WO2009092818A1

WO2009092818A1 - Abuse resistant melt extruded formulation having reduced alcohol interaction

Info

Publication number: WO2009092818A1
Application number: PCT/EP2009/050853
Authority: WO
Inventors: Wolfgang Roth; Alexander Burst; Martina Zietsch
Original assignee: Abbott Gmbh & Co., Kg
Priority date: 2008-01-24
Filing date: 2009-01-26
Publication date: 2009-07-30
Also published as: ZA201005797B; CA2713373A1; NZ586962A; JP2011510048A; MX2010008100A; AU2009207579A1; EP2254553A1; IL207173A0; TW200950776A; CN101977592A; BRPI0907402A2; KR20100110370A

Abstract

The present invention relates to compositions for oral administration. The invention preferably comprises at least one abuse-resistant drug delivery composition for delivering a drug having potential for dose dumping in alcohol, related methods of preparing these dosage forms, and methods of treating a patient in need thereof comprising administering the inventive compositions to the patient. Most preferably, the dosage form includes verapamil.

Description

ABUSE RESISTANT MELT EXTRUDED FORMULATION HAVING REDUCED ALCOHOL INTERACTION

Field of Invention: The present invention relates to compositions for oral administration.

The invention preferably comprises at least one abuse-resistant drug delivery composition for delivering a drug having potential for dose dumping in alcohol, related methods of preparing these dosage forms, and methods of treating a patient in need thereof comprising administering the inventive compositions to the patient.

Background:

Controlled or modified release formulations have distinct advantages, such as enhanced patient compliance due to reduced frequency of dosing and reduced side effects due to reduced fluctuations in blood piasma levels of drug. This comes with the caveat that a controlled/modified release formulation contains a higher amount of the active drug relative to its immediate release counterpart. If the controlled release portion of the formulation is easily defeated, the end result is a potential increase in exposure to the active drug and possible safety concerns. The potential impact of concomitant intake of ethano! on the in vivo release of drugs from modified release oral formulations has recently become an increasing concern. This has stemmed from the recent clinical finding that the co- ingestion of alcohol resulted in a potentially serious dose dumping of hydromorphone from Pailadone™, a controlled release capsule dosage form (FDA Alert, Juiy 2005). The World Health Organization estimates that there are approximately 2 billion people worldwide who consume alcohol (WHO Report, 2004) Since alcohol is one of the most socially acceptable, widely used and easily obtained drugs, the potential for drug interactions is imminent. In order to improve safety and circumvent intentional tampering (e.g. dissolving a controlled release tablet in ethanol to extract the drug), a reduction in the dissolution of the modified release fractions of such formulations, in ethanol, may be of benefit. Accordingly, the need exists to develop new formulations having reduced potential for dose dumping in alcohol

Brief Description of Figures: Figure 1. Dissolution profiles (mean dissolution % [+SD]) of verapamil release from Form A (melt extruded) over time (hours), with increasing ethanol concentrations.

Figure 2, Dissolution profiles (mean dissolution % [±SD]) of verapamil release from Form B (SR) over time (hours), with increasing ethanol concentrations. Figure 3. Dissolution profiles (mean dissolution % [±SD]) of verapamil release from Form C (SR) over time (hours), with increasing ethanol concentrations Figure 4. Dissolution profiles (mean dissolution % [±SD]) of verapamil release from Form D (SR) over time (hours), with increasing ethanol concentrations

Summary of the invention:

In one preferred embodiment, verapamil and other controlled release formulations may be manufactured having reduced or limited dose-dumping effect when concomitantly used with ethanol Preferred embodiments include melt extruded sustained release formulations. One preferred embodiment of the present invention provides 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 Use of such melt extruded matrix is expected to provide a dosage form which has reduced drug-alcohol interaction Preferably, the matrix comprises polymers and copolymers of hydroxyalkylceilulose, hydroxyalkyl alkylcellulose and natrium-alginate Also, preferably, the drug is a salt or an ester of verapamil, gammahydroxybutyrate or flunitrazepam More preferably, the hydroxyaikylceilulose is hydroxypropylcellulose and/or the hydroxyalkyl alkyicellulose is hydroxypropylmethylcellulose In the most preferred embodiment, the drug is a salt or an ester of verapamil. This drug may comprise"! mg to IOOOrng of a salt or an ester of verapamil.

Another embodiment of the invention provides a verapamil melt extruded formulation having 1 to 1000 mg of verapamil, wherein less that 40% of the verapamil in the dosage form is dissolved in 40% ethanol solution using USP dissolution method. Further in this formulation, the dissolution profile for verapamil from the dosage form in 5% or 40% ethanol at eight hours does not differ from the dissolution profile for verapamil from the dosage form in 0% ethanol at eight hours. Most preferably, in all these formulations, the drug comprises 240 mg of a salt or an ester of verapamil. Further, without further undue experiment, it may be ascertained that in these formulations, the reduced in vitro drug alcohol interaction correlates to reduced in vivo drug alcohol interaction .

Yet another embodiment of the present invention provides a method for treating a human patient in need thereof, comprising orally administering to the human patient any dosage form described above

These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the methods of the invention and compositions used therein as more fully described below

Description of Preferred Embodiment:

