TW200950776A

TW200950776A - Abuse resistant melt extruded formulation having reduced alcohol interaction

Info

Publication number: TW200950776A
Application number: TW098103158A
Authority: TW
Inventors: Wolfgang Roth; Alexander Burst; Martina Zietsch
Original assignee: Abbott Gmbh & Co Kg
Priority date: 2008-01-24
Filing date: 2009-01-23
Publication date: 2009-12-16
Also published as: AU2009207579A1; WO2009092818A1; JP2011510048A; MX2010008100A; CN101977592A; KR20100110370A; CA2713373A1; IL207173A0; BRPI0907402A2; EP2254553A1; ZA201005797B; NZ586962A

Abstract

The present invention relates to a melt-extruded dosage form having reduced drug-alcohol interaction, comprising: (a) an abuse relevant drug or a drug having potential for dose dumping in alcohol; and (b) a matrix having a polymer, copolymer or combinations thereof selected from a group of monomers consisting of cellulose ether, cellulose ester, acrylic acid ester, methacrylic acid ester and natrium-alginate. wherein said matrix is melt extruded and wherein the dosage form has reduced drug-alcohol interaction.

Description

200950776 六、發明說明：【發明所屬之技術領域】本發明係關於口服投藥之組合物。本發明㈣包含至少 -種用於傳遞於乙醇中具有劑量傾釋潛在性之藥物的防濫用藥物傳遞組合物；製備該等劑型之相關方法；及治療有此需要之患者的方法，該等方法包含將本發明之組合物投與患者。【先前技術】 & 控制或調節釋放調配物具有獨特優勢，諸如因給藥之頻率降低而患者順應性增強及因藥物之血裂含量波動減小而副作用減少。同時應注意，控制/調節釋放調配物相對於其立即釋放對應物含有更高量之活性藥物。若調配物之控制釋放部分被輕易破壞，則最終結果為對活性藥物之暴露潛在增加及可能之安全問題。乙醇之共同攝入對調節釋放口服調配物中之藥物之活體内釋放的潛在影響最近愈來愈爹受到關注。此源於最近之臨床發現：乙醇之共攝取導致 Pallad〇ne™ (—種控制釋放膠囊劑型）中之氫嗎啡酮 (hydr〇morph〇ne)之潛在嚴重劑量傾釋（FDA AUrt，2〇〇5年 7月）。世界衛生組織（The World Health Organization)估計全世界大約20億人消費乙醇（Wh〇 Rep〇rt，2〇〇4)。由於乙醇為社會最接受、使用最廣泛且獲得最容易之藥物之一，因此藥物交互影響之潛在性為急迫的。為改良安全性且防止故意篡改（例如將控制釋放錠劑溶解於乙醇中以萃取藥物）起見，減少該等調配物之調節釋放部分於乙醇中之溶 138081.doc 200950776 解可為有益的。之劑量傾釋潛在性之新因此，對開發於乙醇中具有減低賴調配物存在需要。【發明内容】在一較佳實施财’可製備與乙醇共較料具有減低或限制之劑量傾釋效應之維拉帕米（verapamii)及其他控制釋放調配物。較佳實施例包括熔融擠出之持續釋放調配200950776 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to a composition for oral administration. The invention (4) comprises at least one anti-abuse drug delivery composition for delivering a drug having a dose-draining potential in ethanol; a method for preparing the same; and a method for treating a patient in need thereof, the method Included is the administration of a composition of the invention to a patient. [Prior Art] & Controlling or regulating the release formulation has unique advantages, such as increased patient compliance due to reduced frequency of administration and reduced side effects due to reduced fluctuations in the blood lysis content of the drug. It should also be noted that the controlled/regulated release formulation contains a higher amount of active drug relative to its immediate release counterpart. If the controlled release portion of the formulation is easily destroyed, the end result is a potential increase in exposure to the active drug and possible safety issues. The potential effects of co-intake of ethanol on the in vivo release of drugs that regulate release of oral formulations have recently received increasing attention. This stems from a recent clinical finding that co-intake of ethanol leads to a potentially severe dose release of hydr〇morph〇ne in Pallad〇neTM (a controlled release capsule dosage form) (FDA AUrt, 2〇〇) 5 years in July). The World Health Organization estimates that approximately 2 billion people worldwide consume ethanol (Wh〇 Rep〇rt, 2.4). Since ethanol is one of the most accepted, widely used, and easily accessible drugs in society, the potential for drug interactions is urgent. In order to improve safety and prevent intentional tampering (e.g., dissolving a controlled release tablet in ethanol to extract the drug), it may be beneficial to reduce the solubility of the modified release portion of the formulation in ethanol 138081.doc 200950776. The potential for dose release is therefore a need for a reduced formulation in ethanol. SUMMARY OF THE INVENTION Verapamii and other controlled release formulations having a reduced or limited dose-dumping effect compared to ethanol can be prepared in a preferred embodiment. Preferred embodiments include sustained release blending of melt extrusion

物。本發明之一較佳實施例提供一種具有減低之藥物-乙醇交互影響之溶融擠出劑型’該劑型包含：⑷濫用相關藥物或於乙醇中具有劑量傾釋潛在性之藥物；及⑻具有聚合物。:共聚物或其組合之基質，該聚合物、共聚物或其組合之單體選自由以下各物組成之群：纖維素㈣、纖維素輯、丙婦酸s日、甲基丙烯酸s旨及海藻酸納^預期使用該溶融擠出基質可提供具有減低之藥物-乙醇交互影響之劑型。較佳地基質包含經基院基纖維素、經基燒基院基纖維素及海藻酸鈉之聚合物及共聚物。此外，該藥物較佳為維拉帕米、γ羥基丁酸或氟硝西泮（flunitrazepam)之鹽或酯。更佳地，羥基烷基纖維素為羥丙基纖維素且/或羥基烷基烷基纖維素為羥丙基甲基纖維素。在最佳實施例中，該藥物為維拉帕米之鹽或酯。此藥物可包含1 mg至1〇〇〇 mg之維拉帕米之鹽或酯。本發明之另一實施例提供具有1至1000 mg維拉帕米之維拉帕米熔融擠出調配物，其中使用USP溶解法溶解於4〇〇/0 乙醇溶液中之該劑型中之維拉帕米少於40% »另外在此調 138081.doc 200950776 . 配物中，該劑型中之維拉帕米在5〇/0或40%乙醇中、在八小時時之溶解曲線無異於該劑型中之維拉帕米在〇%乙醇中、，八小時時之溶解曲線。最佳地，在所有此等調配物中，樂物包含240 mg之維拉帕米之鹽或自旨。另外，無需另 .夕卜之不當實驗’可確定在此等調配物中，活體外藥物乙醇、《互影響之減低與活體内藥物乙醇交互影響之減低相互關聯。 ❹ 本發明之另-實施例提供-種用於治療有此需要之人類患者之方法，其包含向人類患者經口投與任何上述劑型。本發明之此等及其他目的、優點及特徵在熟習此項技術者閱讀以下更充分描述之本發明之方法及其中使用之組合物之詳情後將顯而易見。【實施方式】乙醇之伴隨攝入對調節釋放口服調配物中之藥物之活體内釋放的潛在影響最近愈來愈受到關注。此研究之目的為 ❿測定乙醇對Meltrex®技術之維拉帕米（240 mg)之活體外釋放速率之影響，與三種其他市售維拉帕米（24〇 mg)控制釋放調配物相比，Meltrex®技術之維拉帕米（24〇 mg)為實現藥物穩定固態分散之新穎熔融擠出調配物。此熔融擠出調配物視為一種將溶解性不良之藥物作為固態分散體/固溶體敌埋於生物相容性聚合物基質中之有效及專門化技術。利用緩衝液添加法（磷酸鉀緩衝液）、使用含有0〇/〇、5%、 20°/。及40%遞增濃度之乙醇之介質在標準化條件下進行溶解測試。對於各介質，測試六種錠劑（4種錠劑為在〇◦/〇乙醇 138081.doc 200950776 中之形式C)且在250-300 nm下經分光光度法監測藥物釋放。熔融擠出調配物之溶解曲線展示5%及4〇〇/。乙醇介質 (?>0.05)與0%乙醇介質之間無顯著差異，而2〇%乙醇介質與〇%乙醇介質（P=〇.02)相比，有統計上顯著之釋放減少。 • 對於〇%與40%乙醇之極端條件，平均溶解百分比在i小時時相同（19%)且在8小時時40%乙醇介質（81%)僅略高於〇% 乙醇介質（77%)。相反，三種市售對比物展示，與〇%乙醇條件（P<0.0()1)相比，在較高濃度乙醇（20及40%乙醇）令之溶解在統計上呈顯著增加。在較高乙醇濃度下觀察到初始 .快速釋放，在測試最初2小時内展示99%之平均溶解百分比（範圍為73-107%) 〇低/無乙醇濃度下之溶解展示近零級之穩定釋放，其在最初2小時内具有25°/。之平均溶解百分比。此活體外溶解研究已證明，當在高達4〇%之乙醇濃度下原樣測試時，維拉帕米之新穎熔融擠出調配物（形式A) 不改變其釋放曲線。相反，三種其他市售控制釋放維拉帕參米/辰度在較尚乙醇濃度（20及40%)下展示劑量傾釋效應。此研究提示此新穎熔融擠出調配物當與易達到之乙醇濃度組合時可在活體外環境中抵抗劑量傾釋》測定此調配物在活體内環境中之穩定性之未來研究可有助於測定臨床重要 ^藥物-乙醇交互影響之潛在性。與標準製錠方法（形式3至〇，其中含有藥物之粉末或顆粒係經壓縮）不同，在維拉帕米Meltrex®(形式a)之情況下，熔融擠出為新穎方法，其中該含有藥物之聚合物熔體係直接成形。此外，熔融擠出技術具有作為無溶劑及無塵 138081.doc 200950776 方法之優點，無溶劑及無塵方法通常用於製備均一系統或塊狀中間體，允許環境污染減少、防爆及殘餘有機溶劑減少之清潔加工環境（Breitenbach及Lewis，2003)。當應用於藥物調配物時，熔融擠出技術之治療性優勢包括改良之溶解動力學、增加之生物可用性及從而增加之功效、改良之安全性及形成特定釋放曲線之能力（Breitenbach，2002j Breitenbach及Lewis，2003)。藉由選擇最佳聚合物組成，可製備具有極低脆性之極硬及"塑膠"樣錠劑。熔融擠出錠劑不能如在標準錠劑之情況下壓成細粉，且從而減少物理篡改潛在性。該技術可應用於許多活性藥物成份，可有利於減少每日給藥之頻率’且可有助於阻止篡改（例如鴉片 • 劑、興奮劑）’改良安全性且維持長效釋放曲線。此熔融 ’ 擠出技術已應用於維拉帕米鹽酸鹽，該維拉帕米鹽酸鹽為一種可與乙醇潛在交互影響的市售抗高血壓及抗心絞痛之藥物（Covera-HS Product Monograph，2006)。 ❿ 在一較佳實施例中’可製備與乙醇共同使用時具有減低或限制之劑量傾釋效應之維拉帕米及其他控制釋放調配物。較佳實施例包括熔融擠出之持續釋放調配物。本發明之一較佳實施例提供一種具有減低之藥物_乙醇交互影響之溶融擠出劑型，該劑型包含：（昀濫用相關藥物或於乙醇中具有劑量傾釋潛在性之藥物；及（b)具有聚合物、共聚物或/、、、且σ之基質，該聚合物、共聚物或其組合之單體選自由乂下各物組成之群：纖維素醚、纖維素酯、丙烯酸酯、甲基丙烯酸酯及海藻酸鈉。預期使用該熔融擠出基質可提 138081.doc 200950776 供具有減低之藥物-乙醇交互影響之劑型。較佳地，基質包含經基縣纖維素、μ錢基燒基纖維素及海藻義之聚合物及共聚物。此外’該藥物較佳為維拉帕米、丫經基丁酸或氟硝西泮之鹽或醋。更佳地，經基院基纖維素為經丙基纖維素及/或經基烷基烷基纖維素為經丙基甲基纖維素。在最佳實施例中，該藥物為維拉帕米之鹽或酯。此藥物可包含1 !1^至1000 „^之維拉帕米之鹽或酯。本發明之另一實施例提供具有1至咖哺拉帕米之維拉帕米熔融擠出調配物，其中使用usp溶解法溶解於娜Things. A preferred embodiment of the present invention provides a melt-extruded dosage form having a reduced drug-ethanol interaction effect. The dosage form comprises: (4) a drug that abuses a related drug or has a dose-draining potential in ethanol; and (8) has a polymer . a matrix of a copolymer or a combination thereof, the monomer of the polymer, the copolymer or a combination thereof being selected from the group consisting of cellulose (tetra), cellulose, propylene s, methacrylic acid Alginate sodium is expected to provide a dosage form with reduced drug-ethanol interaction using the molten extruded matrix. Preferably, the matrix comprises a polymer and a copolymer of a base-based cellulose, a base-based cellulose, and a sodium alginate. Further, the drug is preferably a salt or ester of verapamil, gamma hydroxybutyric acid or flunitrazepam. More preferably, the hydroxyalkylcellulose is hydroxypropylcellulose and/or the hydroxyalkylalkylcellulose is hydroxypropylmethylcellulose. In a preferred embodiment, the drug is a salt or ester of verapamil. This medicine may contain from 1 mg to 1 mg of the salt or ester of verapamil. Another embodiment of the present invention provides a verapamil melt-extruded formulation having 1 to 1000 mg verapamil, wherein the vera is dissolved in a 4 〇〇/0 ethanol solution using a USP dissolution method. Pami is less than 40% » In addition, here the 138081.doc 200950776. In the formulation, the dissolution curve of verapamil in this dosage form in 5〇/0 or 40% ethanol at eight hours is no different The dissolution profile of verapamil in the dosage form in 〇% ethanol at eight hours. Most preferably, in all such formulations, the music contains 240 mg of verapamil or a self-acting. In addition, no additional experimentation may be required to determine that in vitro, drug ethanol, the reduction in interaction, and the reduction in the interaction of drug and ethanol in vivo are interrelated. Another embodiment of the present invention provides a method for treating a human patient in need thereof, which comprises orally administering to a human patient any of the above dosage forms. These and other objects, advantages and features of the invention will become apparent to those skilled in the <RTI [Embodiment] The potential effects of concomitant intake of ethanol on the in vivo release of drugs in modified release oral formulations have recently received increasing attention. The purpose of this study was to determine the effect of ethanol on the in vitro release rate of verapamil (240 mg) from Meltrex® technology compared to three other commercially available verapamil (24 mg) controlled release formulations. Meltrex® technology's verapamil (24〇mg) is a novel melt-extruded formulation for stable solid dispersion of drugs. This melt-extruded formulation is considered to be an effective and specialized technique for embedding a poorly soluble drug as a solid dispersion/solid solution in a biocompatible polymer matrix. The buffer addition method (potassium phosphate buffer) was used, and the content was 0 〇 / 〇, 5%, 20 ° /. The medium with 40% increasing concentration of ethanol was subjected to a dissolution test under standardized conditions. For each medium, six lozenges were tested (four lozenges in Form C in 〇◦/〇 ethanol 138081.doc 200950776) and the drug release was monitored spectrophotometrically at 250-300 nm. The dissolution profile of the melt extruded formulation showed 5% and 4 Å/. There was no significant difference between the ethanol medium (?>0.05) and the 0% ethanol medium, while the 2%% ethanol medium showed a statistically significant reduction in release compared to the 〇% ethanol medium (P=〇.02). • For extreme conditions of 〇% and 40% ethanol, the average percent dissolved is the same at i hours (19%) and at 8 hours 40% ethanol medium (81%) is only slightly above 〇% ethanol medium (77%). In contrast, the three commercially available controls showed a statistically significant increase in dissolution at higher concentrations of ethanol (20 and 40% ethanol) compared to the 〇% ethanol condition (P<0.0()1). Initial. Rapid release was observed at higher ethanol concentrations, showing an average percent dissolution of 99% (range 73-107%) during the first 2 hours of the test. Dissolution at low/no ethanol concentration exhibited near zero order stable release. It has 25°/ in the first 2 hours. The average percentage of dissolution. This in vitro dissolution study has demonstrated that the novel melt-extruded formulation of Verapamil (Form A) does not change its release profile when tested as it is at an ethanol concentration of up to 4%. In contrast, three other commercially available controlled release verapamil/tender showed a dose-dumping effect at a higher ethanol concentration (20 and 40%). This study suggests that this novel melt-extruded formulation can resist dose dumping in an in vitro environment when combined with readily available ethanol concentrations. Future studies to determine the stability of this formulation in an in vivo environment can aid in the determination. Clinically important ^ potential of drug-ethanol interactions. Unlike the standard ingot method (form 3 to hydrazine, in which the powder or granule containing the drug is compressed), in the case of verapamil Meltrex® (form a), melt extrusion is a novel method in which the drug is contained The polymer melt system is directly formed. In addition, melt extrusion technology has the advantage of being solvent-free and dust-free 138081.doc 200950776. Solvent-free and dust-free methods are commonly used to prepare homogeneous systems or bulk intermediates, allowing for reduced environmental pollution, explosion protection and reduced residual organic solvents. Clean processing environment (Breitenbach and Lewis, 2003). When applied to pharmaceutical formulations, the therapeutic advantages of melt extrusion techniques include improved dissolution kinetics, increased bioavailability and thus increased efficacy, improved safety and ability to form specific release profiles (Breitenbach, 2002j Breitenbach and Lewis, 2003). By selecting the optimum polymer composition, extremely hard and "plastic"-like tablets can be prepared with very low brittleness. The melt extruded tablet cannot be pressed into a fine powder as in the case of a standard tablet, and thereby reduces the potential for physical tampering. This technique can be applied to many active pharmaceutical ingredients, which can help reduce the frequency of daily dosing' and can help prevent tampering (e.g., opium, stimulant)' improved safety and maintain a long-lasting release profile. This melt' extrusion technology has been applied to verapamil hydrochloride, a commercially available antihypertensive and anti-angina drug that can potentially interact with ethanol (Covera-HS Product Monograph) , 2006). ❿ In a preferred embodiment, verapamil and other controlled release formulations having reduced or limited dose-dumping effects when used in combination with ethanol can be prepared. Preferred embodiments include a melt release continuous release formulation. A preferred embodiment of the present invention provides a melt-extruded dosage form having a reduced drug-ethanol interaction effect, the dosage form comprising: (a drug that abuses a drug or a drug having a dose-drain potential in ethanol; and (b) a matrix having a polymer, a copolymer or/, and a sigma, the monomer of the polymer, copolymer or combination thereof being selected from the group consisting of the underarms: cellulose ether, cellulose ester, acrylate, nail Acrylates and sodium alginate. It is expected that the melt-extruded matrix can be used to provide a dosage form with reduced drug-ethanol interaction. Preferably, the matrix comprises the cellulose of the base, and the base of the base. a polymer and a copolymer of cellulose and seaweed. Further, the drug is preferably a salt of verapamil, lysine or flunitrazepam or vinegar. More preferably, the cellulose based on the base is used. The propylcellulose and/or transalkylalkylalkylcellulose is propylmethylcellulose. In a preferred embodiment, the drug is a salt or ester of verapamil. The drug may comprise 1 !1 ^ to 1000 „^ of the salt or ester of verapamil. Another embodiment of the invention to provide a coffee feeding verapamil 1 Dimension verapamil melt extruded formulation was used in which the dissolution of dissolved Na Yu usp

