WO2009092818A1 - Formulation extrudée à l’état fondu contre l’abus ayant une interaction réduite avec l’alcool - Google Patents

Formulation extrudée à l’état fondu contre l’abus ayant une interaction réduite avec l’alcool Download PDF

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Publication number
WO2009092818A1
WO2009092818A1 PCT/EP2009/050853 EP2009050853W WO2009092818A1 WO 2009092818 A1 WO2009092818 A1 WO 2009092818A1 EP 2009050853 W EP2009050853 W EP 2009050853W WO 2009092818 A1 WO2009092818 A1 WO 2009092818A1
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WO
WIPO (PCT)
Prior art keywords
drug
melt
verapamil
dosage form
ethanol
Prior art date
Application number
PCT/EP2009/050853
Other languages
English (en)
Inventor
Wolfgang Roth
Alexander Burst
Martina Zietsch
Original Assignee
Abbott Gmbh & Co., Kg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Gmbh & Co., Kg filed Critical Abbott Gmbh & Co., Kg
Priority to CA2713373A priority Critical patent/CA2713373A1/fr
Priority to CN2009801104128A priority patent/CN101977592A/zh
Priority to AU2009207579A priority patent/AU2009207579A1/en
Priority to BRPI0907402-3A priority patent/BRPI0907402A2/pt
Priority to MX2010008100A priority patent/MX2010008100A/es
Priority to EP09704585A priority patent/EP2254553A1/fr
Priority to JP2010543521A priority patent/JP2011510048A/ja
Priority to NZ586962A priority patent/NZ586962A/en
Publication of WO2009092818A1 publication Critical patent/WO2009092818A1/fr
Priority to IL207173A priority patent/IL207173A0/en
Priority to ZA2010/05797A priority patent/ZA201005797B/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil

Definitions

  • 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.
  • 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.
  • Figure 1 Dissolution profiles (mean dissolution % [+SD]) of verapamil release from Form A (melt extruded) over time (hours), with increasing ethanol concentrations.
  • 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
  • the matrix comprises polymers and copolymers of hydroxyalkylceilulose, hydroxyalkyl alkylcellulose and natrium-alginate
  • the drug is a salt or an ester of verapamil, gam
  • 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
  • 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
  • melt extrusion is an innovative process where the drug containing polymer melt is directly shaped.
  • 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, Popebach 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)
  • 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.
  • the matrix comprises polymers and copolymers of hydroxyalkylceilulose, hydroxyalkyl aikylcellulose and natrium-alginate
  • 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
  • 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
  • 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
  • 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. CH 3 (H) CH 3
  • Eudragit polymers fuifil the specifications/requirements set in the USP. According to 2007 US Pharmacopoeia, Eudragit is defined as USP 30 / NF 25.
  • type B NF Eudragit S-I OO Methacrylic acid copolymer
  • 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)
  • EUDRAGIT ⁇ (L) will be resistant to gastric fluid and will release the active agent in the colon.
  • 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)
  • 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)
  • the (meth)acrylate polymer polymers preferred 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
  • inventive abuse-deterrent formulation optionally comprises a melt-processed mixture of at least one abuse-relevant drug, at least one cellulose
  • 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.
  • 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
  • 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.
  • Methods 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!
  • METHOCEL F is 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
  • alkyl (alk)acrylate refers to either the corresponding acrylate or alkacrylate ester, which are usually formed from the corresponding acrylic or alkacrylic acids, respectively
  • alkyl (aik)acrylate refers to either an alkyl alkacrylate or an alkyl acrylate
  • the alkyl (alk)acrylate is a (C 1 -C 22 JaIkVi ((C r)
  • Cio)alk)acrylate examples include methyl, ethyl, n-propyl, n-butyl, iso-butyl, tert-butyl, iso-propyl, pentyl, hexyl, cyclohexyl, 2-ethy!
  • the alkyl group may be straight or branched chain
  • the ⁇ d-C ⁇ alkyl group represents a (Ci-C 6 )aikyl group as defined above, more preferably a (Ci-C 4 )a!kyl group as defined above
  • Examples of C 1 - 10 alk groups of the alkyl (alk)acrylate include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,
  • the alk groups may be straight or branched chain
  • the (CrCio)alk group represents a (CrC ⁇ )alk group as defined above, more preferably a (C r C 4 ) alk group as defined above
  • the alky! (alk)acrylate is a (C r C 4 )alkyl ((CrC 4 ) a!k)acrylate, most preferably a (Ci-C 4 )alkyl (meth)acrylate
  • (CrC 4 )alkyl (meth)acrylate refers to either (CrC 4 )a!ky! acrylate or (Cr C.»)alkyl rnethacrylate.
  • Examples of (Ci-C 4 )a!kyi (meth)acrylate include methyl methacrylat ⁇ (MIvIA), ethyl methacrylate (EMA), n-propyl rnethacrylate (PMA), isopropy!
  • the alkacrylic acid monomer is a (CrCio)a!kacry!ic acid
  • (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.
  • the (CrCio)alkacrylic acid is a (CrC 4 )a!kacrylic acid, most preferably methacrylic acid.
  • the alkyl groups may be substituted by aryl groups..
  • alkyl 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 -CONH 2
  • An “alkylamido” group refers to an -CONHR group wherein R is alky! is as defined above.
  • a “dialkylamido” group refers to an -CONRR 1 group wherein R and R' are aikyl as defined above.
  • a "nitro” group refers to an NO 2 group
  • a "carboxy! group refers to a COOH group
  • the alkyl groups may be substituted by aryl groups
  • 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.
  • aryl group also includes an arylalkyl group
  • arylalkyf refers to moieties, such as benzyl, where
  • the acrylic polymer is an acrylic copolymer
  • the acrylic copolymer comprises monomers derived from alkyl (aik)acrylate, and/or acrylic acid and/or alkacrylic acid as defined hereinbefore
  • the acrylic copolymer comprises monomers derived from alkyl (alk)acrylate, i e copolyrnerisable alkyi acrylate and alkyl alkacrylate monomers as defined hereinbefore.
  • acrylic copolymers include a (Ci-C 4 )alkyl acrylate monomer and a copolymerisable (Ci-C 4 )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
  • 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
  • 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!
  • PVP polyvinylpyrrolidone
  • 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 ⁇ oly(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.
  • strong stimulants methamphetamine is one drug that has recently received popular attention as a drug of abuse
  • methamphetamine is one drug that has recently received popular attention as a drug of abuse
  • methamphetamine is one drug that has recently received popular attention as a drug of abuse
  • methamphetamine is one drug that has recently received popular attention as a drug of abuse
  • methamphetamine is one drug that has recently received popular attention as a drug of abuse
  • atropine hyoscyamine
  • phenobarbital scopolamine
  • Another major class of abuse- relevant drugs are analgesics, especially the opioids
  • 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, lofent
  • 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 ⁇ m 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • flow regulators such as colloidal silica, lubricants, fillers, disintegrants, plasticizers, stabilizers such as antioxidants, light stabilizers, radical scavengers or stabilizers against microbial attack
  • 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
  • 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
  • the melt temperature is in the range of 70 to 250 D C, preferably 80 to 180 0 C, most preferably 100 to 140 0 C
  • the melting and/or mixing can take place in an apparatus customarily used for this purpose
  • extruders or kneaders 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
  • 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.
  • 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
  • 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.
  • 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), VerahexalTM 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).
  • 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 5 0 C
  • 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)
  • Hydraulic acid 0. 08N
  • % (v/v) ethanol pH 6.4-7 2
  • 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.
  • 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, CA 1 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.
  • 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).
  • 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).
  • Form C 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).
  • 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).