The potential impact of concomitant intake of ethanol on the in vivo release of drugs from modified release oral formulations has recently become an increasing concern. The aim of this investigation was to determine the influence of ethanol on the in vitro rate of release of verapamil (240 mg) from Meltrex® technology, an innovative melt extrusion formulation that achieves a stable solid dispersion of drug, in contrast to three other marketed verapamil (240 mg) controlled release formulations This melt extrusion formulation is considered to be an efficient and specialized technology embedding poorly soluble drugs as solid dispersion/solid solution into a biocompatible polymer matrix Dissolution testing was conducted under standardized conditions using the buffer addition method (potassium phosphate buffer) with mediums containing increasing ethanol concentrations of 0, 5, 20, and 40%, For each medium, six tablets were tested (4 tablets for Form C in 0% ethanoi) and drug release was monitored spectrophotometrically at 250-300 nm The dissolution profiles for the melt extruded formulation showed no significant differences between the 5% and 40% ethanol media (P>0.05) and 0% ethanol medium, and a statistically significant decrease in release for the 20% ethanol medium compared to the 0% ethanol medium (P=O.02) For both extreme conditions of 0% and 40% ethanol, the mean dissolution percentage was identical at 1 hour (19%) and at 8 hours was only slightly higher in the 40% ethanoi medium (81%) compared to the 0% ethanol medium (77%). In contrast, the three marketed comparators showed a statistically significant increase in dissolution in higher ethanol concentrations (20 and 40% ethanol) compared to the 0% ethanol condition (p<0 001). An initial rapid release was observed at the higher ethanol concentrations, showing a mean dissolution percentage of 99% (range 73-107%), within the first 2 hours of testing

Dissolution at the low/no ethanol concentrations showed a steady release of near zero order, which had a mean dissolution percentage of 25% within the first 2 hours This in vitro dissolution study has demonstrated that the innovative melt extruded formulation of verapamil (Form A) does not alter its release profile when tested intact with ethanol concentrations of up to 40% In contrast, three other marketed controlled release verapamil concentrations showed dose dumping effects at higher ethanol concentrations (20 and 40%). This study suggests that this innovative melt extruded formulation may be resistant to dose dumping in an in vitro environment, when combined intact with concentrations of ethanol that are readily accessible Future studies to determine the robustness of this formulation in an in vivo environment may be of added benefit to determine the potential for a clinically important drug- alcohol interaction.

Unlike standard tabletting processes (Form B-D), where drug- containing powders or granules are compressed, in the case of Verapamil Meltrex® (Form A), melt extrusion is an innovative process where the drug containing polymer melt is directly shaped. In addition, melt extrusion technology has the advantage of being a solvent- and dust-free process, frequently used for the manufacture of uniform systems or bulk intermediates, which allows for a clean processing environment with a reduction in environmental pollution, explosion proofing and residual organic solvents (Breitenbach and Lewis, 2003) The therapeutic advantages of melt extrusion technology, as applied to drug formulations, include improved dissolution kinetics, enhanced bioavailability and therefore efficacy, improved safety, and the ability to tailor-make release profiles (Breitenbach, 2002, Breitenbach and Lewis, 2003) By selecting the optimal polymer composition, a very hard and "plastic" like tablet can be manufactured with very low brittleness. Melt extruded tablets cannot be crushed into a fine powder, as in the case of standard tablets, and thereby reduces the physical tampering potential Such technology can be applied to numerous active drug ingredients which may benefit from reduced frequency of daily dosing, and may aid to deter tampering (e.g. opiates, stimulants), improve safety and sustain the time release profile This melt extrusion technology has been applied to verapamil hydrochloride, a marketed antihypertensive and anti-anginal drug which may potentially interact with alcohol (Covera-HS Product Monograph, 2006)

In one preferred embodiment, verapamil and other controlled release formulations may be manufactured having reduced or limited dose-dumping effect when concomitantly used with ethanol. Preferred embodiments include melt extruded sustained release formulations. One preferred embodiment of the present invention provides 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. Use of such melt extruded matrix is expected to provide a dosage form which has reduced drug-alcohol interaction. Preferably, the matrix comprises polymers and copolymers of hydroxyalkylceilulose, hydroxyalkyl aikylcellulose and natrium-alginate Also, preferably, the drug is a salt or an ester of verapamil, gammahydroxybutyrate or flu nitrazepam. More preferably, the hydroxyalkylceilulose is hydroxypropylcellulose and/or the hydroxyalkyl aikylcellulose is hydroxypropylmethylcellulose In the most preferred embodiment, the drug is a salt or an ester of verapamil This drug may comprise 1 mg to 10OOmg of a salt or an ester of verapamii

Another embodiment of the invention provides a verapamii melt extruded formulation having 1 to 1000 mg of verapamil, wherein less that 40% of the verapamil in the dosage form is dissolved in 40% ethanol solution using USP dissolution method. Further in this formulation, the dissolution profile for verapamil from the dosage form in 5% or 40% ethanol at eight hours does not differ from the dissolution profile for verapamil from the dosage form in 0% ethanol at eight hours Most preferably, in ail these formulations, the drug comprises 240 mg of a salt or an ester of verapamil Further, without further undue experiment, it may be ascertained that in these formulations, the reduced in vitro drug alcohol interaction correlates to reduced in vivo drug alcohol interaction.

Yet another embodiment of the present invention provides a method for treating a human patient in need thereof, comprising orally administering to the human patient any dosage foim described above

In another embodiment, the formulation may use a polymer, or a copolymer, or a combination thereof to create the melt-processed, and more preferably melt-extruded, directly shaped formulation Polymers that are pharmacologically inactive and provide enteric coatings or sustained release profile for the formulation can also be used In one embodiment, suitable polymers/copolymers include poly(meth)acrylate like e.g Eudragit L- or S- type, which are pharmacologically inactive

EUDRAGIT® is a tradename for some preferred polymers that are suitable for use in the invention and are derived from esters of acrylic and methacrylic acid. The properties of the EUDRAGIT polymers are principally determined by functional groups incorporated into the monomers of the EUDRAGIT polymers, The individual EUDRAGIT® grades differ in their proportion of neutral, alkaline or acid groups and thus in terms of physicochemical properties Ammonioalkiyl methacrylate copolymers or methacrylate copolymers may be used having the following formula. CH₃ (H) CH₃

R

Alkyl-OOC

The Eudragit polymers fuifil the specifications/requirements set in the USP. According to 2007 US Pharmacopoeia, Eudragit is defined as USP 30 / NF 25.