乙醇溶液中之劑型中之維拉帕米少於4 〇 %。另外在此調配物中，該劑型之維拉帕米在5%或4〇%乙醇中、在八小時時之溶解曲線無異於該劑型之維拉帕米在〇%乙醇中、在八小時時之溶解曲線。最佳地，在所有此等調配物中，藥物包含240 mg之維拉帕米之鹽或醋。另外，無需另外之不當實驗，可確定在此等調配物中，活體外藥物乙醇交互影響之減低與活體内藥物乙酵交互影響之減低相互關聯。本發明之另一實施例提供一種用於治療有此需要之人類患者之方法，該方法包含向人類患者經口投與任何上述劑型。在另一實施例中，調配物可使用聚合物或共聚物或其組合以形成經熔融加工且更佳經熔融擠出之直接成形調配物。亦可使用在藥理學上為非活性且提供調配物之腸衣或持續釋放曲線的聚合物。在一實施例中，合適之聚合物/ 共聚物包括聚（甲基）丙烯酸酯，例如Eudragit L-型或s- 138081.doc 200950776 型，其在藥理學上為非活性的。 EUDRAGIT®為適用於本發明且由丙稀酸及曱基丙缔酸之酿所衍生之某呰較佳聚合物之商品名稱。EUDRAGIT聚合物之特性主要由併入EUDRAGIT聚合物之單體内的官能基決定。個別等级之EUDRAGIT®在其中性基團、驗性基團或酸性基團之比例方面不同且從而在物理化學特性方面不同。可使用具有下式之録基烧基甲基丙稀酸醋共聚物或曱基丙烯酸酯共聚物：The verapamil in the dosage form in the ethanol solution is less than 4%. In addition, in this formulation, the dissolution profile of the dosage form of verapamil in 5% or 4% ethanol at eight hours is no different from the dosage form of verapamil in 〇% ethanol in eight hours. The dissolution curve at that time. Most preferably, in all such formulations, the drug comprises 240 mg of verapamil or vinegar. In addition, no additional undue experimentation is required to determine that the reduction in the interaction of the in vitro drug ethanol in these formulations correlates with the reduced interaction of the drug in the in vivo drug. Another embodiment of the invention provides a method for treating a human patient in need thereof, the method comprising orally administering to a human patient any of the above dosage forms. In another embodiment, the formulation may use a polymer or copolymer or a combination thereof to form a melt-processed and more melt extruded direct forming formulation. Polymers which are pharmacologically inactive and which provide a casing or sustained release profile of the formulation may also be used. In one embodiment, suitable polymers/copolymers include poly(meth)acrylates such as Eudragit L-form or s-138081.doc 200950776, which are pharmacologically inactive. EUDRAGIT® is the trade name of a preferred polymer suitable for use in the present invention and derived from the brewing of acrylic acid and mercaptopropionic acid. The properties of the EUDRAGIT polymer are primarily determined by the functional groups incorporated within the monomer of the EUDRAGIT polymer. Individual grades of EUDRAGIT® differ in the proportion of their neutral groups, test groups or acidic groups and thus differ in their physicochemical properties. A methacrylic acid methacrylate copolymer or a methacrylate copolymer having the following formula can be used:

Eudragit聚合物滿足USP中所設定之規格/要求。根據 2007 美國藥典（US Pharmacopoeia)，Eudragit 定義為 USP 30/NF 25 ° NF A型曱基丙烯酸共聚物=Eudragit L-100 NF B型甲基丙烯酸共聚物=Eudragit S-100 NF C型曱基丙烯酸共聚物=Eudragit L-100-55(含有少量清潔劑） NF A型敍基曱基丙婦酸酯共聚物=Eudragit RL-100(顆粒） NF A型録基曱基丙烯酸酯共聚物=Eudragit RL-PO(粉末） NF B型銨基曱基丙稀酸酯共聚物=Eudragit RS-100(顆粒） 138081.doc -10· 200950776 NF B型敍基曱基丙稀酸酿共聚物=Eudragit RS-ΡΟ(粉末）歐洲藥典級（Ph· Eur.)30%聚丙烯酸酯分散液=Eudragit NE30D(=30%水性分散液）歐洲藥典級鹼性丁基化曱基丙烯酸酯共聚物=Eudragit E-100 其中官能基具有四級銨（三曱基銨基乙基甲基丙烯酸酯）部分或 R=COOCH2CH2N+(CH3)3Cl·[市面上以 EUDRAGIT® (RL或RS)購得]，或官能基為羧酸或R=COOH[市面上以 EUDRAGIT®(L)購得]»當官能基為羧酸部分時， EUDRAGIT®(L)聚合物具有胃耐受性及腸溶性。因此使用 EUE>RA(3IT®(L·)之調配物耐受胃液且在結腸中釋放活性劑。當官能基為三甲基銨基乙基曱基丙烯酸酯部分時， EUDRAGIT®(RL或RS)聚合物具有不溶性、可滲透性、可分散性及pH無關性。該等EUDRAGIT® (RL或RS)聚合物因此可用於持續釋放型調配物之延遲藥物釋放。 EUDRAGIT®以不同形式出售，諸如以固體形式 (EUDRAGIT® L100/S100/L-100-55、EUDRAGIT® E PO、 EUDRAGIT® RL PO、Eudragit RS PO);顆粒（EUDRAGIT® E100、EUDRAGIT®RL 100/RS 100);分散液（L 30 D-55/FS 30D 30%、EUDRAGIT® NE 30 D/40 D 30%/40°/〇聚合物含量、EUDRAGIT®RL 30 D RS 30 D 30%)及有機溶液 (EUDRAGIT® L 12.5、EUDRAGIT® E12.5、EUDRAGIT® RL 12.5/RS 12.5-12.5%有機溶液）。當使用至少兩種經熔融加工之聚合物時，一種較佳為纖 138081.doc 11 200950776 維素衍生物’更佳為絲絲纖維㈣生物且視情況為輕丙土甲基纖維素，且另一種聚合物獨立地、較佳地為(尹基）丙埽酸醋聚合物（諸如任何合適之Eudragh聚合物）。在本發月之上下文中較佳之（甲基）丙烯酸酯聚合物為 Eudragit L及Eudragit RS。在本發明之上下文中，_種更佳之聚合物為Eudragit RL。Eudragh聚合物可組合使用，其中較佳為Eudragit RS與RL之混合物。Eudragit polymers meet the specifications/requirements set forth in the USP. According to the 2007 US Pharmacopoeia, Eudragit is defined as USP 30/NF 25 ° NF A-type methacrylic acid copolymer = Eudragit L-100 NF B type methacrylic acid copolymer = Eudragit S-100 NF C-type methacrylic acid Copolymer = Eudragit L-100-55 (with a small amount of detergent) NF A type sulfhydryl propyl acrylate copolymer = Eudragit RL-100 (granules) NF A type thiol acrylate copolymer = Eudragit RL -PO (powder) NF B-type ammonium mercapto acrylate copolymer = Eudragit RS-100 (granules) 138081.doc -10· 200950776 NF B-type sulfhydryl acrylate copolymer = Eudragit RS- ΡΟ (powder) European Pharmacopoeia (Ph· Eur.) 30% polyacrylate dispersion = Eudragit NE30D (= 30% aqueous dispersion) European Pharmacopoeia grade alkaline butylated methacrylate copolymer = Eudragit E-100 Where the functional group has a quaternary ammonium (tridecyl ammonium ethyl methacrylate) moiety or R = COOCH2CH2N + (CH3) 3Cl · [commercially available as EUDRAGIT® (RL or RS)], or the functional group is a carboxy group Acid or R=COOH [commercially available as EUDRAGIT® (L)]» When the functional group is a carboxylic acid moiety, the EUDRAGIT® (L) polymer has a stomach Tolerance and enteric solubility. Therefore, the formulation of EUE>RA (3IT®(L·) is resistant to gastric juice and the active agent is released in the colon. When the functional group is a trimethylammonium ethylmercaptoacrylate moiety, EUDRAGIT® (RL or RS) The polymers are insoluble, permeable, dispersible and pH-independent. These EUDRAGIT® (RL or RS) polymers can therefore be used for delayed drug release in sustained release formulations. EUDRAGIT® is sold in different forms, such as In solid form (EUDRAGIT® L100/S100/L-100-55, EUDRAGIT® E PO, EUDRAGIT® RL PO, Eudragit RS PO); pellets (EUDRAGIT® E100, EUDRAGIT® RL 100/RS 100); dispersion (L 30 D-55/FS 30D 30%, EUDRAGIT® NE 30 D/40 D 30%/40°/〇 polymer content, EUDRAGIT® RL 30 D RS 30 D 30%) and organic solution (EUDRAGIT® L 12.5, EUDRAGIT ® E12.5, EUDRAGIT® RL 12.5/RS 12.5-12.5% organic solution). When using at least two melt-processed polymers, a preferred fiber 138081.doc 11 200950776 vitamin derivative is better The filament fiber (4) is biological and optionally mildine methyl cellulose, and the other polymer is independently, preferably (Yinji) propionate polymer (such as any suitable Eudragh polymer). Preferred (meth)acrylate polymers in the context of this month are Eudragit L and Eudragit RS. In the context of the present invention Among them, a better polymer is Eudragit RL. Eudragh polymers can be used in combination, and a mixture of Eudragit RS and RL is preferred.

