Tamper Resistant Dosage Form Composition And Process Of Making The Same

Abstract

A tamper-resistant dosage form including a therapeutic agent-substrate complex embedded in a thermo-formable matrix; such that the complex includes at least one therapeutic agent bound to at least one substrate to form the therapeutic agent-substrate complex. The at least one substrate is being selected from the group consisting of a polyelectrolyte, an organic counter-ion, a pharmacologically inert organic component of a prodrug, an inclusion compound and an inorganic adsorbent; and the thermo-formable matrix includes one or more thermoplastic polymers and optionally at least one pharmaceutical additive.

What is claimed is: 
     
         1 . A tamper resistant dosage form composition, comprising: a therapeutic agent-substrate complex prepared by an extrusion process. 
     
     
         2 . The dosage form of  claim 1 , wherein the weight ratio of the therapeutic agent to substrate of the therapeutic agent-substrate complex is from between 1:20 and 20:1. 
     
     
         3 . A tamper resistant dosage form composition, comprising a therapeutic agent-substrate complex; said therapeutic agent-substrate complex is embedded in an erodible thermo-formable matrix prepared by a granulation process. 
     
     
         4 . The dosage form of  claim 3 , wherein the weight ratio of the therapeutic agent-substrate complex to the erodible thermo-formable matrix is from between 1:10 to 10:1. 
     
     
         5 . The dosage form of  claim 3 , wherein the therapeutic agent-substrate and a free substrate is embedded in the erodible thermo-formable by the granulation process. 
     
     
         6 . The tamper resistant dosage form composition, comprising an erodible thermo-formable matrix comprising at least one cellulosic thermoplastic polymer and optionally at least one non-cellulosic thermoplastic polymer and at least one pharmaceutical additive. 
     
     
         7 . The tamper resistant dosage form of  claim 6 , wherein the amount of the pharmaceutical additives in the thermo-formable matrix is less than 20% by weight. 
     
     
         8 . The tamper resistant dosage form composition, comprising: monolithic tablets and multiparticulates comprising a therapeutic agent-substrate complex embedded in an erodible thermo-formable matrix, wherein the dosage form is resistant to tampering through a synchronized barrier mechanism. 
     
     
         9 . The tamper resistant dosage form composition, comprising: monolithic tablets and multiparticulates comprising a therapeutic agent-substrate complex embedded in an erodible thermo-formable matrix, wherein the release mechanism eliminates or reduces the effect of intentional or unintentional dosing of multiple tablets. 
     
     
         10 . The tamper resistant dosage form composition, comprising: monolithic tablets and multiparticulates comprising a therapeutic agent-substrate embedded in an erodible thermo-formable matrix, wherein said dosage forms comprise drug independent template formulations. 
     
     
         11 . The tamper resistant dosage form composition, comprising: monolithic tablets and multiparticulates comprising a therapeutic agent-substrate complex embedded in an erodible thermo-formable matrix wherein the formulations impart physical and chemical stability on to dosage form. 
     
     
         12 . The tamper resistant dosage form composition, comprising: monolithic tablets and multiparticulates comprising a therapeutic agent-substrate complex embedded in an erodible thermo-formable matrix wherein the release profiles extend from one hour to 24 hours. 
     
     
         13 . The dosage form in  claim 1  wherein the extrusion process comprises a reactive extrusion process wherein the therapeutic agent and the substrate interact to form the complex. 
     
     
         14 . The dosage form in  claim 13  wherein the substrate has an average particle size distribution is from 5 u up to 250 u. 
     
     
         15 . The dosage form in  claim 3  wherein the granulation process comprises melt granulation, wet granulation and dry granulation. 
     
     
         16 . The dosage form in  claim 6  wherein the cellulosic thermoplastic polymer comprises hydroxylpropyl cellulose, hydroxylpropyl methylcellulose, hydroxyethyl cellulose, and methylcellulose. 
     
     
         17 . The dosage form in  claim 6  wherein the non-cellulosic thermoplastic polymer comprises polyvinyl pyrrolidone, polyvinyl acetate polyvinyl alcohol, butyl/methyl methacrylate-dimethylaminoethylmethacrylate copolymer, polyethylene glycol, polyethylene oxide, polypropylene glycol and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. 
     