Methacrylic acid copolymer, type A NF = Eudragit L-100 Methacrylic acid copolymer, type B NF = Eudragit S-I OO Methacrylic acid copolymer, type C NF - Eudragit L-100-55 {contains a small detergent amount) Ammonio Methacrylate Copolymer, type A NF = Eudragit RL-100

(granules)

Ammonio Methacrylate Copolymer, type A NF = Eudragit RL-PO (powder)

Ammonio Methacrylate Copolymer, type B NF = Eudragit RS-100 (granules)

Ammonio Methacrylate Copolymer, type B NF = Eudragit RS-PO (powder)

Polyacrylate Dispersion 30 Percent Ph, Eur. = Eudragit NE30D (= 30% aqueous dispersion) Basic butylated methacrylate copolymer Ph. Eur = Eudragit E-100 wherein the functional group has a quaternary ammonium (trimethylammonioethyl methacrylate) moiety or R = COOCH₂CH₂N⁺(CH₃)SCi^' [commercially available as EUDRAGIT© (RL or RS)] or the functional group is a carboxylic acid, or R = COOH [commercially available as EUDRAGIT© (L)]- When the functional group is a carboxylic acid moiety, the EUDRAGIT© (L,) polymer is gastroresistant and enterosoluble. Thus formulations using EUDRAGIT© (L) will be resistant to gastric fluid and will release the active agent in the colon. When the functional group is a trimethylammonioethyl methacrylate moiety, the EUDRAGIT© (RL or RS) polymers are insoluble, permeable, dispersible and pH-independent, These EUDRAGIT© (RL. or RS) polymers may therefore be used for delayed drug release for sustained ielease formulations. EUDRAGIT© is sold in various forms such as in solid form (EUDRAGIT® LlOO/ S300/ L-100-55, EUDRAGIT© E PO, EUDRAGIT© RL PO, Eudragil RS PO), gianules (EUDRAGIT® ElOO, EUDRAGIT©RL 100/RS 100), dispeisions (L 30 D-55/FS 3OD 30%, EUDRAGIT© NE 30 D/40 D 30%/40% polymer content, EUDRAGIT®RL 30 D RS 30 D 30%) and organic solutions (EUDRAGIT© L 12 5, EUDRAGIT© E 12.5, EUDRAGIT© RL 12,5/RS 12.5 - 12.5% organic solution)

When at least two melt-processed polymers are employed, one is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a (meth)acrylate polymer (such as, any suitable Eudragit polymer) Among the (meth)acrylate polymer polymers preferred In the context of the invention are Eudragit L and Eudragit RS. One more preferred polymer in the context of the invention is Eudragit RL The Eudragit polymers can be used in combinations, with mixtures of Eudragit RS and RL being preferred

Persons that (albeit inadvisedly) drink substantial quantities of

alcoholic beverages when taking physician prescribed medications can

substantially alter the composition of the gastric juices contained in the stomach, and in extreme cases these gastric juices can comprise

up to 40% alcohol. Advantageously, embodiments of the inventive abuse-deterrent formulation optionally comprises a melt-processed mixture of at least one abuse-relevant drug, at least one cellulose

ether or cellulose ester, and at least one (meth)acrylic polymer,

wherein the amount of the drug that is extracted from the formulation by 20% aqueous ethanol, or 40% aqueous ethanol, or both, within one

hour at 37 "C is less than or equal 1 ,5 times the amount of the drug

that is extracted by 0.01 N hydrochloric acid within one hour at 37 ⁰C,

or at 25 ⁰C or both. The resistance to extraction by 40% ethanol is advantageous in those situations in which an individual purposefully attempts to extract an abuse relevant drug from a medicine containing an abuse relevant drug.

Exemplary preferred compositions of the invention comprise cellulose ethers and cellulose esters, which can be used alone or in combination in the invention have a preferable molecular weight in the range of 50,000 to 1 ,250,000 daltons. Cellulose ethers are preferably selected from alkylceliuloses, hydroxalkyScelluloses, hydroxyalkyl alkylcelluloses or mixtures therefrom, such as ethylceliulose, methylcellulose, hydroxypropyl cellulose (NF), hydroxyethyl cellulose (NF), and hydroxpropyl methylcellulose (USP), or combinations thereof Useful cellulose esters are, without limitation, cellulose acetate (NF), cellulose acetate butyrate, cellulose acetate propionate, hydroxypropylmethy! cellulose phthalate, hydroxypropylmethyl cellulose acetate phthalate, and mixtures thereof. Most preferably, non-ionic polymers, such as hydroxypropylmethyl cellulose may be used.

The amount of substituent groups on the anhydroglucose units of cellulose can be designated by the average number of substituent groups attached to the ring, a concept known to cellulose chemists as "degree of substitution" (D S ). If all three available positions on each unit are substituted, the D S. is designated as 3, if an average of two on each ring are reacted, the D S. is designated as 2, etc

In preferred embodiments, the cellulose ether has an alkyl degree of substitution of 1 ,3 to 2 0 and hydroxyalky! molar substitution of up to 0.85 in preferred embodiments, the alkyl substitution is methyl Further, the preferred hydroxyalkyl substitution is hydroxpropyl- These types of polymers with different substitution degrees of methoxy- and hydroxypropoxy- substitutions are summarized listed in pharmacopoeas, e g. USP under the name "Hypromellose"

Methylcellulose is available under the brand name METHOCEL A. METHOCEL A has a methyl (or methoxyl) D S of 1.64 to 1.92. These types of polymers are listed in pharmacopoeas, e.g. USP under the name "Methylcellulose". A particularly preferred cellulose ether is hydroxpropyl methylceSluiose Hydroxpropyl methylcellulose is available under the brand name METHOCEL E (methy! D S about 1 9, hydroxypropyl moiar substitution about 0.23), METHOCEL F (methyl D S about 1 8, hydroxypropyl molar substitution about 0.13), and METHOCEL K (methyl D, S, about 1 4, hydroxypropyl molar substitution about 0 21) METHOCEL F and METHOCEL K are preferred hydroxpropyl methylcelluloses for use in the present invention