❹ 服用醫師所開處方之藥物時飲用大量乙醇飲料(儘管不妥）的個人會使胃中所含胃液之組成大體上改變且在極端情況下，該等胃液可包含高達4〇Q/。之乙醇。有利地本發明防濫用型調配物之實施例視情況包含具有至少一種产用相關藥物、至少一種纖維素醚或纖維素酯及至少一種 (曱基）丙烯酸聚合物之熔融加工混合物，其中在37^下、在1小時内藉由20%乙醇水溶液或40%乙醇水溶液或兩者自調配物所萃取之藥物之量小於或等於在37^下或在25„c下或在兩者溫度下、在1小時内藉由001 N鹽酸所萃取之藥物之量的1.5倍。在個別有意試圖自含有濫用相關藥物之藥σσ中卒取}監用相關樂物的彼等情丨兄下，财受4 〇 %乙醇萃取為有利的。本發明之例示性較佳組合物包含可在本發明中單獨戈組合使用、具有50,000至1，250,〇〇〇道爾頓（daiton)範圍内之較佳分子量的纖維素醚及纖維素酯。纖維素醚較佳係選*** 基纖維素、羥基烷基纖維素、羥基烷基烷基纖維素或其混合物，諸如乙基纖維素、曱基纖維素、羥丙基纖維素 138081.d〇( •12- 200950776 (NF)、羥乙基纖維素（NF)及羥丙基甲基纖維素（usp)或其組。。適用之纖維素酯為（但不限於）乙酸纖維素（nf)、乙酸丁酸纖維素、乙酸丙酸纖維素、鄰苯二甲酸經丙基f基 .纖維素、乙酸鄰苯二甲酸經丙基甲基纖維素及其混合物。 ‘ 最佳可使用非離子性聚合物，諸如羥丙基甲基纖維素。纖維素之脫水葡萄糖單元上之取代基的數量可由與環連接取代基的平均數目指定，纖維素化學家稱此概念為取代度（D.S.)。若各單元上之全部三個可利用位置皆經取4戈則D.S.指定為3，若各環上平均兩個發生反應，則 D.S.指定為2，等等。在較佳實施例中，纖維素醚具有13至2 〇之烷基取代度及高達0.85之羥基烷基莫耳取代度。在較佳實施例中’烷基取代基為甲基。此外，較佳之羥基院基取代基為經丙基。具有甲氧基取代及經基丙氧基取代之不同取代度的該等聚合物類型總結列舉於藥典（例如 ❹ USP)中"經丙基甲基纖維素"名下。甲基纖維素可以商品名METH〇CEL A購得。 A具有1.64至192之甲基（或甲氧基）Ds.。該等聚合物類型列舉於藥典（例如usp)中•，甲基纖維素"名下。 ' 尤其較佳之纖維素醚為羥丙基甲基纖維素。羥丙基甲基纖維素可以商品；gMETH〇CEL E(甲基D s心9，經丙基莫耳取代度約〇.23)、METH〇CEL F(曱基DS約丨8，羥丙基莫耳取代度約〇.13)及METH0CEL κ(曱基Ds⑴4,經丙基莫耳取代度約〇.21)購得。meth〇cel f&meth〇cel I38081.doc -13- 200950776 κ為用於本發明之較佳羥丙基曱基纖維素。丙烯酸系聚合物合適地包括包含丙烯酸及/或烷基丙烯酸及/或（烷基）丙烯酸烷酯之單體的均聚物及共聚物（該術 s吾包括具有兩個以上不同重複單元的聚合物）。如本文中 • 所使用，術語"（烷基）丙烯酸烷酯"係指通常分別由相應丙烯酸或烷基丙烯酸形成之相應丙烯酸酯或烷基丙烯酸酯。換言之’術語"（烷基）丙烯酸烷酯”係指烷基丙烯酸烷酯或丙稀酸烧醋。 0 (烧基）丙烯酸烷酯較佳為（(C^Cio)烷基）丙烯酸（CrCn) 烧醋。（烷基）丙烯酸烷酯之Ci-Cn烷基之實例包括甲基、乙基、正丙基、正丁基、異丁基、第三丁基、異丙基、戊基、己基、環己基、2-乙基己基、庚基、辛基、壬基、癸基、異癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烧基、二十二烷基及其異構體。烷基可為直鏈或 ❿ 支鍵。（ci_C22)烷基較佳表示如上定義之（CrCd烷基，更佳表示如上疋義之（Cj-C4)院基。（烧基）丙稀酸院醋之c,-丨〇烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、戊基、己基、環己基、2_乙基己基、庚基、辛基、壬基、癸基及其異構體。烷基可為直鏈或支鍵° (C〗-Cu))烧基較佳表示如上定義之（Ci_c6)烷基，更佳表示如上定義之（CrCO烷基。 (烧基）丙烯酸烧酯較佳為（（Ci_C4)烷基）丙烯酸（Ci_C4)烷酯，最佳為（曱基）丙烯酸（Ci_C4)烷酯。應瞭解，術語（曱 138081.doc -14- 200950776 基）丙烯酸（CrCd烷酯係指丙烯酸（c「c4)烷酯或甲基丙烯酸（Ci-CO烷酯。（曱基）丙烯酸（Ci-Cd烷酯之實例包括甲基丙烯酸曱酯（MMA)、曱基丙烯酸乙酯（EMA)、甲基丙烯酸正丙酯（PMA)、甲基丙烯酸異丙酯（IPMA)、甲基丙烯酸正丁酯（BMA)、甲基丙烯酸異丁酯（IBMA)、曱基丙烯酸第三丁酯（TBMA);丙烯酸曱酯（MA)、丙烯酸乙酯（EA)、丙烯酸正丙酯（PA)、丙烯酸正丁酯（B A)、丙烯酸異丙酯（IPA)、丙烯酸異丁酯（IBA)及其組合。烷基丙烯酸單體較佳為（CrCw)烷基丙烯酸。（Ci-CM烷基丙烯酸之實例包括甲基丙烯酸、乙基丙烯酸、正丙基丙烯酸、異丙基丙烯酸、正丁基丙烯酸、異丁基丙烯酸、第三丁基丙烯酸、戊基丙烯酸、己基丙烯酸、庚基丙烯酸及其異構體。（CrCw)烷基丙烯酸較佳為（Ci-C4)烷基丙烯酸，最佳為曱基丙烯酸。在某些實施例中，烧基可經芳基取代。如本文中所使用’"烧基”係指直鏈、支鍵或環狀飽和或不飽和脂族烴。烷基具有1 -1 6個碳，且可未經取代或經一或多個選自以下各基之基團取代：齒素、經基、烧氧基鼓基、醯胺基、烧基醯胺基、二烷基醯胺基、硝基、胺基、烷基胺基、二烷基胺基、羧基、硫基及硫烷基。”羥基"係指OH基團◊"燒氧基"係指其中烷基如上定義之_〇_烷基。"硫基，，係指_SH 基團。"硫烷基”係指其中R為如上定義之烷基之_SR基團。胺基''係指-NH2基團。"烧基胺基"係指其中r為如上定義之烷基之-NHR基團。"二烷基胺基"係指其中R及Ri皆如上 138081.doc -15- 200950776 定義之-NRR'基團。，，醯胺基”係指_c〇NH^ ,，烷基醯胺基” 係指其中R為如上定義之烷基之_c〇NHR基團。"二烷基醯胺基係扎其中尺及尺'為如上定義之烷基之-CONRR，基團。硝基係指N〇2基團》"羧基"係指c〇〇h基團。 . 在某些實施例中，烷基可經芳基取代。如本文中所使 • 用芳基包括為單環與稠合多環之碳環芳族環與雜環芳族環，其中芳族環可為5員環或6員環。代表性單環芳基包 ❹ 括（但不限於）苯基、呋喃基、吡咯基、噻吩基、吡啶基、喷咬基、嚼嗤基、異„惡唾基、β比嗤基、咪嗤基、嗟唾基、異噻唑基及其類似基團。稠合多環芳基為包括5員或ό員芳族環或雜芳族環作為稠環系統中之一或多個環的彼等芳族基團。代表性稠合多環芳基包括萘、蒽、吲哚嗪、吲哚、異吲哚、苯并呋喃、苯并噻吩、吲唑、苯并咪唑、苯并噻唑、嘌呤、喹啉、異喹啉、>4啉、酞嗪、喹唑啉、喹喏琳、1，8-喑啶、喋啶、咔唑、吖啶、啡嗪、啡噻嗪、啡噁 Φ 嗪及奠。亦如本文中所使用，芳基亦包括芳基烷基。此外’如本文中所使用之"芳基烷基"係指諸如苄基之部分，其中芳族與烧基連接。丙烯酸系聚合物較佳為丙烯酸系共聚物。丙烯酸系共聚物較佳包含由如上文中所定義之（烷基）丙烯酸烷酯及/或丙稀酸及/或烷基丙烯酸所衍生之單體。丙烯酸系共聚物最佳包含由（烷基）丙烯酸烷酯（亦即，如上文中所定義之可共聚丙烯酸烷酯及烷基丙烯酸烷酯）所衍生之單體。尤其較佳之丙烯酸系共聚物包括丙烯酸（CrCU)烷酯單體及可共聚 138081.doc -16- 200950776 (c〗-c4)烷基丙烯酸（CrCU)烷酯共聚單體，尤其由曱基丙烯酸甲S旨所形成之共聚物及丙稀酸甲酯及/或丙晞酸乙酯及/ 或丙烯酸正丁酯之可共聚共聚單體。 (甲基）丙烯酸系聚合物較佳為離子型（曱基）丙烯酸系聚合物，尤其為陽離子型（曱基）丙烯酸系聚合物》離子型（甲基）丙稀酸系聚合物係藉由使攜有離子基之（曱基）丙稀酸系單體與中性（甲基）丙烯酸系單體共聚合來製備。離子基較佳為四級録基。 (甲基）丙烯酸系聚合物一般不溶於水，但在水溶液及消化液中可膨脹且可滲透。陽離子基團與中性（甲基）丙缔酸西旨之莫耳比容許控制調配物之水滲透性β在較佳實施例中，（曱基）丙烯酸系聚合物為共聚物或共聚物之混合物，其中陽離子基團與中性（甲基）丙烯酸酯之莫耳比平均而言在約1:20至1:35之範圍内。可藉由選擇適當之市售陽離子型（甲基）丙烯酸系聚合物或藉由將陽離子型（甲基）丙缔酸系聚合物與適量中性（甲基）丙烯酸系聚合物摻合來調整該比率。合適之（甲基）丙烯酸系聚合物可以商品名Eudragit(較佳个人 Individuals who drink large amounts of alcoholic beverages (although not appropriate) when taking medication prescribed by the physician will generally change the composition of the gastric juice contained in the stomach and, in extreme cases, such gastric fluids may contain up to 4〇Q/. Ethanol. Advantageously, embodiments of the abuse-preventing formulation of the invention optionally comprise a melt-processed mixture having at least one production-related drug, at least one cellulose ether or cellulose ester, and at least one (fluorenyl) acrylic polymer, wherein The amount of the drug extracted by the 20% ethanol aqueous solution or the 40% aqueous ethanol solution or both in less than 1 hour is less than or equal to 37 ° or at 25 ° c or both, 1.5 times the amount of the drug extracted by 001 N hydrochloric acid in one hour. In the case of individual intentional attempts to arrest the drug σσ containing the drug of abuse 〇% ethanol extraction is advantageous. Exemplary preferred compositions of the present invention comprise a preferred molecular weight in the range of from 50,000 to 1,250, daiton, which can be used in combination in the present invention. Cellulose ether and cellulose ester. The cellulose ether is preferably selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose or a mixture thereof, such as ethyl cellulose, mercapto cellulose, Hydroxypropyl cellulose 13 8081.d〇 ( •12- 200950776 (NF), hydroxyethyl cellulose (NF) and hydroxypropyl methylcellulose (usp) or its group. Suitable cellulose esters are (but not limited to) acetate fibers (nf), cellulose acetate butyrate, cellulose acetate propionate, phthalic acid via propyl f-based cellulose, phthalic acid phthalic acid via propylmethylcellulose and mixtures thereof. Nonionic polymers such as hydroxypropyl methylcellulose are used. The number of substituents on the anhydroglucose unit of cellulose can be specified by the average number of substituents attached to the ring, which cellulose chemists call the concept of substitution ( DS) DS is assigned to 3 if all three available locations on each cell are taken 4, and if the average of two rings on each ring reacts, DS is designated 2, etc. In a preferred embodiment The cellulose ether has an alkyl substitution degree of 13 to 2 Torr and a hydroxyalkyl mole substitution degree of up to 0.85. In a preferred embodiment, the 'alkyl substituent is a methyl group. Further, a preferred hydroxy-based substituent is preferred. Is a propyl group. It has a methoxy substitution and a substitution with a propyloxy group. A summary of the types of such polymers of the code is listed in the Pharmacopoeia (for example, ❹ USP) under the name "propyl propyl cellulose". Methyl cellulose is commercially available under the trade name METH 〇 CEL A. A has 1.64 to Methyl (or methoxy) Ds. of 192. These types of polymers are listed in the Pharmacopoeia (eg usp), under the name "methylcellulose". ' Especially preferred cellulose ether is hydroxypropylmethyl Cellulose. Hydroxypropyl methylcellulose is commercially available; gMETH〇CEL E (methyl D s heart 9, substituted by propyl mole of about 〇.23), METH 〇 CEL F (mercapto DS is about 8, Hydroxypropyl mole substitution degree is about 13.13) and METH0CEL κ (mercapto Ds(1)4, propyl molar substitution degree about 21.21) is commercially available. Meth〇cel f&meth〇cel I38081.doc -13- 200950776 κ is a preferred hydroxypropyl fluorenyl cellulose for use in the present invention. The acrylic polymer suitably comprises homopolymers and copolymers of monomers comprising acrylic acid and/or alkylacrylic acid and/or (alkyl)alkyl acrylate (this process comprises polymerization with more than two different repeating units) ()). As used herein, the term "alkylalkyl acrylate" refers to the corresponding acrylate or alkyl acrylate typically formed from the corresponding acrylic acid or alkyl acrylate, respectively. In other words, the term 'alkylalkyl acrylate' means alkyl alkyl acrylate or acrylic acid vinegar. 0 (alkyl) alkyl acrylate is preferably ((C^Cio)alkyl) acrylic acid (CrCn) Burning vinegar. Examples of the Ci-Cn alkyl group of the alkyl (alkyl) acrylate include methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, isopropyl, pentyl, Hexyl, cyclohexyl, 2-ethylhexyl, heptyl, octyl, decyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecane , hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, behenyl and isomers thereof. The alkyl group may be a straight or oxime bond. The ci_C22)alkyl group preferably represents as defined above (CrCd alkyl group, more preferably represents the above-mentioned (Cj-C4) yard group. (Chenyl) acrylic acid vinegar c, - decyl group examples include Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclohexyl, 2-ethylhexyl, heptyl, octyl, decyl, fluorene And its isomers. The alkyl group can be The linear or branched bond (C-Cu) is preferably represented by a (Ci_c6) alkyl group as defined above, more preferably as defined above (CrCO alkyl. (alkyl) acrylate is preferably (( Ci_C4)alkyl)Ci_C4 alkyl acrylate, preferably (Ci_C4) alkyl ester. It should be understood that the term (曱138081.doc -14-200950776) acrylic acid (CrCd alkyl ester refers to acrylic acid ( c "c4" alkyl ester or methacrylic acid (Ci-CO alkyl ester. (mercapto) acrylic acid (Examples of Ci-Cd alkyl esters include methacrylic acid methacrylate (MMA), ethyl methacrylate (EMA), A N-propyl acrylate (PMA), isopropyl methacrylate (IPMA), n-butyl methacrylate (BMA), isobutyl methacrylate (IBMA), tert-butyl methacrylate (TBMA); Ethyl acrylate (MA), ethyl acrylate (EA), n-propyl acrylate (PA), n-butyl acrylate (BA), isopropyl acrylate (IPA), isobutyl acrylate (IBA), and combinations thereof. The acrylic monomer is preferably (CrCw) alkylacrylic acid. (Examples of Ci-CM alkylacrylic acid include methacrylic acid, ethacrylic acid, positive Propylacrylic acid, isopropylacrylic acid, n-butylacrylic acid, isobutylacrylic acid, tert-butylacrylic acid, pentylacrylic acid, hexylacrylic acid, heptylacrylic acid, and isomers thereof. (CrCw)alkylacrylic acid is preferably (Ci-C4) Alkylacrylic acid, most preferably methacrylic acid. In certain embodiments, the alkyl group may be substituted with an aryl group. As used herein, '"alkyl" refers to a straight chain, a bond or a cyclic saturated or unsaturated aliphatic hydrocarbon. The alkyl group has 1 to 16 carbons and may be unsubstituted or substituted with one or more groups selected from the group consisting of dentate, thiol, alkoxy Drum, amidino, alkylamino, dialkylguanidino, nitro, amine, alkylamino, dialkylamino, carboxy, thio and thioalkyl. "Hydroxy" refers to an OH group ◊ "Alkoxy" refers to an alkyl group as defined above, and a thiol group, which means a _SH group. "sulfanyl group" Refers to the _SR group wherein R is an alkyl group as defined above. Amino" refers to a -NH2 group. "Acetylamino" means an -NHR group wherein r is an alkyl group as defined above. "Dialkylamino" means the NRR' group wherein R and Ri are as defined above by 138081.doc -15- 200950776. , "Amino" refers to _c〇NH^, and alkylamino" refers to a _c〇NHR group wherein R is an alkyl group as defined above. "Dialkylhydrazine The amine group is entangled in the ruler and the ruler' is an alkyl group as defined above-CONRR, a group. Nitro refers to the N〇2 group ""carboxy" refers to the c〇〇h group. In certain embodiments, an alkyl group can be substituted with an aryl group. As used herein, the aryl group includes a monocyclic and fused polycyclic carbon ring aromatic ring and a heterocyclic aromatic ring, wherein the aromatic ring may be a 5-membered ring or a 6-membered ring. Representative monocyclic aryl groups include, but are not limited to, phenyl, furanyl, pyrrolyl, thienyl, pyridyl, acenaphthyl, decyl, oxime, beta thiol, imipenyl a sulfhydryl group, an isothiazolyl group, and the like. A fused polycyclic aryl group is one or more rings including a 5-membered or an aromatic ring or a heteroaromatic ring as a fused ring system. Aromatic groups. Representative fused polycyclic aryl groups include naphthalene, anthracene, pyridazine, anthracene, isoindole, benzofuran, benzothiophene, carbazole, benzimidazole, benzothiazole, anthracene, Quinoline, isoquinoline, > 4 porphyrin, pyridazine, quinazoline, quinoxaline, 1,8-acridine, acridine, oxazole, acridine, phenazine, phenothiazine, phenazine Also as used herein, an aryl group also includes an arylalkyl group. Further, "arylalkyl" as used herein refers to a moiety such as a benzyl group, wherein the aromatic group is attached to the alkyl group. The acrylic polymer is preferably an acrylic copolymer. The acrylic copolymer preferably comprises an alkyl (meth)acrylate and/or acrylic acid as defined above and/or a monomer derived from an alkyl acrylate. The acrylic copolymer preferably comprises a monomer derived from an alkyl (alkyl) acrylate (i.e., a copolymerizable alkyl acrylate and an alkyl acrylate as defined above). Particularly preferred acrylic copolymers include acrylic acid (CrCU) alkyl ester monomers and copolymerizable 138081.doc -16 - 200950776 (c-c4) alkyl acrylate (CrCU) alkyl comonomers, especially thiol acrylates. The copolymer formed by the copolymer and the copolymerizable comon of methyl acrylate and/or ethyl acrylate and/or n-butyl acrylate. The (meth)acrylic polymer is preferably ionic ( Acrylate based acrylic polymer, especially cationic (fluorenyl) acrylic polymer. The ionic (meth)acrylic acid polymer is made by carrying an ionic group-containing (fluorenyl) acrylic acid system. The monomer is prepared by copolymerization with a neutral (meth)acrylic monomer. The ionic group is preferably a quaternary substrate. The (meth)acrylic polymer is generally insoluble in water but swellable in aqueous solution and digestive juice. And permeable. Cationic groups and neutral ( The molar ratio of propionate is allowed to control the water permeability of the formulation. In a preferred embodiment, the (fluorenyl) acrylic polymer is a copolymer or a mixture of copolymers, wherein the cationic group is The molar ratio of the (meth) acrylate is on the order of about 1:20 to 1:35 on average. It can be selected by selecting a suitable commercially available cationic (meth)acrylic polymer or by cation The type (meth) propionic acid-based polymer is blended with an appropriate amount of a neutral (meth)acrylic polymer to adjust the ratio. A suitable (meth)acrylic polymer is commercially available under the trade name Eudragit (preferably

