TW200950776A - Abuse resistant melt extruded formulation having reduced alcohol interaction - Google Patents

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 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

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 (?&gt;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&lt;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 &quot;plastic&quot;-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&apos; and can help prevent tampering (e.g., opium, stimulant)&apos; 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

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 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&gt;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.

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 &quot;alkylalkyl acrylate&quot; 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, '&quot;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. &quot;sulfanyl group&quot; Refers to the _SR group wherein R is an alkyl group as defined above. Amino" refers to a -NH2 group. &quot;Acetylamino&quot; means an -NHR group wherein r is an alkyl group as defined above. &quot;Dialkylamino&quot; 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. &quot;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 "&quot;carboxy&quot; 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, &gt; 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, &quot;arylalkyl&quot; 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 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 &quot;polyvinyl alcohol&quot;); 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&quot; 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.

The term &quot;opioid&quot; 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), 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

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 &quot;solid solution&quot;. 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&amp;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)&apos; 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) 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) 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&gt;;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&lt;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 &lt; 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&lt; 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&lt;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 &lt; 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 &lt; 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 &lt; 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 &lt; 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&lt;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 &quot;dose dumping&quot; (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 and Horie, 2007; Vourvahis and

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

Modified-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.

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 (suppl. 1): S52-S62.

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 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 o

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]) &amp; Ethanol concentration at the concentration, Form B (SR) over time (hours) of verapamil release # &amp; 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 (1)

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. 138081.doc 2-