The acrylic polymer suitably includes homopoiymers and copolymers (which term includes polymers having more than two different repeat units) comprising monomers of acrylic acid and/or alkacrylic acid and/or an alkyl (alk)acrylate As used herein, the term "alkyl (alk)acrylate" refers to either the corresponding acrylate or alkacrylate ester, which are usually formed from the corresponding acrylic or alkacrylic acids, respectively In other words, the term "alkyl (aik)acrylate" refers to either an alkyl alkacrylate or an alkyl acrylate Preferably, the alkyl (alk)acrylate is a (C₁-C₂₂JaIkVi ((C_r

Cio)alk)acrylate Examples of C₁-C₂₂ alkyl groups of the alkyl (alk)acrylates include methyl, ethyl, n-propyl, n-butyl, iso-butyl, tert-butyl, iso-propyl, pentyl, hexyl, cyclohexyl, 2-ethy! hexyl, heptyl, octyl, nonyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, behenyl, and isomers thereof The alkyl group may be straight or branched chain Preferably, the {d-C^alkyl group represents a (Ci-C₆)aikyl group as defined above, more preferably a (Ci-C₄)a!kyl group as defined above Examples of C₁-₁₀ alk groups of the alkyl (alk)acrylate include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, 2-ethy! hexyl, heptyl, octyl, nonyl, decyl and isomers thereof The alk groups may be straight or branched chain Preferably, the (CrCio)alk group represents a (CrCβ)alk group as defined above, more preferably a (C_r C₄) alk group as defined above

Preferably, the alky! (alk)acrylate is a (C_rC₄)alkyl ((CrC₄) a!k)acrylate, most preferably a (Ci-C₄)alkyl (meth)acrylate It will be appreciated that the term (CrC₄)alkyl (meth)acrylate refers to either (CrC₄)a!ky! acrylate or (Cr C.»)alkyl rnethacrylate. Examples of (Ci-C₄)a!kyi (meth)acrylate include methyl methacrylatθ (MIvIA), ethyl methacrylate (EMA), n-propyl rnethacrylate (PMA), isopropy! methacrylate (!PMA), n-buty! methacrylate (BMA), isobutyl methacrylate (IBMA), tert-butyl methacrylate (TBMA). methyl acrylate (MA)₁ ethyl acrylate (EA), n-propyl acrylate (PA), n-butyl acrylate (BA), isopropyl acrylate (IPA), isobutyl acrylate (IBA), and combinations thereof.

Preferably, the alkacrylic acid monomer is a (CrCio)a!kacry!ic acid Examples of (CrCio)alkacrylic acids include methacrylic acid, ethacrylic acid, n-propacrylic acid, iso-propacrylic acid, n-butacrylic acid, iso-butacrylic acid, teri-butacrylic acid, pentacrylic acid, hexacrylic acid, heptacrylic acid and isomers thereof. Preferably the (CrCio)alkacrylic acid is a (CrC₄)a!kacrylic acid, most preferably methacrylic acid.. In certain embodiments, the alkyl groups may be substituted by aryl groups.. As used herein "alkyl" group refers to a straight chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbons. The alkyl group has 1-16 carbons, and may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl A "hydroxy" group refers to an OH group An "alkoxy" group refers to an -O-alkyl group wherein alkyl is as defined above A "thio" group refers to an -SH group. A "thioalkyl" group refers to an -SR group wherein R is aikyl as defined above An "amino" group refers to an -NHz group An "alkylamino" group refers to an --NHR group wherein R is alkyl is as defined above A "dialkylamino" group refers to an --NRR' group wherein R and R' are all as defined above.. An "amido" group refers to an -CONH₂ An "alkylamido" group refers to an -CONHR group wherein R is alky! is as defined above. A "dialkylamido" group refers to an -CONRR¹ group wherein R and R' are aikyl as defined above. A "nitro" group refers to an NO₂ group, A "carboxy!" group refers to a COOH group

In certain embodiments, the alkyl groups may be substituted by aryl groups As used herein, "aryl" includes both carbocyciic and heterocyclic aromatic rings, both monocyclic and fused polycyclic, where the aromatic rings can be 5- or 6-membered rings Representative monocyclic aryl groups include, but are not limited to, phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazoly! and the like. Fused polycyclic aryl groups are those aromatic groups that include a 5- or 6-membered aromatic or heteroaromatic ring as one or more rings in a fused ring system Representative fused polycyclic aryl groups include naphthalene, anthracene, indoliztne, indole, isoindoie, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1 ,8- naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazine, phenoxazine, and azulene. Also as used herein, aryl group also includes an arylalkyl group Further, as used herein "arylalkyf" refers to moieties, such as benzyl, wherein an aromatic is linked to an alkyl group

Preferably, the acrylic polymer is an acrylic copolymer Preferably, the acrylic copolymer comprises monomers derived from alkyl (aik)acrylate, and/or acrylic acid and/or alkacrylic acid as defined hereinbefore Most preferably, the acrylic copolymer comprises monomers derived from alkyl (alk)acrylate, i e copolyrnerisable alkyi acrylate and alkyl alkacrylate monomers as defined hereinbefore. Especially preferred acrylic copolymers include a (Ci-C₄)alkyl acrylate monomer and a copolymerisable (Ci-C₄)alkyl {CrC^alkacrylate comonomer, particularly copolymers formed from methyl rnethacrylate and a copolymerisable comonomer of methyl acrylate and/or ethyl acrylate and/or n~buty! acrylate

Preferably, the (meth)acrylic polymer is a ionic (meth)acrylic polymer, in particular a cationic (meth)acrylic polymer Ionic (meth)acrylic polymer are manufactured by copoSyrnerising (meth)acrylic monomers carrying ionic groups with neutral (meth)acrylic monomers The ionic groups preferably are quaternary ammonium groups.