Eudragit RL及 Eudragit RS)購自 Rohm Pharma。Eudragit RL 及Eudragit RS為具有低含量之四級銨基的丙烯酸酯與甲基丙烯酸酯之共聚物，銨基與剩餘中性（曱基）丙烯酸酯之莫耳比在Eudragit RL·中為1:2〇且在Eudragh rs中為1:40。平均分子量為約150,000。除（曱基）丙烯酸系聚合物之外，可將其他醫藥學上可接 138081.doc •17- 200950776 受之聚合物併入本發明之調配物中’以便調整調配物之特性及/或改良其易製備性。該等聚合物可選自包含以下各物之群：N-乙烯基内醯胺之均聚物，尤其聚乙烯吡咯啶酮 (PVP) ; N-乙烯基内醯胺與一或多種可與其共聚合之共聚單體的共聚物，該等共聚單體係選自含氮單體及含氧單體；尤其N-乙烯基吡咯啶酮與羧酸乙烯酯之共聚物，較佳實例為N-乙烯基吡咯啶酮與乙酸乙烯酯之共聚物或N乙烯基吡咯啶酮與丙酸乙烯酯之共聚物；聚乙烯醇-聚乙二醇接枝共聚物（可以例如Kollicoat® IR購自BASF AG Ludwigshafen，Germany);高分子聚氧化烯，諸如聚氧化乙烯及聚氧化丙烯，及氧化乙烯與氧化丙烯之共聚物；聚丙埽醯胺，乙酸乙浠酯聚合物，諸如乙酸乙浠酯與丁稀酸之共聚物、部分水解之聚乙酸乙烯酯（亦稱為部分皂化之 "聚乙烯醇"）；聚乙烯醇；聚（經基酸），諸如聚（乳酸）、聚 (乙醇酸）、聚（3-羥基丁酸酯）及聚（3_羥基丁酸酯-共_3•經基戊酸酯）；或其中一或多者之混合物。PVP在擠壓期間產生氫可_ N-氧化物（hydrocodone N-oxide)，因此使用pvp聚合物及PVP共聚物並非總為較佳。然而，當使用少量（全部調配物之0.2-0.6 〇/〇 w/w)抗氧化劑時，則使用pvp較佳。濫用相關藥物"旨在意謂其分配經受管制限制之任何.生物學有效成份。在本發明之上下文中可有效調配之濫用藥物包括（但不限於）假麻黃素（pseudoephedrine)、抗抑餐劑、強刺激劑、減肥藥、類固醇及非類固醇消炎劑。在強刺激劑之類別中’曱基安非他明（methamphetamine)為最近 138081.doc -18- 200950776 作為濫用藥物受到廣泛注意之一種藥物。目前對於阿托品 (atropine)、Κ 菪素（hyoscyamine)、***（phenobarbital)、莨菪鹼（scopolamine)及其類似物之濫用潛在性亦存在一些關注。濫用相關藥物之另一主要類別為止痛劑，尤其類鴉片（opioid)。Eudragit RL and Eudragit RS) were purchased from Rohm Pharma. Eudragit RL and Eudragit RS are copolymers of acrylate and methacrylate with a low content of quaternary ammonium groups. The molar ratio of ammonium to residual neutral (mercapto) acrylate is 1: in Eudragit RL. 2〇 and 1:40 in Eudragh rs. The average molecular weight is about 150,000. In addition to the (mercapto)acrylic polymer, other pharmaceutically acceptable polymers can be incorporated into the formulations of the present invention to adjust the properties and/or improve the formulation. It is easy to prepare. The polymers may be selected from the group consisting of homopolymers of N-vinyl decylamine, especially polyvinylpyrrolidone (PVP); N-vinyl decylamine with one or more a copolymer of polymerized comonomers selected from the group consisting of nitrogen-containing monomers and oxygen-containing monomers; especially copolymers of N-vinylpyrrolidone and vinyl carboxylate, preferably N- Copolymer of vinylpyrrolidone with vinyl acetate or copolymer of N vinylpyrrolidone with vinyl propionate; polyvinyl alcohol-polyethylene glycol graft copolymer (for example, Kollicoat® IR available from BASF AG Ludwigshafen, Germany); high molecular weight polyoxyalkylenes, such as polyethylene oxide and polypropylene oxide, and copolymers of ethylene oxide and propylene oxide; polyacrylamide, ethyl acetate polymer, such as ethyl acetate and butadiene Copolymer of acid, partially hydrolyzed polyvinyl acetate (also known as partially saponified "polyvinyl alcohol"); polyvinyl alcohol; poly(transbasic acid), such as poly(lactic acid), poly(glycolic acid) , poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-total_3 Via yl valerate); or wherein one or more of the mixture. PVP produces hydrocodone N-oxide during extrusion, so the use of pvp polymers and PVP copolymers is not always preferred. However, when a small amount (0.2-0.6 〇/〇 w/w of the total formulation) of the antioxidant is used, it is preferred to use pvp. Abuse of related drugs" is intended to mean any biologically active ingredient whose distribution is subject to regulatory restrictions. Abuse drugs that are effective in the context of the present invention include, but are not limited to, pseudoephedrine, anti-allergic agents, strong irritants, diet pills, steroids, and non-steroidal anti-inflammatory agents. In the category of strong stimulants, methamphetamine is a recent drug that has received extensive attention as a drug of abuse 138081.doc -18- 200950776. There is also some concern about the potential for abuse of atropine, hyoscyamine, phenobarbital, scopolamine and their analogues. Another major class of analgesics for the abuse of related drugs, especially opioids.