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Abstract

La présente invention concerne des compositions pour une administration orale. L’invention comprend de préférence au moins une composition d’administration d’un médicament contre l’abus pour administrer un médicament avec un potentiel de libération massive dans l’alcool, des procédés apparentés de préparation de ces formes de dosage, et des méthodes de traitement d’un patient ayant besoin de celle-ci qui comprend l’administration des compositions de l’invention au patient. Idéalement, la forme de dosage comprend du vérapamil.
PCT/EP2009/050853 2008-01-24 2009-01-26 Formulation extrudée à l’état fondu contre l’abus ayant une interaction réduite avec l’alcool WO2009092818A1 (fr)

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CA2713373A CA2713373A1 (fr) 2008-01-24 2009-01-26 Formulation extrudee a l'etat fondu contre l'abus ayant une interaction reduite avec l'alcool
CN2009801104128A CN101977592A (zh) 2008-01-24 2009-01-26 具有减少的醇相互作用的滥用抗性的熔体挤出制剂
AU2009207579A AU2009207579A1 (en) 2008-01-24 2009-01-26 Abuse resistant melt extruded formulation having reduced alcohol interaction
BRPI0907402-3A BRPI0907402A2 (pt) 2008-01-24 2009-01-26 Formulação extrudada fundida resistente a abuso tendo reduzida interação alcoólica
MX2010008100A MX2010008100A (es) 2008-01-24 2009-01-26 Formulacion extruida por fusion resistente al abuso que tiene interaccion reducida del alcohol.
EP09704585A EP2254553A1 (fr) 2008-01-24 2009-01-26 Formulation extrudée à l'état fondu contre l'abus ayant une interaction réduite avec l'alcool
JP2010543521A JP2011510048A (ja) 2008-01-24 2009-01-26 低減したアルコール相互作用を有する乱用抵抗性溶融押出製剤
NZ586962A NZ586962A (en) 2008-01-24 2009-01-26 Abuse resistant melt extruded formulation having reduced alcohol interaction
IL207173A IL207173A0 (en) 2008-01-24 2010-07-22 Abuse resistant melt extruded formulation having reduced alcohol interaction
ZA2010/05797A ZA201005797B (en) 2008-01-24 2010-08-13 Abuse resistant melt extruded formulation having reduced alcohol interaction