The (meth)acrylic polymers are generally water-insoluble, but are swellable and permeable in aqueous solutions and digestive fluids The molar ratio of cationic groups to the neutral (meth)acrylic esters allows for are control of the water-permeabilty of the formulation in preferred embodiments the (meth)acrylic polymer is a copolymer or mixture of copolymers wherein the molar ratio of cationic groups to the neutral (meth)acrylic esters is in the range of about 1.20 to 1.35 on average. The ratio can by adjusted by selecting an appropriate commercially available cationic (meth)acrylic polymer or by blending a cationic (meth)acrylic polymer with a suitable amount of a neutral (meth)acrylic polymer Suitable (meth)acrylic polymers are commercially available from Rohm Pharma under the Tradename Eudragit, preferably Eudragit RL and Eudragit RS Eudragit RL and Eudragit RS are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the moiar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1.20 in Eudragit RL and 1 40 in Eudragit RS The mean molecular weight is about 150,000

Besides the (meth)acrylic polymers, further pharmaceutically acceptable polymers may be incorporated in the inventive formulations in order to adjust the properties of the formulation and/or improve the ease of manufacture thereof These polymers may be selected from the group comprising, homopolymers of N-vinyl lactams, especially polyvinylpyrrolidone (PVP), copolymers of a N-vinyl lactam and and one or more comonomers copolymerizable therewith, the comonomers being selected from nitrogen- containing monomers and oxygen-containing monomers; especially a copolymer of N-vinyi pyrrolidone and a vinyl carboxylate, preferred examples being a copolymer of N-vinyl pyrrolidone and vinyl acetate or a copolymer of N-viny! pyrrolidone and vinyl propionate, polyvinyl alcohoi-polyethylene giycol- graft copolymers (available as, e g._t Kollicoat® IR from BASF AG, Ludwigshafen, Germany), high molecular polyalkylene oxides such as polyethylene oxide and poiypropylene oxide and copolymers of ethylene oxide and propylene oxide; polyacrylamides, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"), polyvinyl alcohol, poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid), poly(3-hydroxybutyrate) and ρoly(3~hydroxybutyrate~co-3-hydroxyvalerate), or mixtures of one or more thereof. PVP generates hydrocodone N-oxide during extrusion, therefore use of PVP-polymers and -copolymers is not always preferred However, when a small amount (0 2 - 0 6 % w/w of the total formulation) of antioxidant is used, then PVP may be used preferably

"Abuse-relevant drug" is intended to mean any biologically effective ingredient the distribution of which is subject to regulatory restrictions Drugs of abuse that can be usefully formulated in the context of the invention include without limitation pseudoephedrine, anti-depressants, strong stimulants, diet drugs, steroids, and non-steroidal anti-infiammatory agents. In the category of strong stimulants, methamphetamine is one drug that has recently received popular attention as a drug of abuse There is also some concern at the present time about the abuse potential of atropine, hyoscyamine, phenobarbital, scopolamine, and the like Another major class of abuse- relevant drugs are analgesics, especially the opioids

By the term "opioid," it is meant a substance, whether agonist, antagonist, or mixed agonist-antagonist, which reacts with one or more receptor sites bound by endogenous opioid peptides such as the enkephalins, endorphins and the dynorphins. Opioids include, without limitation, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dirnepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethyimorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylrnorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norpipanone, opium, oxycodone, oxymorphone, papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tiiidine, and tramadol, and salts and mixtures thereof In some preferred embodiments, the inventive formulation includes at least one additional therapeutic drug In even more preferred embodiments, the additional therapeutic dug can be, without limitation, selected from the group consisting of non-steroidal, non-opioidal analgesics, and is optionally further selected from the group consisting of acetaminophen, aspirin, fentaynl, ibuprofen, indomethacin, ketorolac, naproxen, phenacetin, piroxicam, sufentanyl, sunlindac, and interferon alpha Particularly preferred are those combinations of drug currently sold as fixed dose combinations to the public under the authority of a suitable national or regional regulatory agency, such as (by way of example) the U S Food and Drug Administration Such drugs include without limitation a (fixed dose) combination of hydrocodone and acetaminophen, or a (fixed dose) combination of hydrocodone and ibuprofen. The abuse-relevant drug(s) are preferably dispersed evenly throughout a matrix that is preferably formed by a cellulose ether or cellulose ester, and one acrylic or methacryiic polymer as well as other optional ingredients of the formulation This description is intended to also encompass systems having small particles, typically of less than 1 μm in diameter, of drug in the matrix phase These systems preferably do not contain significant amounts of active opioid ingredients in their crystalline or microcrystaliine state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS). At least 98% (by weight) of the total amount of drug is preferably present in an amorphous state. If additional non-abuse relevant drug actives like e.g. acetaminophen are additionally present in a formulation according to the present invention, this additional drug active(s) may be in a crystalline state embedded in the formulation.

When the dispersion of the components is such that the system is chemically and physically uniform or substantially homogenous throughout or consists of one thermodynamic phase, such a dispersion is called a "solid solution" Solid solutions of abuse-relevant actives are preferred- The formulation can also comprise one or more additives selected from sugar alcohols or derivatives thereof, maltodextrines; pharmaceutically acceptable surfactants, flow regulators, d is integrants, bulking agents and lubricants Useful sugar alcohols are exemplified by mannitol, sorbitol, xylitol, useful sugar alcohol derivatives include without limitation isomalt, hydrogenated condensed palatinose and others that are both similar and dissimilar.