術語"類鴉片”意謂與一或多個由内源性類鴉片肽（諸如腦 °扑肽（enkephalin)、内°非肽（endorphin)及強°非肽 (dynorphin))結合之受體位點反應的物質，不論為促效劑、拮抗劑或混合型促效劑-拮抗劑。類鴉片包括（但不限於）阿芬太尼（alfentanil)、稀丙羅定（allylprodine)、阿法羅定（alphaprodine)、阿尼利定（anileridine)、苄嗎啡 (benzylmorphine)、苯腈米特（bezitramide)、丁丙諾 _ (buprenorphine)、布托啡諾（butorphanol)、氯尼他秦 (clonitazene)、可待因（codeine)、環佐辛（cyclazocine)、地素嗎 _ (desomorphine)、右旋嗎酿胺（dextromoramide)、地佐辛（dezocine)、地恩丙胺（d.iampromide)、二氫可待因 (dihydrocodeine)、二氫嗎啡（dihydromorphine)、地美沙多 (dimenoxadol)、地美庚醇（dimepheptanol)、二甲胺二嘆吩丁烯（dimethylthiambutene)、嗎苯丁 S旨（dioxaphetyl butyrate)、地匹派_(dipipanone)、依他佐辛（eptazocine)、依索庚嗓（ethoheptazine)、甲乙胺二嗟吩丁浠 (ethylmethylthiambutene)、乙基嗎啡、依託尼秦（etonitazene)、芬太尼（fentanyl)、海洛英（heroin)、氫可酮、氫嗎啡酮 (hydromorphone)、經派替咬（hydroxypethidine)、異*** 138081.doc -19- 200950776The term "opioid" means a receptor that binds to one or more endogenous opioid peptides, such as enkephalin, endorphin, and dynorphin. Site-reactive substances, whether agonists, antagonists or mixed agonists-antagonists. Opioids include, but are not limited to, alfentanil, allylprodine, alpha Alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene , codeine, cyclazocine, desomorphine, dextromoramide, dezocine, d. iampromide, dihydrogen Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate ,dipipanone, etazocine Eptazocine), ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone Hydromorphone, hydroxypethidine, isomezicin 138081.doc -19- 200950776

(isomethadone)、凱托米剩（ketobemidone)、左洛# 烧 (levallorphan)、左芬啡烧（levophenacylmorphan)、左 # 諾 (levorphanol)、洛芬太尼（lofentanil)、派替。定（meperidine)、美普他盼（meptazinol)、美他佐辛（metazocine)、*** (methadone)、美托酮（metopon)、嗎啡、麥羅°非（myrophine)、納布啡（nalbulphine)、那碎因（narceine)、煙醯嗎啡 (nicomorphine)、諾匹口底 _ (norpipanone)、鴻片、氧可酮 (oxycodone)、氧嗎啡 _ (oxymorphone)、阿片全驗 (papvretum)、喷他佐辛（pentazocine)、苯嗎庚嗣 (phenadoxone)、非那佐辛（phenazocine)、非諾嗎烧 (phenomorphan)、苯口底利定（phenoperidine)、匹米諾定 (piminodine) 、丙0比胺(propiram) 、丙氧吩 (propoxyphene)、舒芬太尼（sufentanil)、替利定（tilidine)及曲馬多（tramadol)，及其鹽及混合物。在某些較佳實施例中，本發明之調配物包括至少一種其他治療藥物。在甚至更佳之實施例中，其他治療藥物可選自（但不限於）由非類固醇、非類鴉片止痛劑組成之群，且視情況進一步選自由以下各物組成之群：乙醯胺苯酚 (acetaminophen)、阿司匹靈（aspirin)、芬太尼、布洛芬 (ibuprofen)、0引0朵美辛（indomethacin)、酮洛酸（ketorolac)、萘普生（naproxen)、非那西汀（phenacetin)、0比羅昔康 (piroxicam)、舒芬太尼、蘇林酸（sunlindac)及干擾素α。尤其較佳者為在合適國家或區域管制機構（諸如（舉例而言）美國食品與藥物管理局（U.S· Food and Drug Administration)) 138081.doc -20- 200950776 授權下目前以固定劑量組合售於公眾之彼等藥物組合。該等藥物包括（但不限於）氫可酮與乙醯胺苯酚之（固定劑量）組合’或氳可酮與布洛芬之（固定劑量）組合。濫用相關藥物較佳均勻分散於整個基質中，該基質較佳由纖維素趟或纖維素酯及一種丙烯酸系或曱基丙酸烯系聚合物以及調配物之其他可選成份形成。本說明書亦意欲涵蓋基質相中具有直徑通常小於丨μηι之藥物小顆粒的系統。 ❹(isomethadone), ketobemidone, levolorphan, levophenacylmorphan, left levorphanol, lofentanil, and placemat. Meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbulphine, Narcine, nicomorphine, norpipanone, oxycodone, oxymorphone, papvretum, pentazo Pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, acetaminophen (propiram), propoxyphene, sufentanil, tilidine and tramadol, and salts and mixtures thereof. In certain preferred embodiments, the formulations of the present invention comprise at least one other therapeutic agent. In an even more preferred embodiment, the other therapeutic agent may be selected from, but not limited to, a group consisting of non-steroidal, non-opioid analgesics, and optionally further selected from the group consisting of acetaminophen ( Acetaminophen), aspirin, fentanyl, ibuprofen, 0-indomethacin, ketorolac, naproxen, phenacetin (phenacetin), 0 piroxicam, sufentanil, sunlindac, and interferon alpha. Particularly preferred is currently sold in a fixed dose combination under the authority of a suitable national or regional regulatory agency such as, for example, the US Food and Drug Administration 138081.doc -20- 200950776 The pharmaceutical combination of the public. Such drugs include, but are not limited to, a combination of hydrocodone and acetaminophen (fixed dose) or a combination of ketone and ibuprofen (fixed dose). Preferably, the abuse-related drug is uniformly dispersed throughout the matrix, and the matrix is preferably formed from cellulose oxime or cellulose ester and an acrylic or mercaptopropionic acid-based polymer and other optional ingredients of the formulation. The present specification is also intended to encompass systems in the matrix phase having small particles of drug having a diameter generally less than 丨μηι. ❹

