旋: %層。 π.如請求項2之錠劑，其中該第二或第三層之該崩解性錠 背1基貝包含填充劑、黏合劑、崩解劑及視情況選用之其 它賦形劑及佐劑。 12·如請求項^之錠劑，其中該等其它賦形劑及佐劑係選自 載劑、稀釋劑、潤滑劑、流動控制劑、增溶劑、著色 劑、pH值控制劑、界面活性劑及乳化劑。 13·如请求項1之錠劑，其中該第一層含有丨〇_丨6〇 ，較佳 20-80 mg或40-80 mg之替米沙坦。 14 ·如叫求項1之鍵劑，其中該第二層含有1 -20 mg，較佳5 10 mg之雷米普利及視情況6 25至5〇 mg，較佳12.5至25 mg之氫氣噻嗪。 15·如請求項2之錠劑，其中該第三層含有6.25至50 mg，較 佳12·5至25 mg之氫氯噻嗪。 16·如請求項丨之錠劑，其係包在防潮包裝材料如鋁箔泡殼 包裝或聚丙烯管及高密度聚乙烯（HDPE)瓶中。 17. —種用於製造如請求項1或2之錠劑以治療或預防選自由 中風、心肌梗塞、短暫性腦缺血、心血管疾病、糖尿 病、認知衰退及癡呆組成之群之病症的方法。 99043doc.doc 200533389 七、指定代表圖·· (一) 本案指定代表圖為無） (二) 本代表圖之元件符號簡單說明··八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：99043.doc -4-
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| US20050186274A1 (en) | 2005-08-25 |
| WO2005079762A1 (en) | 2005-09-01 |
| NO20063997L (no) | 2006-11-14 |
| RU2006133453A (ru) | 2008-03-27 |
| ECSP066779A (es) | 2006-12-20 |
| BRPI0507887A (pt) | 2007-08-07 |
| AR047806A1 (es) | 2006-02-22 |
| AU2005215115A1 (en) | 2005-09-01 |
| MXPA06008225A (es) | 2006-08-31 |
| JP2007523112A (ja) | 2007-08-16 |
| KR20060130671A (ko) | 2006-12-19 |
| ZA200604913B (en) | 2007-11-28 |
| EP1718281A1 (en) | 2006-11-08 |
| CN1921840A (zh) | 2007-02-28 |
| DE102004008804A1 (de) | 2005-09-08 |
| PE20051127A1 (es) | 2006-01-31 |
| CA2552902A1 (en) | 2005-09-01 |
| UY28753A1 (es) | 2005-09-30 |
| IL177536A0 (en) | 2006-12-10 |
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