Pharmaceutically acceptable surfactants are preferably pharmaceutically acceptable non-ionic surfactant Incorporation of surfactants is especially preferred for matrices containing poorly water-soluble active ingredients and/or to improve the wettability of the formulation The surfactant can effectuate an instantaneous emulsification of the active ingredient released from the dosage form and prevent precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract, Some additives include polyoxyethylene alkyl ethers, e g polyoxyethylene (3) lauryi ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers, e g polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethyiene (4) nonylphenyl ether or polyoxyethylene (3) octylphenyl ether, polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300 dioleate, aikyiene glycol fatty acid mono esters, e g. propylene glycol mono- and dilaurate (Lauroglycol®), sucrose fatty acid esters, e g. sucrose monostearate, sucrose distearate, sucrose monolaurate or sucrose dilaurate, sorbitan fatty acid mono- and diesters such as sorbitan mono laurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), or sorbitan stearate, polyoxyethylene castor oii dehvates, e g. poiyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oii (Cremophor® EL; BASF Corp ) or polyoxyethyieneglycerol oxystearate such as polyethytenglycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyieneglycol such as Pluronic® F68, Pluronic® F127, Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp.); or mono fatty acid esters of polyoxyethylene (20) sorbitan, e.g. polyoxyethyiene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopaimitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20), and the like as well as mixtures of two, three, four, five, or more thereof

Various other additives may be included in the melt, for example flow regulators such as colloidal silica, lubricants, fillers, disintegrants, plasticizers, stabilizers such as antioxidants, light stabilizers, radical scavengers or stabilizers against microbial attack Further, since the acetaminophen- containing overcoat layer has a bitter taste derived from acetaminophen itself, sweeteners and/or flavors etc. may be used as additives to reduce this bitter taste One preferred way to reduce the bitter taste is a thin additional non- acetaminophen-containing overcoat

The formulations of the invention can be obtained through any suitable melt process such as by the use of a heated press, and are preferably prepared by melt extrusion In order to obtain a homogeneous distribution and a sufficient degree of dispersion of the drug, the drug-containing melt can be kept in the heated barrel of a melt extruder during a sufficient residence time Melting occurs at the transition into a liquid or rubbery state in which it is possible for one component to be homogeneously embedded in the other Melting usually involves heating above the softening point of meltable excipients of the formulation, e g. a cellulose ether/ester, sugar alcohol and/or (meth)acrylic polymer The preparation of the melt can take place in a variety of ways

Usually, the melt temperature is in the range of 70 to 250 ^DC, preferably 80 to 180 ⁰C, most preferably 100 to 140 ⁰C

When the melt process comprises melt extrusion, the melting and/or mixing can take place in an apparatus customarily used for this purpose Particularly suitable are extruders or kneaders Suitable extruders include single screw extruders, intermeshing screw extruders, and multiscrew extruders, preferably twin screw extruders, which can be co-rotating or counterrotating and are optionally equipped with kneading disks It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used Part of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements. However, the friction and shearing of the material in the extruder may also provide the mixture with a substantial amount of energy and aid in the formation of a homogeneous melt of the components

Further, following examples are provided to illustrate the preferred embodiments of the present invention, and should not be deemed to limit its scope

Examples of Preferred Embodiments

Materials Ethanol of analysis (99.9% v/v) was standard reagent grade (Baker, Germany) . Sodium chloride (Merck, Germany), hydrochloric acid (Baker, Germany), and potassium phosphate (Fluka, Switzerland) were all used as received. Dionised water was received from the in house water system ionic exchanger.

Drug Formulations

Verapamil formulations lsoptin SR-E 240 mg (Meltrex®, Form A) (Abbott Laboratories, EU), sustained release (SR) lsoptin SR 240 mg (Form B) (Abbott Laboratories, EU), Verahexal™ SR 240 mg (Form C) (Hexal Pharma Ltd, Germany), and Verapamil retard-Ratiopharm® 240 mg (Form D) (Ratiopharm, Germany) were used as received. Form A (melt extruded) contained verapamil hydrochloride in a hydroxypropylceliulose and hypromellose matrix. Form B (sustained release), C (sustained release) and D (sustained release) contained verapamil hydroch oride in a natrium-alginate matrix (as a retarding agent). Dissolution Testing

Dissolution testing for Form A (melt extruded) and Form B was performed using a buffer addition method, according to the United States Pharmacopeia (USP) standards, For consistency, the same method and conditions were used for formulation C and D in this study HCI Buffer Addition Method

Drug release was monitored using a (Dissolution Apparatus as per Ph EUR, USP) (Paddle) with a rotation speed of 100 rpm in 900 mL of medium at 37.0 ±0 5⁰C Media comprised of a potassium phosphate buffer, adjusted with hydrochloric acid (0 08N) with 0, 5, 20 or 40 % (v/v) ethanol (pH 6.4-7 2) For each medium, six tablets were tested and drug release was monitored spectrophotometrically at 250-300 nm The exception to this was Form C, which was tested using four tablets in the 0% ethanol medium only. Sampling was generally conducted at 60, 120, 240, and 480 minutes and at 600 minutes for Form B, according to the valid product specification, and Forms C-D. Additional samples were collected at 300 minutes for Form A (40% ethanol), Form A (0% and 20% ethanol in place of 240 minutes), Form B (40% ethanol), and Forms C and D (0% ethano!) For Forms C and D (0% ethano! only) additional samples were collected at 30, 90, 180, and 360 minutes. Drug Solubility

The drug release of the test formulations in different hydro-ethanolic dissolution media were determined spectrophotometrically (Fa Agiient, Type 8453, Agilent Technologies Inc., Santa Clara, CA₁ USA) using UV detection at a wavelength between 250-300 nm at room temperature, A reference standard containing verapamil (Chemical Reference Substance of Ph, EUR) was used. Data Analysis