如藉由熱分析法（DSC)或X射線繞射分析法（WAXS)所證明’ 5亥等系統較佳不含有大量呈結晶態或微晶態之活性類鴉片成份。藥物總量中之至少98重量％較佳以非晶態存在。若本發明之調配物中另外存在其他非濫用相關活性藥物例如乙醯胺苯酚，則此其他活性藥物可以結晶態嵌埋於該調配物中。當該等組份之分散液使得系統在化學上及在物理上處處均"或大體均質’或由一種熱力學相組成，則該分散液稱為"固溶體"。濫用相關活性藥物之固溶體為較佳。該調配物亦可包含一或多種選自以下各物之添加劑：糖 :或其何生物、麥芽糊精；醫藥學上可接受之界面活性 :、流動調節劑、崩解劑、增積劑及润滑劑。適用之糖醇 =甘露糖醇、山梨糖醇、木糖醇；適用之糖醇衍生物 U限於)異麥芽糖、氫化濃縮巴拉金糖a· 及其帅似與相異之_衍生物。非可接受之界面活性劑較佳為醫藥學上可接受之非離子料面活性劑。合併界面活性劑對於含有不良水溶 13808 丨.doc -21 - 200950776 性之活性成份的基質及/或改良調配物之可濕性而言尤其較佳。界面活性劑可實現該劑型中所釋放之活性成份的瞬時乳化且防止活性成份沈澱於胃腸道之水性流體中。某些添加劑包括：聚氧乙烯烷基醚，例如聚氧乙烯（3) • 月桂基醚、聚氧乙烯（5)鯨蠟基醚、聚氧乙烯（2)硬脂基 . _、聚氧乙烯（5)硬脂基縫；聚氧乙烯烧基芳基μ，例如聚氧乙烯（2)壬基苯基醚、聚氧乙烯（3)壬基苯基醚、聚氧乙 ❹ 烯（4)壬基苯基醚或聚氧乙烯（3)辛基苯基醚；聚乙二醇脂肪酸酯，例如PEG-200單月桂酸酯、pEG_2〇〇二月桂酸西曰PEG-300一月桂酸醋、peg_4〇〇:月桂酸酯、pEG-3〇〇一硬脂酸酯或PEG-300二油酸酯；烷二醇脂肪酸單酯，例如丙一醇單月桂酸酯及丙二醇二月桂酸酯 (Lauroglycol®)，蔗糖脂肪酸醋，例如嚴糖單硬脂酸酯、蔗糖二硬脂酸酯、蔗糖單月桂酸酯或蔗糖二月桂酸酯；脫水山梨糖醇脂肪酸單酯及脫水山梨糖醇脂肪酸二酯，諸如 Ο 脫水山梨糖醇單月桂酸酯（Span® 20)、脫水山梨糖醇單油酸、脫水山梨糖醇單棕櫚酸酯（Span@ 4〇)或脫水山梨糖 • #硬月θ k S日’聚氧乙稀ϋ麻油衍生物，例如聚氧乙稀甘油三蓖麻油酸酯或聚氧乙烯醚35蓖麻油（Cremoph〇r® Ε[; BASF Corp.)或聚氧乙烯甘油氧硬脂酸酯，諸如聚乙二醇 4〇氫化萬麻油（Cremoph〇r(g) RH 4〇)或聚乙二醇6〇氫化乾麻油（Cremophor® RH 6〇);或氧化乙浠與氧化丙烯之嵌段共聚物，亦稱作聚氧乙烯聚氧丙稀欲段共聚物或聚氧乙稀聚丙二醇，諸如piuronic® F68、piur〇nic⑧ Fm、p〇i〇xamer⑧ 138081.doc ·22· 200950776 124、Poloxamer® 188、Poloxamer® 237、Ρ〇1〇χ&ηιβΓφ 388 或 Poloxamer® 407(BASF Wyandotte Corp.);或聚氧乙稀 (20)脫水山梨糖醇之單脂肪酸酯，例如聚氧乙稀（2〇)脫水山梨糖醇單油酸酯（Tween® 80)、聚氧乙烯（2〇)脫水山架糖 • 醇單硬脂酸酯（Tween® 60)、聚氧乙烯（20)脫水山梨糖醇單棕櫚酸酯（Tween® 40)、聚氧乙烯（20)脫水山梨糖醇單月桂酸酯（Tween® 20) ’及其類似物，以及其兩者、三者、四者、五者或五者以上之混合物。 ❹ 溶體中可包括各種其他添加劑’例如流動調節劑（諸如膠體二氧化矽）、潤滑劑、填充劑、崩解劑、增塑劑穩定劑（諸如抗氧化劑、光穩定劑、自由基淨化劑或抵禦微生物攻擊之穩定劑）。此外，由於含有乙醯胺苯酚之外塗層具有乙醯胺苯酚本身所致之苦味，因此可使用甜味劑及 /或調味劑等作為減少該苦味之添加劑。減少苦味之一種較佳方式為另一不含乙醯胺苯酴之薄外塗層。 ❹ 本發明之調配物可經由任何合適之熔融方法（諸如藉由使用熱麼機）而獲得且較佳藉由熔融擠出法來製備。為獲，仔藥物之均勻分布及足夠分散度，可使含有藥物之熔體在溶融擠出機之熱㈣中保持足夠之滯留時間。溶融在轉變成液態或橡膠態時發生，其中一種組份可均勻嵌埋於另— 組份中。炼融通常包括加熱至高於調配物之可熔融賦形劑 (例如纖維素醚/酯、糖醇及/或（甲基）丙烯酸系聚合物）之軟化點。熔體之製備可以多種方式進行。熔融溫度通常在7(TC至250。〇之範圍内，較佳在8〇t至 138081.doc -23- 200950776 180C之範圍内，最佳在1〇〇。〇至14〇。0之範園内。當溶融方法包含炫融擠出時，熔融及/或混合可在常用於此目的之裝置中進行。擠出機或捏合機尤其合適。合適之擠出機包括單螺桿擠出機、嚙合螺桿擠出機及多螺桿擠 . 出機（較佳為雙螺桿擠出機），其可同向旋轉或反向旋轉且視情況裝配有捏合盤。應瞭解，工作溫度亦將依據擠出機之類型或所用擠出機内之組態類型來確定。在擠出機中將各組份炼融、混合且溶解所需之能量之部分可由加熱元件 ® 提供。然而’播出機中對材料之摩擦及剪切亦可向混合物提供大量能量且有助於形成各組份之均質熔體。此外’提供以下實例以說明本發明之較佳實施例，且不應認為限制其範疇。較佳實施例之實例材料为析乙醇（99.9/〇 v/v)為標準級試劑（Baker，Germany)。 ❺ 氯化納（Merck，Germany)、鹽酸（Baker，Germany)及填酸鉀 (Fluka，Switzerland)皆原樣使用。去離子水來源於内部水系統離子交換器。 # 藥物調配物 ' 維拉帕米調配物異搏定（Isoptin)SR-E 240 mg (Meltrex®，形式 A)(Abbott Laboratories，EU)、持續釋放 (SR)異搏定 SR 240 mg(形式 B)(Abbott Laboratories，EU)、 Verahexal™ SR 240 mg(形式 C)(Hexal Pharma Ltd，As evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS), the system such as 5H preferably does not contain a large amount of active opioid components in a crystalline or microcrystalline state. At least 98% by weight of the total amount of the drug is preferably present in an amorphous state. If other non-abuse-related active drugs such as acetaminophen are additionally present in the formulations of the present invention, the other active agent may be embedded in the formulation in a crystalline state. When the dispersion of the components causes the system to be chemically and physically "or substantially homogeneous" or consists of a thermodynamic phase, the dispersion is referred to as "solid solution". It is preferred to abuse the solid solution of the relevant active drug. The formulation may also comprise one or more additives selected from the group consisting of: sugar: or any organism thereof, maltodextrin; pharmaceutically acceptable interfacial activity: flow regulator, disintegrant, accumulator And lubricants. Applicable sugar alcohol = mannitol, sorbitol, xylitol; suitable sugar alcohol derivatives U is limited to isomaltose, hydrogenated concentrated palatinose a · and its similar and different derivatives. Unacceptable surfactants are preferably pharmaceutically acceptable nonionic surfactants. The combined surfactants are especially preferred for the wettability of the matrix and/or modified formulation containing the poorly water soluble active ingredients of the active ingredients. The surfactant can effect instantaneous emulsification of the active ingredient released in the dosage form and prevent the active ingredient from precipitating in the aqueous fluid of the gastrointestinal tract. Some additives include: polyoxyethylene alkyl ethers, such as polyoxyethylene (3) • lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl. _, polyoxyethylene (5) a hard-fat joint; a polyoxyethylene alkyl aryl group, such as polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) Nonylphenyl ether or polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty acid ester, such as PEG-200 monolaurate, pEG_2 bismuth dilaurate PEG-300 lauric acid vinegar , peg_4〇〇: laurate, pEG-3 〇〇 monostearate or PEG-300 dioleate; alkanediol fatty acid monoesters, such as propanol monolaurate and propylene glycol dilaurate ( Lauroglycol®), sucrose fatty acid vinegar, such as sucrose monostearate, sucrose distearate, sucrose monolaurate or sucrose dilaurate; sorbitan fatty acid monoester and sorbitan fatty acid II Esters such as Ο sorbitan monolaurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span@ 4〇) Or sorbitan • #硬月θ k S 日' polyoxyethylene castor oil derivative, such as polyoxyethylene glycerol triricinoleate or polyoxyethylene ether 35 castor oil (Cremoph〇r® Ε[; BASF Corp.) or polyoxyethylene glyceryl oxystearate, such as polyethylene glycol 4 〇 hydrogenated cannabis oil (Cremoph〇r (g) RH 4 〇) or polyethylene glycol 6 〇 hydrogenated dry sesame oil (Cremophor® RH 6 〇); or a block copolymer of oxidized acetamethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene blister copolymer or polyoxyethylene polypropylene glycol, such as piuronic® F68, piur〇nic8 Fm, p〇 I〇xamer8 138081.doc ·22· 200950776 124, Poloxamer® 188, Poloxamer® 237, Ρ〇1〇χ&ηιβΓφ 388 or Poloxamer® 407 (BASF Wyandotte Corp.); or polyoxyethylene (20) sorbitan Mono-fatty acid esters of alcohols, such as polyoxyethylene (2〇) sorbitan monooleate (Tween® 80), polyoxyethylene (2〇) dehydrated sugar • Alcohol monostearate (Tween) ® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate Ester (Tween® 20)' and its analogs, and mixtures of the two, three, four, five or more. Various other additives may be included in the ' solution such as flow regulators (such as colloidal cerium oxide), lubricants, fillers, disintegrants, plasticizer stabilizers (such as antioxidants, light stabilizers, free radical scavengers) Or a stabilizer against microbial attack). Further, since the coating layer containing acetaminophen has a bitter taste due to acetaminophen itself, a sweetener and/or a flavoring agent or the like can be used as an additive for reducing the bitterness. One preferred way to reduce bitterness is another thin outer coating that does not contain acetaminophen. The formulations of the present invention can be obtained by any suitable melting method, such as by using a thermal machine, and are preferably prepared by melt extrusion. In order to obtain a uniform distribution of the drug and sufficient dispersion, the drug-containing melt can be maintained in the heat (4) of the melt extruder for a sufficient residence time. The melting occurs when it is converted into a liquid or rubber state, and one of the components can be uniformly embedded in the other component. Smelting typically involves heating to a softening point above the meltable excipients (e.g., cellulose ethers, sugar alcohols, and/or (meth)acrylic polymers) of the formulation. The preparation of the melt can be carried out in a variety of ways. The melting temperature is usually in the range of 7 (TC to 250 〇, preferably in the range of 8 〇 t to 138081.doc -23 - 200950776 180C, preferably in the range of 1 〇〇. 〇 to 14 〇. When the melting method comprises smelting and extruding, melting and/or mixing can be carried out in a device commonly used for this purpose. An extruder or a kneader is particularly suitable. Suitable extruders include a single screw extruder, an intermeshing screw Extruder and multi-screw extrusion. Outlet (preferably twin-screw extruder), which can rotate in the same direction or in the opposite direction and is equipped with a kneading disc as appropriate. It should be understood that the operating temperature will also depend on the extruder. The type or type of configuration in the extruder used is determined. The portion of the energy required to smelt, mix and dissolve the components in the extruder can be supplied by the heating element®. However, the friction of the material in the broadcaster And shearing may also provide a substantial amount of energy to the mixture and aid in the formation of a homogeneous melt of the components. Further, the following examples are provided to illustrate preferred embodiments of the invention and should not be construed as limiting the scope thereof. The example material is ethanol (99.9/〇v/v) ) is a standard grade reagent (Baker, Germany). M Chloride (Merck, Germany), hydrochloric acid (Baker, Germany) and potassium hydride (Fluka, Switzerland) are used as they are. Deionized water is derived from internal water system ion exchange. #药物药物' Verapamil formulation Isoptin SR-E 240 mg (Meltrex®, Form A) (Abbott Laboratories, EU), sustained release (SR) Verapamil SR 240 mg ( Form B) (Abbott Laboratories, EU), VerahexalTM SR 240 mg (Form C) (Hexal Pharma Ltd,

Germany)及延遲型維拉帕米-Ratiopharm® 240 mg(形式D) 138081.doc -24- 200950776 (Ratiopharm，Germany)原樣使用。形式A(熔融擠出）在羥丙基纖維素及羥丙基甲基纖維素基質中含有維拉帕米鹽酸鹽。形式B(持續釋放）、C(持續釋放）及1)(持續釋放）在海藻酸鈉基質（作為阻滯劑）中含有維拉帕米鹽酸鹽。溶解測試根據美國藥典（USP)標準、使用緩衝液添加法對形式 A(熔融擠出）及形式b進行溶解測試。為了一致性，在此研究中對於調配物C及D使用相同方法及條件。 % HCI緩衝液添加法在37.0±0.5°C下、在900 mL介質中、使用具有1〇〇 rpm轉速之溶解裝置（符合Ph.EUR、USP)(槳式攪拌器）監測藥物釋放。介質包含以鹽酸（〇·〇8 N)調節之磷酸鉀緩衝液及 0〇/〇、5%、20%或40%卜〜）乙醇（卩11值6.4-7,2)。對於各介質而言，測試六種錠劑且經分光光度法在250-300 nm下監測藥物釋放。例外情況為形式C ’其僅在〇°/〇乙醇介質中使用 0 四種錠劑測試。一般在60、120、240及480分鐘時及600分鐘時對形式B(根據有效產品規格）及形式C-D取樣。在300 分鐘時收集形式A(4〇%乙醇）、形式A(0%及20%乙醇，而 •非240分鐘）、形式B(40%乙醇）及形式C及D(0%乙酵）之其他樣本。在30、90、180及360分鐘時收集形式C及D(僅〇% 乙醇）之其他樣本。藥物溶解性在室溫下、使用UV偵測、在介於250-300 nm之間之波長下用分光光度計（Fa Agilent，8453型’ Agilent 138081.doc -25- 200950776Germany) and delayed verapamil-Ratiopharm® 240 mg (Form D) 138081.doc -24- 200950776 (Ratiopharm, Germany) used as received. Form A (melt extrusion) contains verapamil hydrochloride in a hydroxypropylcellulose and hydroxypropylmethylcellulose matrix. Form B (sustained release), C (sustained release) and 1) (sustained release) contain verapamil hydrochloride in a sodium alginate matrix (as a retarder). Dissolution Test The dissolution test was performed on Form A (melt extrusion) and Form b according to the United States Pharmacopoeia (USP) standard using a buffer addition method. For consistency, the same methods and conditions were used for formulations C and D in this study. % HCI Buffer Addition Drug release was monitored at 37.0 ± 0.5 °C in a 900 mL medium using a dissolution apparatus (Ph.EUR, USP) (paddle stirrer) with a 1 rpm rotation speed. The medium contains potassium phosphate buffer adjusted with hydrochloric acid (〇·〇8 N) and 0〇/〇, 5%, 20% or 40% by weight of ethanol (卩11 value 6.4-7, 2). For each medium, six lozenges were tested and the drug release was monitored spectrophotometrically at 250-300 nm. The exception is Form C ' which is tested in the 〇 ° / 〇 ethanol medium using 0 four lozenges. Form B (according to valid product specifications) and form C-D are typically sampled at 60, 120, 240 and 480 minutes and at 600 minutes. Form A (4% by weight ethanol), Form A (0% and 20% ethanol, and • not 240 minutes), Form B (40% ethanol) and Forms C and D (0% Ethanol) at 300 minutes Other samples. Other samples of Forms C and D (only 〇% ethanol) were collected at 30, 90, 180 and 360 minutes. Drug Solubility Spectrophotometer at room temperature using UV detection at wavelengths between 250-300 nm (Fa Agilent, Model 8453 ' Agilent 138081.doc -25- 200950776