     
         18 . The dosage form in  claim 6  wherein the at least one pharmaceutical additives are selected from the group consisting of a plasticizer, a wax, a surfactant, inorganic filler, an anti-adherent, an erosion enhancer, a stabilizer, and mixtures thereof. 
     
     
         19 . The dosage form in  claim 1  further comprising a synchronized barrier mechanism comprising physical, mechanical and chemical components. 
     
     
         20 . The dosage form in  claim 20  wherein the synchronized barrier provides resistance to chewing, crushing, milling, extraction or vaporization. 
     
     
         21 . The dosage form in  claim 19  wherein the synchronized barrier prevents drug abuse by swallowing, snorting, injection or smoking. 
     
     
         22 . The dosage form in  claim 1  wherein a release mechanism reduces or eliminates the undesirable effects of swallowing multiple dosage forms in a manner not intended by the dosing instructions. 
     
     
         23 . The dosage form in  claim 1  wherein a drug independent template formulations comprise formulations that permit substitution of one therapeutic agent for another without altering dissolution profiles and tampering properties. 
     
     
         24 . The dosage form in  claim 3 , wherein physical and chemical stability of the therapeutic agent and physical stability of the matrix is achieved by a combination of the therapeutic agent-substrate complex and the rigid, erodible thermo-formable matrix. 
     
     
         25 . The dosage form in  claim 1 , wherein the tablets release the therapeutic agent in 4 to 24 hours. 
     
     
         26 . The dosage form in  claim 1 , wherein the multiparticulates release the therapeutic agent in 1 to 24 hours. 
     
     
         27 . The dosage form in  claim 1  wherein the therapeutic agent is selected from the group consisting of morphine, hydromorphone, oxymorphone, codeine, hydrocodone oxycodone, pentazocine, naloxone, noltrexone, alprazolam, zopiclone, amphetamine, methylphenidate, dextromethorphan, ephedrine, pseudoephedrine, chlorpheniramine, propranolol, verapamil, clonidine, albuterol and acceptable salts thereof. 
     
     
         28 . The dosage form in  claim 1  wherein the substrate is selected from the group consisting of a polyelectrolyte, a fatty acid, an inorganic adsorbent and an inclusion compound. 
     
     
         29 . The dosage form in  claim 1  wherein reactive extrusion is carried out in a twin screw extruder under controlled conditions of temperature, pressure and pH. 
     
     
         30 . The dosage form in  claim 3 , wherein the melt granulation is carried out in a twin screw extruder at processing temperatures below 150° C. 
     
     
         31 . The dosage form in  claim 28  wherein the polyelectrolyte is selected from the group consisting of nucleic acids, poly (L-lysine), poly (L-glutamic acid), carrageenan, alginates, hyaluronic acid, pectin, chitosan (deacetylation of chitin), cellulose-based, starch-based, dextran-based polymers, poly (vinylbenzyl trialkyl ammonium), poly (4-vinyl-N-alkyl-pyridimiun), poly (acryloyl-oxyalkyl-trialkyl ammonium), poly (acryamidoalkyl-trialkyl ammonium), poly (diallydimethyl-ammonium), poly (acrylic or methacrylic acid), and poly (itaconic acid) and maleic acid/diallyamine copolymer, carbopols, crosscarmellose, and ion exchange resin. 
     
     
         32 . The dosage form in  claim 30  wherein the ion exchange resin is selected from the group consisting of a sulfonated copolymer of styrene and divinylbenzene, a carboxylate copolymer of styrene and divinylbenzene, a copolymer of styrene and divinylbenzene containing quaternary ammonium groups. 
     
     
         33 . The dosage form in  claim 28  wherein the fatty acid is selected from the group consisting of arachidonic acid, capric acid, caprylic acid, dihomo-γ-linoleic acid, docesenoic acid, docosatetraenoic acid, docosohexaconic acid, docosopentanoic acid, eicosapentanoic acid, gondoic acid, lauric acid, linoleic acid, α-linoleic acid, 6-linoleic acid, myristic acid, nervonic acid, oleic acid, oleostearic acid, palmitic acid, palmitoleic acid, stearic acid, vaccenic acid and mixtures thereof. 
     