Dissolution was calculated as a percentage (%) based on the amount of drug (mg) measured per volume, accounting for changes in volume during testing over time. The dissolution profiles (Figures 1-4) were illustrated using the mean dissolution percentage and standard deviation, as derived from the raw scores from 6 trials (4 trials for Form C at 0% ethanol), over time (hours). Comparative statistics for each formulation were calculated using the t-test (assuming a two-tailed distribution and 2 sample equal variance), from the weighted means (dissolution percentage over all time points not including 0) calculated for each trial per dissolution medium. The dissolution profiles of verapamil release from Form A (melt extruded formulation), tested in 5% and 40% ethanol medium over 8 hours did not significantly differ from the 0% alcohol condition (P>0,05) (Figure 1) The dissolution profile under 20% ethanol was significantly lower compared to the 0% ethanol condition (P=O 02) This difference was most prominent at 8 hours, where the mean dissolution percentage (%) was lower in the 20% ethanoi condition (64%) relative to the 0% ethanol condition (77%). For both extreme conditions of 0% and 40% ethanol, the mean dissolution percentage was identical at 1 hour (19%) and at 8 hours was only slightly higher in the 40% ethanol medium (81 %) compared to the 0% ethanol medium (77%). Release profiles under all conditions were characterised by an initial rapid release rate which progressively decreased over time, suggesting a sustained release mechanism with a near zero-order release

Form B, a sustained release compound, showed significant alterations in dissolution profiles at higher ethanol concentrations (20 and 40%) compared to the no ethanol condition (0%) (p<0 001), conducted over 10 hours (Figure 2). At !ow/no ethanoi concentrations (0 and 5%), a near zero- order release was observed and no statistically significant differences were observed between the two conditions (p=0.5) At higher ethanol concentrations (20 and 40%), an initial rapid release was seen within the first hour This effect was dependent on ethano! concentration and a higher mean dissolution percentage (%) was reached in the 40% ethanol medium (94%) compared to 20% ethanot medium (57%), both of which were significantly higher compared to the 0% ethanol condition (17%) (P<0 001). For the 20% ethanol medium, a continued release was observed over time and a plateau was reached at approximately 8 hours (mean dissolution 101%). This plateau was reached sooner for the 40% ethanol concentration, at approximately 2 hours (107% dissolution). At 2 hours, a mean dissolution of 73% and 107% was observed for ethanol concentrations of 20 and 40%, respectively, compared to a mean dissolution of 26% observed with 0% ethanol, demonstrating a 3-4 fold increase in dissolution at higher alcohol concentrations

Similar to Form B, the same alterations in the dissolution profiles at higher ethanol concentrations (20 and 40%) were observed for the two sustained release formulations, Forms C and D. Form C showed significant increases in the dissolution profiles at higher ethanol concentrations (20 and 40%) compared to the no ethanol condition (0%) (p<0 0001), conducted over 10 hours (Figure 3). At higher ethanol concentrations (20 and 40%), an initial rapid release was seen within the first hour, where the mean dissolution percentage at 1 hour was higher in the 20% ethanol medium ( 102%) compared to the 40% ethanol medium (64%) The higher ethanol conditions, however, were both significantly higher at 1 hour compared to the 0% ethanol condition (15%) (P<0.00001) For the 20% ethanol medium, a plateau in drug release was reached at approximately 1 hour (mean dissolution 102%) This plateau was slightly later for the 40% ethanol concentration, at 2 hours (mean dissolution 106%) At the lower ethanol concentration (5%), the dissolution profile for up to 4 hours was nearly identical to that observed for 0% ethanol (P=O 4 at 1 hour) Between 4 and 10 hours, the dissolution profile was lower for the 5% ethano! condition, resulting in an overall significantly lower dissolution relative to 0% ethanoi (P<0,001 ) The differences between both conditions was most prominent at 8 hours, showing a mean dissolution percentage difference (%) of 10% between the 5% ethanoi condition (76%) compared to 0% ethanoi condition (76%) (P<0 001 ) Mean dissolution percentages for the 0% and 5% ethanoi conditions reached close to 100% dissolution at 10 hours, showing 97% and 92% mean dissolution, respectively

Similar to the trends observed for both Forms B and C, Form D showed significant increases in the dissolution profiles at higher ethanoi concentrations (20 and 40%) compared to the no ethanoi condition (0%) (p<0.00001), conducted over 10 hours (Figure 4) At low/no ethanoi concentrations (0 and 5%), a near zero-order release was observed and no statistically significant differences were observed between the two conditions (p=0 5) At higher ethanoi concentrations (20 and 40%), an initial rapid release was seen within the first hour. This effect was dependent on ethanoi concentration and a higher mean dissolution percentage (%) was reached in the 40% ethanoi medium (101 %) compared to 20% ethanoi medium (93%), both of which were significantly higher compared to the 0% ethanoi condition (12%) (P<0 0001 ) For the 20% ethanoi medium, rapid release was observed for the first two hours, reaching a plateau at 2 hours (mean dissolution 98%), which was significantly higher than the 0% ethanoi condition (12%) (P<0,00001), This plateau was reached sooner for the 40% ethanoi concentration, following a rapid release, at approximately 1 hour (101 % mean dissolution), which was significantly higher compared to the 0% ethanoi condition at 1 hour (23%) (PO.00001). At the final time point of 10 hours, full dissolution (100%) was not observed for either the 0% or 5 % ethanoi conditions, which showed a mean dissolution percentage of 65% and 69%, respectively