Technologies Inc.，Santa Clara，CA，USA)測定測試調配物在不同鹽酸-乙醇（hydro-ethanolic)溶解介質中之藥物釋放。使用含有維拉帕米之參考標準物（Ph.EUR之化學參考物質）。資料分析溶解以基於每體積量測之藥物之量（mg)之百分比（％)計舁’說明測試期間體積隨時間之變化。使用如依據6次試驗（4次試驗針對〇 %乙醇條件下之形式C )之原始計分所得之平均溶解百分比及標準偏差說明一定時期（小時）之溶解曲線（圖1-4)。使用t檢驗法（假定雙尾分布及2個樣本方差相等）、由針對每種溶解介質之每次試驗所計算之加權平均值（不包括0之全部時點之溶解百分比）計算各種調配物之比較統計數據。在5%及40%乙醇介質中所測試之形式A(熔融擠出調配物）之維拉帕米釋放在8小時期間之溶解曲線與〇%乙醇條件 ❿ 下之溶解曲線並無顯著差異（P>0.05)(圖1卜在20%乙醇條件下之溶解曲線與〇 %乙醇條件下相比顯著更低（p=〇. 〇 2 )。，此差異在8小時時最顯著，其中相對於〇%乙醇條件 (77%)，20%乙醇條件下之平均溶解百分比更低 (64%)。對於0%與4〇%乙醇之極端條件，平均溶解百分比在1小蚪時相同（19%)且在8小時時，4〇%乙醇介質（81%)僅略高於0%乙醇介質(77%)。所有條件下之釋放曲線之特徵為初始快速釋放速率隨時間逐漸減小，表示具有近零級釋放之持續釋放機理。 13808i.doc -26· 200950776 形式B(一種持續釋放化合物）展示，執行10小時後，較局乙醇濃度（20%及40%)下之溶解曲線與無乙醇條件（〇0/〇) 下相比發生顯著變化（p<〇.〇〇1)(圖2)。在低/無乙醇濃度（〇及5%)下觀察到近零級釋放，且未觀察到兩種條件之間之統計學顯著差異（P=〇,5)。在較高乙醇濃度（20及40%)下，初始快速釋放見於最初一小時内。此影響視乙醇濃度而定，且與20%乙醇介質（57%)相比，在4〇%乙醇介質中達到 ❹ 的平均溶解百分比（％)更高（94%)，兩者皆顯著高於〇β/0乙醇條件下之平均溶解百分比（17%)(ρ<0 001)。對於20%乙醇介質而言’觀察到隨時間連續釋放且在大約8小時時達到平穩階段（平均溶解1〇1%)。對於4〇%乙醇濃度而言，在大約2小時時（1 〇7%溶解）更快達到此平穩階段。在2小時時，與針對0%乙醇所觀察到之26%之平均溶解相比，對於 20%及40%之乙醇濃度分別觀察到73%及ι〇7%之平均溶解，說明在較高乙醇濃度下，溶解增加3_4倍。 φ 類似於形式Β，在較高乙醇濃度（20%及40%)下對於兩種持績釋放調配物（形式C及D)觀察到溶解曲線之相同改變。形式C展示，執行1〇小時後，較高乙醇濃度（2〇%及4〇%)下之溶解曲線與無乙醇條件（〇%)下相比顯著增大 (ρ<0.0001)(圖3)。在較高乙醇濃度下（2〇%及4〇%)，初始快速釋放見於最初一小時内，其中在丨小時時、2〇%乙醇介質中之平均溶解百分比（1〇2%)高於4〇%乙醇介質中之平均溶解百分比（64%)。然而，在1小時時、較高乙醇條件下之平均溶解百分比皆比〇%乙醇條件下之平均溶解百分比 138081.doc •27· 200950776 (15¼)顯著更高（P<〇〇〇〇〇1)。對於2〇%乙醇介質而言，藥物釋放在大約1小時時達到平穩階段（平均溶解1 〇2%)。對於40°/〇乙醇濃度而言，此平穩階段略遲在2小時時達到（平均溶解106%)。在較低乙醇濃度（5%)下，長達4小時之溶解曲線與所觀察之0%乙醇之溶解曲線幾乎相同（在1小時時 P=0.4) 〇在4與10小時之間，5%乙醇條件之溶解曲線更低’導致整體溶解相對於〇%乙醇而言顯著更低 (P<0.001)。兩種條件之間之差異在8小時時最顯著，展示 5°/〇乙醇條件（76%)與〇%乙醇條件（76%)之間1〇%之平均溶解百分比差異（％)(Ρ<〇.〇〇1)。〇%及5%乙醇條件之平均溶解百分比在10小時時接近100%溶解，分別展示97%及92°/〇之平均溶解。類似於對形式B及C所觀察到之趨勢，形式D展示，執行 10小時後’較高乙醇濃度（20%及40%)下之溶解曲線與無乙醇條件（0%)下相比顯著增大（p<0.00001)(圖4)。在低/無乙醇濃度（0及5%)下觀察到近零級釋放，且未觀察到兩種條件之間之統計學顯著差異（p=0_5)。在較高乙醇濃度（2〇及40%)下，初始快速釋放見於最初一小時内。此影響視乙醇濃度而定，且與20%乙醇介質（93%)相比，40%乙醇介質中達到的平均溶解百分比（％)更高（101%)，兩者皆顯著高於0%乙醇條件（12%)(Ρ<0·0001)。對於20%乙醇介質而言，在最初兩小時觀察到快速釋放，在2小時時達到平穩階段 (平均溶解98%)，其顯著高於0%乙醇條件（12%) (Ρ<0·00001)。對於40%乙醇濃度，在快速釋放後，在大約 138081.doc •28· 200950776 1小時時更快達到此平穩階段（101%平均溶解），其顯著高於1小時時之0%乙醇條件23%(p<0.00001)。在1〇小時之最終時點’對於0%或5%乙醇條件均未觀察到完全溶解 (1 00%) ’其分別展示65%及69%之平均溶解百分比。 - 此活體外溶解研究之結果表明，當原樣時及含於5%乙 • 醇介質（相當於大多數啤酒、涼酒中所見之濃度）、20%乙醇介質（相當於在強烈混合飲料中所見之濃度，且略高於 ❹ 大多數葡萄酒中所見之濃度（10-15¾))及40。/〇乙醇介質（相當於大多數未經稀釋之烈酒（亦即，伏特加酒（v〇dka)、杜权子酒）中所見之濃度）中時，含有維拉帕米之新穎熔融擠出調配物可耐受乙醇之溶解作用。相反，三種其他市售持績釋放調配物展示維拉帕米釋放顯著加快，尤其在較高乙醇濃度（20及40%乙醇）下。在最高乙醇濃度（4〇%)下市售持續釋放比較物在最初1 _2小時内展示急劇之藥物釋放，隨後為溶解百分比之平穩階段（達到1〇〇%溶解），說明全部 Ο 劑量已傾釋於溶解介質中。在20。/。乙醇濃度下、在2小時内亦觀察到此，，劑量傾釋"，但對於形式B而言，此情況發 • 纟較遲’在大約8小時時發生。對於形式a(熔融擠出)未觀察到劑量傾釋。對於形式A而言，5%及4〇%乙醇條件下之 -溶解曲線與0〇/。乙醇條件並無顯著差異。2〇%乙醇條件下之 /合解曲線甚至顯著低於〇%條件，此情況之原因未知。與在較高乙醇濃度下之其他市f調配物相比，無論條件如何，形式A之溶解曲線呈近零級且未展示初始釋放尖峰。在2小時時，形式A發生約30%溶解(所有介質)。在8小時時 138081.doc -29· 200950776 未發生完全溶解’平均溶解百分比範圍為64%(20%乙醇介質）至81%(40%乙醇介質）。鑒於乙醇使用廣泛且易得，因此乙醇與處方藥物之間之交互影響備受關注。交互影響可在多種情況（範圍可為服用藥物且消費乙醇類飲料之患者至故意篡改調配物以萃取控制釋放調配物中之藥物或增強藥物與乙醇之藥效作用 (如藥物濫用者中所常見）)下發生。其他該等情況可包括將藥物溶解且掩蔽於乙醇中用於犯罪企圖（諸如•約會強姦，）， ® 如在γ羥基丁酸（gbh)或氟硝西泮（RohypnolTM)之情況下，乙醇使其藥物作用加強（Schwartz等人，2001)。尤其因為控制釋放調配物含有較高藥物含量且可造成安全性問題，因此控制釋放調配物之穩定性為不可或缺之特徵。因此，不易溶於諸如乙醇之溶劑中的防濫用調配物，諸如形式 A(熔融擠出型），可具有優於其他易經受"劑量傾釋”之持續釋放調配物（McColl及Sellers, 2006)之顯著優點。 Q 此研究中之溶解法並非在整個溶解測試期間在低值條件下進行。相反，溶解測試開始2小時pH值為，隨 • 後使pH值增加至大約6.8。應注意，一旦攝入，則乙醇在低pH值之胃環境（PH值2.0)下之長期組合可證明溶解曲線改變。將來之研究可藉由檢查含有乙醇之酸性介質或擬胃液介質中之完整熔融擠出錠劑及碎裂之熔融擠出錠劑來解決此問題。此外，重點應注意：藥物交互影響之病原學不限於溶質與溶劑之間之物理及化學交互影響。藥物交互影響可由藥物動力學、藥效、遺傳及免疫因素介導仏丫^^及 138081.doc 200950776Technologies Inc., Santa Clara, CA, USA) Determination of test formulations Drug release in different hydro-ethanolic dissolution media. A reference standard containing verapamil (a chemical reference material of Ph. EUR) was used. Data Analysis Dissolution is based on the percentage (%) of the amount of drug (ppm) measured per volume. ’ Describes the change in volume over time during the test. The average dissolution percentage and standard deviation, as determined by the original score based on 6 tests (4 tests for 〇% ethanol), are used to illustrate the dissolution curve for a certain period (hours) (Figures 1-4). Comparison of various formulations was calculated using the t-test (assuming a two-tailed distribution and two sample variances equal), a weighted average calculated for each test for each dissolution medium (excluding the percentage of dissolution at all points of zero) Statistical data. The dissolution profile of verapamil release in Form A (melt extrusion formulation) tested in 5% and 40% ethanol media over 8 hours was not significantly different from the dissolution profile under 〇% ethanol conditions (P>;0.05) (Fig. 1 The dissolution curve under 20% ethanol is significantly lower than that under 〇% ethanol (p=〇. 〇2). This difference is most significant at 8 hours, which is relative to 〇 % ethanol conditions (77%), lower average percent dissolution (%) at 20% ethanol. For extreme conditions of 0% vs. 4% ethanol, the average percent dissolved is the same at 1 hour (19%) and At 8 hours, the 4% ethanol medium (81%) was only slightly higher than the 0% ethanol medium (77%). The release profile under all conditions was characterized by an initial rapid release rate that gradually decreased with time, indicating near zero. Release mechanism of sustained release. 13808i.doc -26· 200950776 Form B (a sustained release compound) exhibits dissolution curves and ethanol-free conditions compared to local ethanol concentrations (20% and 40%) after 10 hours of execution (〇 0/〇) Significant change (p<〇.〇〇1) (Fig. 2). Low/no ethanol concentration Near zero order release was observed (〇 and 5%) and no statistically significant difference between the two conditions was observed (P = 〇, 5). At higher ethanol concentrations (20 and 40%), initial Rapid release was seen within the first hour. This effect was dependent on the ethanol concentration and the average percent dissolved (%) in 〇4% ethanol medium was higher (%) compared to 20% ethanol medium (57%). Both were significantly higher than the average percent dissolution (17%) of 〇β/0 ethanol (ρ < 0 001). For 20% ethanol media, 'continuous release over time was observed and at approximately 8 hours Achieving a plateau (average dissolution of 1〇1%). For a 4〇% ethanol concentration, this plateau is reached faster at about 2 hours (1〇7% dissolution). At 2 hours, with 0% ethanol Compared with the average dissolution of 26% observed, an average dissolution of 73% and ι〇7% was observed for 20% and 40% ethanol concentrations, respectively, indicating a 3-4 fold increase in dissolution at higher ethanol concentrations. In the form of hydrazine, observed at higher ethanol concentrations (20% and 40%) for both performance release formulations (forms C and D) The same change in the solution curve. Form C shows that after 1 hour of execution, the dissolution curve at higher ethanol concentrations (2% and 4%) is significantly increased compared to the ethanol-free condition (〇%) (ρ< 0.0001) (Fig. 3). At higher ethanol concentrations (2% and 4%), the initial rapid release is seen in the first hour, with an average dissolved percentage in the 2% ethanol medium at hourly (1) 〇 2%) The average percentage of dissolution (64%) in the ethanol medium above 4%. However, the average percent dissolved at 1 hour, under higher ethanol conditions, was significantly higher than the average dissolved percentage at 〇% ethanol, 138081.doc •27·200950776 (151⁄4) (P<〇〇〇〇〇1) . For the 2% ethanol medium, the drug release reached a plateau (approximately 1 〇 2% on average) at approximately 1 hour. For the 40 ° / 〇 ethanol concentration, this plateau phase was achieved slightly later than 2 hours (average dissolution 106%). At lower ethanol concentrations (5%), the dissolution profile for up to 4 hours is almost identical to the observed 0% ethanol dissolution curve (P = 0.4 at 1 hour) 〇 between 4 and 10 hours, 5% The lower dissolution profile for ethanol conditions' resulted in significantly lower overall dissolution relative to 〇% ethanol (P < 0.001). The difference between the two conditions was most pronounced at 8 hours, showing an average percent dissolution percentage (%) of 1% by weight between 5 ° / 〇 ethanol conditions (76%) and 〇 % ethanol conditions (76%) (Ρ < 〇.〇〇1). The average percent dissolution of 〇% and 5% ethanol conditions approached 100% dissolution at 10 hours, showing an average dissolution of 97% and 92°/〇, respectively. Similar to the trends observed for Forms B and C, Form D shows that after 10 hours of execution, the dissolution curve at higher ethanol concentrations (20% and 40%) is significantly higher than in ethanol-free conditions (0%). Large (p < 0.00001) (Figure 4). Near zero order release was observed at low/no ethanol concentrations (0 and 5%) and no statistically significant difference between the two conditions was observed (p = 0-5). At higher ethanol concentrations (2 〇 and 40%), the initial rapid release was seen within the first hour. This effect is dependent on the ethanol concentration and the average percent dissolution (%) achieved in the 40% ethanol medium is higher (101%) than in the 20% ethanol medium (93%), both of which are significantly higher than 0% ethanol. Condition (12%) (Ρ < 0·0001). For the 20% ethanol medium, a rapid release was observed during the first two hours and a plateau (average dissolution of 98%) was achieved at 2 hours, which was significantly higher than the 0% ethanol condition (12%) (Ρ < 0·00001) . For a 40% ethanol concentration, this plateau (101% average dissolution) was reached faster at approximately 138081.doc •28·200950776 1 hour after rapid release, which was significantly higher than the 0% ethanol condition at 1 hour. (p<0.00001). At the end of 1 hour, no complete dissolution (100%) was observed for 0% or 5% ethanol conditions, which showed an average dissolution percentage of 65% and 69%, respectively. - The results of this in vitro dissolution study indicate that it is as it is and contained in 5% B-alcohol medium (equivalent to the concentration seen in most beer, cool wine), 20% ethanol medium (equivalent to seeing in strongly mixed drinks) The concentration is slightly higher than the concentration seen in most wines (10-153⁄4) and 40. /〇Ethanol medium (equivalent to the concentration seen in most undiluted spirits (ie, vodka (v〇dka), Duquan)), containing the novel melt extrusion of verapamil The formulation is resistant to the dissolution of ethanol. In contrast, three other commercially available release formulations showed a significant increase in verapamil release, especially at higher ethanol concentrations (20 and 40% ethanol). The commercially available sustained release comparator exhibited a dramatic drug release over the first 1-2 hours at the highest ethanol concentration (4%), followed by a plateau phase of dissolution (up to 1% dissolution), indicating that all sputum doses have been dumped Released in a dissolution medium. At 20. /. At the ethanol concentration, this was also observed within 2 hours, and the dose was released. However, for Form B, this occurred later than about 8 hours. No dose dumping was observed for Form a (melt extrusion). For Form A, the dissolution curve at 5% and 4% ethanol is 0 〇 /. There were no significant differences in ethanol conditions. The /recombination curve at 2〇% ethanol is even significantly lower than the 〇% condition, and the reason for this is unknown. The dissolution profile of Form A was near zero order and did not exhibit an initial release spike, regardless of the conditions, compared to other municipal formulations at higher ethanol concentrations. At 2 hours, Form A occurred approximately 30% dissolution (all media). At 8 hours 138081.doc -29· 200950776 No complete dissolution occurred. The average percent dissolution ranged from 64% (20% ethanol medium) to 81% (40% ethanol medium). Given the widespread and readily available use of ethanol, the interaction between ethanol and prescription drugs has received much attention. Interaction effects can occur in a variety of situations (ranging from taking a drug and consuming an alcoholic beverage to deliberate tampering with the formulation to extract the drug in the controlled release formulation or to enhance the pharmacodynamics of the drug and ethanol (as is common in drug abusers) )) occurs under. Other such conditions may include dissolving the drug and masking it in ethanol for criminal purposes (such as • dating rape), ® in the case of gamma hydroxybutyrate (gbh) or flethrazepam (RohypnolTM), ethanol Its drug effect is enhanced (Schwartz et al., 2001). Controlled release formulations are an indispensable feature, especially since controlled release formulations contain higher drug levels and can pose safety concerns. Thus, anti-abuse formulations that are not readily soluble in solvents such as ethanol, such as Form A (melt extruded), may have sustained release formulations that are superior to other readily accommodating "dose dumping" (McColl & Sellers, 2006) Significant advantages. Q The dissolution method in this study was not performed under low conditions throughout the dissolution test. Instead, the pH value at the beginning of the dissolution test was 2 hours, and the pH was increased to approximately 6.8. Once ingested, the long-term combination of ethanol in a low pH gastric environment (pH 2.0) can demonstrate a change in the dissolution profile. Future studies can be performed by examining the complete melt extrusion in an acidic medium or a gastric fluid containing ethanol. Lozenges and shredded melt-extruded tablets are used to solve this problem. In addition, it is important to note that the etiology of drug interactions is not limited to the physical and chemical interactions between solutes and solvents. Drug interactions can be catalyzed by pharmacokinetics. Pharmacodynamic, genetic and immune factors mediate 仏丫^^ and 138081.doc 200950776