     
         34 . The dosage form in  claim 28  wherein the inorganic adsorbent is selected from the group consisting of silicon dioxide, aluminum silicate, attapulgite, bentonite, calcium silicate, kaolin, lithium magnesium aluminum silicate, lithium magnesium silicate, lithium magnesium sodium silicate, magnesium silicate, magnesium trisilicate, montmorillonite, pyrophyllite, sodium magnesium silicate, zeolite, and zirconium silicate and mixtures thereof. 
     
     
         35 . The dosage form in  claim 28  wherein the inclusion compound is selected from the group consisting of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. 
     
     
         36 . The dosage form in  claim 18 , wherein the plasticizer is selected from the group consisting of dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol, triacetin, tributyl citrate, and triethyl citrate and mixtures thereof. 
     
     
         37 . The dosage form in  claim 18 , wherein the wax is selected from the group consisting of bee's wax, candilila wax, carnuba wax, and paraffin wax and mixtures thereof. 
     
     
         38 . The dosage form in  claim 18 , wherein the surfactant is selected from the group consisting of alkyl benzene sulfones, alkyl sulfates, ether carboxylates, glycerol/propylene glycol fatty acid esters, hexadecyl triammonium bromide, hydroxylated lecithin, lauryl carnitine, lower alcohol-fatty acid esters, mono-/di-glycerides, Ovothin®, polyethylene glycol alkyl ethers, polyethylene glycol-fatty acid monoesters, polyethylene glycol-glycerol esters, polyethylene glycol phenols, polyethylene glycol-sorbitan fatty acid esters, polyglyceride fatty acids, polyoxyethylene-polyoxypropylene block copolymers, propylene glycol-fatty acid esters, sodium cholate, sodium lauryl sulfate, sodium palmitate, sodium taurocholate, sorbitan-fatty acid esters, sterol and sterol derivatives, sugar esters, and mixtures thereof. 
     
     
         39 . The dosage form in  claim 18 , wherein the inorganic fillers is selected from the group consisting of aluminum silicate, attapulgite, bentonite, calcium silicate, kaolin, lithium magnesium aluminum silicate, lithium magnesium silicate, lithium magnesium sodium silicate, magnesium silicate, magnesium trisilicate, montmorillonite, pyrophyllite, sodium magnesium silicate, zeolite, and zirconium silicate and mixtures thereof. 
     
     
         40 . The dosage form in  claim 18 , wherein the anti-adherent is selected from the group consisting of calcium carbonate, dicalcium phosphate, kaolin, talc, and titanium dioxide, and mixtures thereof. 
     
     
         41 . The dosage form in  claim 18 , wherein the erosion enhancer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene oxide, polyvinyl pyrollidone, mannitol, malitol, sorbitol, xylitol, lactose, sodium lauryl sulfate, Polysorbate 80, and chremophor and mixtures thereof. 
     
     
         42 . The dosage form in  claim 18 , wherein the stabilizer is selected from the group consisting of butylhydroxytoulene, butylhydroxyanisole, propyl gallate, ascorbic acid, vitamin E-TPGS, phosphates, citrates, acetates, oxides, carbonates and mixtures thereof. 
     
     
         43 . A process for making a tamper resistant dosage form; the process comprising:
 (1) blending at least one therapeutic agent and at least one substrate in a therapeutic agent-to-substrate ratio between 1:20 to 20:1 by weight;   (2) reacting the at least one therapeutic agent and the at least one substrate to form a therapeutic agent-substrate complex;   (3) forming a thermo-formable matrix blend with at least one thermoplastic polymer and optionally at least one pharmaceutical additive;   (4) mixing the therapeutic agent-substrate complex and the thermo-formable matrix blend in a ratio between 1:10 to 10:1 by weight;   (5) granulating the therapeutic agent-substrate complex and the thermo-formable matrix blend to form the tamper-resistant dosage form in which the therapeutic agent-substrate complex is embedded in the thermo-formable matrix; and   (6) shaping the tamper-resistant dosage form into a tablet and multiparticulates.