The results from this in vitro dissolution study indicate that a innovative melt extrusion formulation containing verapamil can withstand the solubilizing effects of ethanoi, when intact and contained in mediums of 5% ethanoi (equivalent to the concentrations found in most beers, wine coolers), 20% ethanoi (equivalent to the concentrations found in a strong mixed drink, and slightly higher than those found in most wines ( 10-15%) and 40% ethanoi (equivalent to the concentrations found in most undiluted spirits, i.e. vodka, gin) In contrast, three other marketed sustained release formulations showed a significantly rapid increase in verapamil release, particularly with higher ethanol concentrations (20 and 40 % ethanol).. At the highest ethanol concentration (40%), the marketed sustained release comparators showed a steep drug release within the first 1-2 hours, followed by a plateau in dissolution percentage (reaching 100% dissolution), suggesting that the entire dose had been dumped into the dissolution medium Such "dose dumping" was also observed at the 20% ethanol concentration within 2 hours, although this occurred later for Form B, at approximately 8 hours. Dose dumping was not observed for Form A (melt extruded) . The dissolution profiles for Form A, with 5, and 40% ethanol were not significantly different than the 0% ethanol condition. The dissolution profile for 20% was even significantly lower than the 0% condition, the reason for this is unknown. The dissolution profiles for Form A were of a near zero order and did not show an initial spike in release, regardless of condition, as compared to the other marketed formulations under higher ethanol concentrations At 2 hours, approximately 30% dissolution had occurred for Form A (all mediums) Full dissolution had not occurred at 8 hours, with a mean dissolution percentage range between 64% (20% ethanol medium) to 81% (40% ethanol medium).

Given the widespread use and accessibility of ethanol, interactions between alcohol and prescription drugs are of great concern. Interactions may occur in various scenarios, which may be range from a patient taking medications and consuming an alcoholic beverage to intentional tampering with a formulation to extract a drug from a controlled release formulation, or to enhance the pharmacodynamic effects of both drug and alcohol, as is often seen with drug abusers. Other such scenarios may include dissolving and masking a drug in alcohol for condemnable intentions such as 'date rape', as in the case of gammahydroxybutyrate (GBH) or fiunitrazepam (Rohypnol™), the drugs effects of which are further potentiated by alcohol (Schwartz et al., 2001 ). The robustness of controlled release formulations, particularly because they contain higher drug levels and may pose safety concerns, is an integral feature Hence an abuse deterrent formulation which is not readily soluble in solvents such as ethanol, such as Form A (melt extruded), may have distinct advantages over other sustained release formulations that are susceptible to "dose dumping" (McCoII and Sellers, 2006)

The dissolution methods in this study were not conducted under conditions of a low pH for the entire dissolution testing period Rather dissolution testing was started with a pH of 1 1-1 2 for 2 hours, followed by an increase in pH to approximately 6 8 it should be noted that once ingested, the combination of ethanol in the low pH of the gastric environment (pH 2 0) for extended periods, may demonstrate an altered dissolution profile. Future studies may address this by examining intact and crushed melt extruded tablets in an acidified medium or simulated gastric juice medium, containing ethanol 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 may be mediated by pharmacokinetic, pharmacodynamic, genetic and immune factors (Lynch and Price, 21007,

Masubichi and Horie, 2007, Vourvahis and Kashuba, 2007) For example, the product monograph for verapamil warns that the co-administration with ethanol may result in increased blood alcohol levels and therefore enhanced impairment, an interaction of a pharmacokinetic nature (Covera-HS Product Monograph, 2006) Determining the integrity of the formulation in an in vivo, clinical trial may also be beneficial in elucidating the potential for a clinically important drug-alcohol interaction

This in vitro dissolution experiments has demonstrated that a innovative formulation of verapamil using melt extrusion technology does not have its release profile altered when tested intact with ethanol concentrations of up to 40% In contrast, three other marketed sustained release verapamil formulations showed dose dumping effects at higher ethanol concentrations (20 and 40%), reaching approximately 100% dissolution within the first two hours of testing This invention suggests that this innovative melt extruded formulation may be resistant to dose dumping in an in vitro environment, when combined intact with concentrations of ethanol that are readily accessible. Similarly, this formulation is expected to have limited drug-alcohol interaction in an in vivo environment The foregoing detailed description and accompanying examples are merely illustrative and not intended as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and are part of the present invention. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, can be made without departing from the spirit and scope thereof

References

Breitenbach J , 2002. Melt extrusion, from process to drug delivery technology Eur J Pharmaceutics Biopharmaceutics 54.107-117,

Breitenbach J., Lewis J. 2003 Two concepts, one technology: controlled- release and solid dispersions with Meltrex. In: Modified-Release Drug Delivery Technology, Editor. Marcel Dekker, lnc , pp.125-134.

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

McCoIl 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 lnc 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-Palladone™ interaction.

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

World Health Organization Global Status Report on Alcohol 2004

Claims

CLAIMS 03/04/2009

1. 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.

2. The melt-extruded dosage form of claim 1 , wherein the monomer is hydroxyalkylcellulose, hydroxyalkyl alkylcellulose and natrium-alginate.

3. The melt-extruded dosage form of claim 1 , wherein the drug is a salt or an ester of verapamil, gammahydroxybutyrate 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 hydroxyalkyl alkylcellulose is hydroxypropylmethylcellulose.

6. The melt-extruded dosage form of claim 1 , wherein the drug is a salt or an ester of verapamil.

7. The melt-extruded dosage form of claim 1 , wherein the drug comprises 1 mg to IOOOmg of a salt or an ester of verapamil.

8. A verapamil melt extruded formulation having 1 to 1000 mg of verapamil, wherein less that 40% of the verapamil in the dosage form is dissolved in 40% ethanol solution using USP dissolution method.

9. The verapamil melt-extruded formulation of claim 8, wherein the dissolution profile for verapamil from the dosage form in 5% or 40% ethanol at eight hours does not differ

RECTIFIED SHEET (RULE gI) ISA/EP from the dissolution profile for verapamil from the dosage form in 0% ethanol at eight hours.

10. The melt-extruded dosage form of any one of the claims 1-9, wherein the drug comprises 240 mg of a salt or an ester of verapamil.

11. The melt-extruded dosage form of any one of the claims 1-10, wherein the reduced in vitro drug alcohol interaction correlates to reduced in vivo drug alcohol interaction.

12. A method for treating a human patient in need thereof, comprising orally administering to the human patient the dosage form of any one of the claims 1-11.

RECTIFIED SHEET (RULE 91) ISA/EP