Price，21007 ; Masubichi 及 Horie，2007 ; Vourvahis 及Price, 21007; Masubichi and Horie, 2007; Vourvahis and

Kashuba，2007)。舉例而言，維拉帕米之產品專論警告：與乙醇共投與可導致血液乙醇含量增加且因此損害增加，此為藥物動力學性質之交互影響（Covera_HS Product Mon〇graPh，2006)。在活體内臨床試驗中測定該調配物之完整性亦可有益於說明臨床上重要之藥物_乙醇交互影響之潛在性。 .❹ 此活體外溶解實驗已證明，當在高達40%之乙醇濃度下原樣測試時’使用熔融擠出技術之維拉帕米新穎調配物不改變其釋放曲線。相反，三種其他市售持續釋放維拉帕米調配物在較高乙醇濃度（2〇及40%)下展示劑量傾釋，在測試最初兩小時内達到大約100%溶解。本發明說明，此新穎熔融擠出調配物當原樣與易達到之乙醇濃度組合時可在活體外環境中抵抗劑量傾釋^類似地，預期此調配物在活體内環境中可具有有限之藥物-乙醇交互影響。 ❹ 以上實施方式及隨附實例僅具說明性且不希望限制本發明之範疇，本發明之範疇僅由隨附申請專利範圍及其均等案限定。對所揭示實施例之各種變更及修改對於熟習此項技術者而δ顯而易見且為本發明之部分。該等變更及修改包括（但不限於）與化學結構、取代基、衍生物、中間物、合成法、調配物及/或本發明之使用方法相關之彼等變更及修改，可在不悖離本發明之精神及範疇的情況下進行。參考文獻Kashuba, 2007). For example, Verapamil's product monograph warns that co-administration with ethanol can result in increased blood ethanol levels and therefore increased damage, which is an interaction of pharmacokinetic properties (Covera_HS Product Mon〇graPh, 2006). Determining the integrity of the formulation in an in vivo clinical trial may also be useful in illustrating the potential of a clinically important drug-ethanol interaction. ❹ This in vitro dissolution test has demonstrated that the verapamil novel formulation using melt extrusion technology does not change its release profile when tested as it is at an ethanol concentration of up to 40%. In contrast, three other commercially available sustained release verapamil formulations exhibited dose decantation at higher ethanol concentrations (2 and 40%), reaching approximately 100% dissolution during the first two hours of the test. The present invention demonstrates that the novel melt-extruded formulation can resist dose dumping in an in vitro environment when combined with readily available ethanol concentrations. Similarly, it is expected that the formulation will have limited drug in an in vivo environment - Ethanol interactions. The above embodiments and the accompanying examples are merely illustrative and are not intended to limit the scope of the invention, and the scope of the invention is limited only by the scope of the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments are apparent to those skilled in the art and are part of the invention. Such changes and modifications include, but are not limited to, changes and modifications relating to chemical structures, substituents, derivatives, intermediates, synthetic methods, formulations, and/or methods of use of the present invention. The spirit and scope of the present invention are carried out. references

Breitenbach J., 2002. Melt extrusion: from process to drug 138081.doc -31- 200950776 delivery technology. Eur J Pharmaceutics Biopharmaceutics 54:107-117 〇Breitenbach J., 2002. Melt extrusion: from process to drug 138081.doc -31- 200950776 delivery technology. Eur J Pharmaceutics Biopharmaceutics 54:107-117 〇

Breitenbach J., Lewis J. 2003. Two concepts, one technology: controlled-release and solid dispersions with Meltrex.於:Breitenbach J., Lewis J. 2003. Two concepts, one technology: controlled-release and solid dispersions with Meltrex.

Modified-Release Drug Delivery Technology, Editor: Marcel Dekker，Inc.，第 125-134頁中。 ❹Modified-Release Drug Delivery Technology, Editor: Marcel Dekker, Inc., pp. 125-134. ❹

Lynch T.，Price A.，2007. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 76(3):348-351。Lynch T., Price A., 2007. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 76(3): 348-351.

Masubichi Y” Horie T·，2007. Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol. 37(5):389-412。Masubichi Y" Horie T., 2007. Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol. 37(5): 389-412.

McColl S., Sellers E.M., 2006. Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Dep. 83(增刊 1):S52-S62。McColl S., Sellers E.M., 2006. Research design strategies to evaluate the impact of formulations on abuse liability. Drug Alcohol Dep. 83 (suppl. 1): S52-S62.

Product Monograph Covera-HS™ (verapamil hydrochloride) controlled-onset extended release tablets. Pfizer Canada Inc. 2006 »Product Monograph Covera-HSTM (verapamil hydrochloride) controlled-onset extended release tablets. Pfizer Canada Inc. 2006 »

Schwartz R.H., Milteer R., LeBeau M.A., 2001. Drug-facilitated sexual assault ('date rape*). South Med J. 93(6):655-656。 U.S. Food and Drug Administration alert for healthcare professionals 2005· Alcohol-PalladoneTM.interaction 0Schwartz R.H., Milteer R., LeBeau M.A., 2001. Drug-facilitated sexual assault ('date rape*). South Med J. 93(6): 655-656. U.S. Food and Drug Administration alert for healthcare professionals 2005· Alcohol-PalladoneTM.interaction 0

Vourvahis M.,Kashuba A.D., 2007. Mechanisms of pharmacokinetic 138081.doc -32- 200950776 and pharmacodynamic drug interactions associated it ritonavir-enhanced tipranavir. Pharhamcotherapy. 27(6):888-909 oVourvahis M., Kashuba A.D., 2007. Mechanisms of pharmacokinetic 138081.doc -32- 200950776 and pharmacodynamic drug interactions associated it ritonavir-enhanced tipranavir. Pharhamcotherapy. 27(6):888-909 o

World Health Organization Global Status Report on Alcohol 2004 ° 【圖式簡單說明】闽1 :在诚您增之乙醇濃度下、形式Α(熔融擠出型）隨時間 (小^之維教帕米釋放之溶解曲線（平均溶解％[±SD])。 &遞増之乙醇濃度下、形式B(SR)隨時間（小時）之維拉帕米釋# & 评I之溶解曲線（平均溶解％[±SD])。 03 ·在遞增之乙醇濃度下、形式C(SR)隨時間（小時）之維拉帕米釋# 坪狄之溶解曲線（平均溶解％[±8〇])。圖4 ·在谈4ίή 増之乙醇濃度下、形式D(SR)隨時間（小時）之維拉帕米釋於β 坪狄之溶解曲線（平均溶解％[土SD])。 138081.doc •33-World Health Organization Global Status Report on Alcohol 2004 ° [Simplified Schematic] 闽1: In the case of your increased ethanol concentration, the form Α (melt extrusion type) over time (small ^ Weizhi teaches the release curve of Pami ( % average dissolution [±SD]) & Ethanol concentration at the concentration, Form B (SR) over time (hours) of verapamil release # & I evaluation of dissolution curve (average dissolution % [± SD] 03 · At the increasing ethanol concentration, the form C (SR) with time (hours) of verapamil release # pingdi's dissolution curve (average dissolved % [± 8 〇]). Figure 4 · Talk about 4 ή At the ethanol concentration of hydrazine, Form D (SR) is released over time (hours) by the dissolution curve of verapamil released to β pingdi (average lysis % [soil SD]). 138081.doc •33-

Claims

200950776 七、申請專利範園： 1. 一種具有減低之藥物-乙醇交互影響之熔融擠出劑型，該劑型包含： (a) 邀用相關藥物或於乙醇中具有劑量傾釋潛在性之藥物；及 (b) 具有聚合物、共聚物或其組合之基質，該聚合物、共聚物或其組合之單體選自由以下各物組成之群：纖維素醚、纖維素酯、丙浠酸酯、甲基丙烯酸醋及海藻酸鈉；其中該基質係經熔融擠出且其中該劑型具有減低之藥物_ 乙醇交互影響。 2. 如請求項1之熔融擠出劑型，羥基烷基纖維素、羥基烷基炫基纖維素及海藻酸納。 3. 如請求項1之熔融擠出劑型，其中該藥物為維拉帕米 (verapamil)、γ 羥基丁酸（gammahydr〇xybutyrate)或氟硝 φ 西泮（flunitrazepam)之鹽或酯。 4. 如凊求項2之熔融擠出劑型，其中該羥基烷基纖維素為羥丙基纖維素。 5. 如請求項2之熔融擠出劑型，其中該羥基烷基烷基纖維 • 素為羥丙基甲基纖維素。 6·如請求机熔融擠出劑型，其中該藥物為維拉帕米之鹽或醋。 7.如請求項！之溶融擠出劑型，其中該藥物包含i邮至 1000 mg之維拉帕米之鹽或醋。 138081.doc 200950776 /、有1至1 〇〇〇 mg維拉帕米的維拉帕米炫融擠出調配物其中使用USP溶解方法溶於4〇%乙醇溶液中之該劑型中之維拉帕米少於。月求項8之維拉帕米熔融擠出調配物，其中該劑型中 . <維拉帕米在5%或·乙醇中、在八小時時之溶解曲線 . 無異於該劑型中之維拉帕米在0〇/〇乙醇中、在八小時時之溶解曲線》 ❹10.如請求項1-9中任一項之熔融擠出劑型，纟中該藥物包含 240 mg之維拉帕米之鹽或酯。 11. 如請求項1-1〇中任—項之熔融擠出劑型，其中該減低之活體外藥物乙醇交互影響與減低之活體内藥物乙醇交互影響相互關聯。 12. —種用於治療有需要之人類患者之方法，該方法包含向該人類患者經口投與如請求項1_1 i中任—項之劑型。200950776 VII. Application for Patent Park: 1. A melt-extruded dosage form with a reduced drug-ethanol interaction effect, the dosage form comprising: (a) an inviting drug or a drug having a dose-drain potential in ethanol; (b) a substrate having a polymer, a copolymer or a combination thereof, the monomer of the polymer, copolymer or combination thereof being selected from the group consisting of: cellulose ether, cellulose ester, propionate, A Acrylic vinegar and sodium alginate; wherein the matrix is melt extruded and wherein the dosage form has a reduced drug-ethanol interaction. 2. The melt-extruded dosage form of claim 1, hydroxyalkyl cellulose, hydroxyalkyl dalcyl cellulose, and sodium alginate. 3. The melt-extruded dosage form of claim 1, wherein the drug is a salt or ester of verapamil, gammahydr〇xybutyrate or flunitrazepam. 4. The melt extruded dosage form of claim 2, wherein the hydroxyalkylcellulose is hydroxypropylcellulose. 5. The melt-extruded dosage form of claim 2, wherein the hydroxyalkylalkylcellulose is hydroxypropylmethylcellulose. 6. A request for a melt extrusion dosage form wherein the drug is verapamil salt or vinegar. 7. As requested! The melt-extruded dosage form, wherein the drug comprises a salt of valparam or vinegar of 1,000 mg. 138081.doc 200950776 /, Verapamil with 1 to 1 〇〇〇mg verapamil in a dosage form of Verapamil in a dosage form prepared by dissolving USP in a 4% ethanol solution using USP dissolution method Less than a meter. The Verapamil melt-extruded formulation of Month 8 in which the dissolution curve of the & verapamil in 5% or ethanol at eight hours is no different from the dimension in the dosage form. The dissolution profile of lapamim in 0 〇 / 〇 ethanol at eight hours ❹ 10. The melt-extruded dosage form of any one of claims 1-9, wherein the drug comprises 240 mg of verapamil Salt or ester. 11. The melt-extruded dosage form of claim 1-1, wherein the reduced in vitro drug ethanol interaction is associated with a reduced interaction of the drug in the living body. 12. A method for treating a human patient in need thereof, the method comprising orally administering to the human patient a dosage form as claimed in claim 1_1 i.

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