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WO2011068723A1 (fr) * 2009-12-04 2011-06-09 Abbott Laboratories Préparation extrudée par fusion, à pouvoir addictif réduit et ayant une interaction réduite avec l'alcool
US20120164209A1 (en) * 2007-08-13 2012-06-28 Inspirion Delivery Technologiies, Llc Abuse resistant drugs, method of use and method of making
WO2012159142A1 (fr) 2011-05-26 2012-11-29 G.L. PHARMA GmbH Formulation orale retardatrice
US10420726B2 (en) 2013-03-15 2019-09-24 Inspirion Delivery Sciences, Llc Abuse deterrent compositions and methods of use
US10729685B2 (en) 2014-09-15 2020-08-04 Ohemo Life Sciences Inc. Orally administrable compositions and methods of deterring abuse by intranasal administration
US11065224B2 (en) 2016-07-22 2021-07-20 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11400065B2 (en) 2019-03-01 2022-08-02 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

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US10688051B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release oxycodone, method of use, and method of making
US20120164209A1 (en) * 2007-08-13 2012-06-28 Inspirion Delivery Technologiies, Llc Abuse resistant drugs, method of use and method of making
US10688054B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release morphine, method of use and method of making
US10736852B2 (en) * 2007-08-13 2020-08-11 OHEMO Life Sciences, Inc. Abuse resistant oral opioid formulations
US10688052B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release oxymorphone, method of use and method of making
US11045422B2 (en) 2007-08-13 2021-06-29 Oheno Life Sciences, Inc. Abuse resistant drugs, method of use and method of making
US10688053B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences, Llc Abuse resistant forms of extended release hydrocodone, method of use and method of making
US10688055B2 (en) 2007-08-13 2020-06-23 Inspirion Delivery Sciences, Llc Abuse resistant forms of extended release morphine, method of use and method of making
US10736851B2 (en) 2007-08-13 2020-08-11 Ohemo Life Sciences Inc. Abuse resistant forms of extended release morphine with oxycodone, method of use and method of making
US10695298B2 (en) 2007-08-13 2020-06-30 Inspirion Delivery Sciences, Llc Abuse resistant forms of extended release hydromorphone, method of use and method of making
US10702480B2 (en) 2007-08-13 2020-07-07 OHEMO Life Sciences, Inc. Abuse resistant forms of extended release morphine, method of use and method of making
US10729657B2 (en) 2007-08-13 2020-08-04 Ohemo Life Sciences Inc. Abuse resistant forms of extended release morphine, method of use and method of making
US10729656B2 (en) 2007-08-13 2020-08-04 Ohemo Life Sciences Inc. Abuse resistant forms of immediate release oxycodone, method of use and method of making
WO2010083894A1 (fr) * 2009-01-26 2010-07-29 Abbott Gmbh & Co., Kg Formulation extrudée à l'état fondu résistant à l'abus présentant une interaction à l'alcool réduite
WO2011068723A1 (fr) * 2009-12-04 2011-06-09 Abbott Laboratories Préparation extrudée par fusion, à pouvoir addictif réduit et ayant une interaction réduite avec l'alcool
WO2012159142A1 (fr) 2011-05-26 2012-11-29 G.L. PHARMA GmbH Formulation orale retardatrice
US11571390B2 (en) 2013-03-15 2023-02-07 Othemo Life Sciences, Inc. Abuse deterrent compositions and methods of use
US10420726B2 (en) 2013-03-15 2019-09-24 Inspirion Delivery Sciences, Llc Abuse deterrent compositions and methods of use
US10729685B2 (en) 2014-09-15 2020-08-04 Ohemo Life Sciences Inc. Orally administrable compositions and methods of deterring abuse by intranasal administration
US11602513B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11839597B2 (en) 2016-07-22 2023-12-12 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11766418B2 (en) 2016-07-22 2023-09-26 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11826335B2 (en) 2016-07-22 2023-11-28 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11896572B2 (en) 2016-07-22 2024-02-13 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11065224B2 (en) 2016-07-22 2021-07-20 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11400065B2 (en) 2019-03-01 2022-08-02 Flamel Ireland Limited Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics

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KR20100110370A (ko) 2010-10-12
IL207173A0 (en) 2010-12-30
CA2713373A1 (fr) 2009-07-30
MX2010008100A (es) 2010-12-21
TW200950776A (en) 2009-12-16
NZ586962A (en) 2012-07-27
ZA201005797B (en) 2011-04-28
JP2011510048A (ja) 2011-03-31
BRPI0907402A2 (pt) 2015-07-21
AU2009207579A1 (en) 2009-07-30
CN101977592A (zh) 2011-02-16

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