ABUSE RESISTANT DRUGS, METHOD OF USE AND METHOD OF MAKING

• US 20120164209A1
• Filed: 02/29/2012
• Published: 06/28/2012
• Est. Priority Date: 08/13/2007
• Status: Active Grant

• Current Assignee: Ohemo Life Sciences Inc.
• Original Assignee: Inspirion Delivery Technologies, LLC
• Inventors: Shah, Manish S., Difalco, Ray
• Granted Patent: US 10,736,852 B2
• Time in Patent Office: Days
• US Class Current: 424/440
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 : containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/28 : Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2846 : Poly(meth)acrylates
• CPC Class Codes: A61K 9/2886 : having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/4808 : characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 : Organic compounds
• CPC Class Codes: A61K 9/4866 : Organic macromolecular compounds
• CPC Class Codes: A61K 9/4891 : Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/5026 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5042 : Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 : Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 : with drug-free core
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/26 : Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: Y10T 156/10 : Methods of surface bonding and/or assembly therefor

Abstract

An abuse resistant oral pharmaceutical composition, comprising: a barrier layer, comprising a first polymer; a diffusion layer, comprising a second polymer, substantially covering the barrier layer, wherein the diffusion layer is bonded to the barrier layer and comprises a drug that is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the gastrointestinal (GI) tract; and optionally an expansion layer comprising an expandable polymer, wherein the expansion layer is substantially covered by the barrier layer. Methods of making the same and methods of using the same are also provided.

Claims

1. An oral pharmaceutical composition, comprising:

a barrier layer, comprising a first polymer;

a diffusion layer, comprising a second polymer, substantially covering the barrier layer, wherein the diffusion layer is bonded to the barrier layer and comprises a drug, wherein the drug is substantially homogeneously distributed within the second polymer and diffuses from the diffusion layer within the gastrointestinal (GI) tract; and

an expansion layer comprising an expandable polymer, wherein the barrier layer substantially covers the expansion layer;

wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is physically compromised and particles of the pharmaceutical composition comprising the diffusion layer and the barrier layer are formed, the bond between the diffusion layer and barrier layer within the particles is substantially preserved.

2. The oral pharmaceutical composition of claim 1, wherein the first polymer and second polymer, independent from each other, are selected from the group consisting of acrylic polymers and acrylic copolymers.

3. The oral pharmaceutical composition of claim 2, wherein the acrylic polymers and acrylic copolymers are selected from the group consisting of:

quarternary ammonium acrylic polymers, methacrylic polymers, ethyl acrylic polymers, methyl methyacrylic polymers, and copolymers thereof.

4. The oral pharmaceutical composition of claim 1, wherein the first polymer and second polymer comprise different polymers.

5. The oral pharmaceutical composition of claim 1, wherein the first polymer and second polymer comprise the same polymer.

6. The oral pharmaceutical composition of claim 1, wherein the first polymer comprises a copolymer of ethyl acrylate and methyl methacrylate.

7. The oral pharmaceutical composition of claim 1, wherein the second polymer comprises a copolymer of ethyl acrylate and methyl methacrylate.

8. The oral pharmaceutical composition of claim 1, wherein the diffusion layer comprises a pore forming agent.

9. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is physically compromised and particles of the pharmaceutical composition comprising the expansion layer are formed and exposed to a liquid, the expandable polymer of the expansion layer absorbs at least a portion of the liquid.

10. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in an intact form, the first polymer of the barrier layer is substantially undissolved in the GI tract.

11. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the Cmax and/or AUC achieved after a time period selected from the group consisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48 hours after administration is substantially the same or lower than the Cmax and/or AUC achieved when the pharmaceutical composition is administered in an intact form.

12. The oral pharmaceutical composition of claim 11, wherein the pharmaceutical composition is configured such that the Cmax and/or AUC achieved after a time period selected from the group consisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48 hours after administration, is 20-75% lower than the Cmax and/or AUC achieved when the pharmaceutical composition is administered to a subject in an intact form.

13. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises an additional release layer, wherein the additional release layer is an immediate release layer substantially covering the diffusion layer, wherein the additional release layer comprises at least one additional drug.

14. The oral pharmaceutical composition of claim 13, wherein the at least one additional drug in the additional release layer is selected from the group consisting of acetaminophen and nonsteroidal anti-inflammatory drugs.

15. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the Cmax/AUC achieved after administration is lower than the Cmax/AUC achieved after a time period selected from the group consisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48 hours after administration, of a physically compromised bioequivalent composition not comprising means for deterring abuse.

16. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the Cmax and/or AUC achieved after administration is lower than the Cmax and/or AUC achieved after a time period selected from the group consisting of 2 hours, 4, hours, 8 hours, 12 hours, 24 hours, and 48 hours after administration, of a bioequivalent composition not comprising means for deterring abuse.

17. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition in configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the rate of drug released from the composition within a time period selected from the group consisting of 2 hours, 4 hours, 8 hours, and 16 hours, is substantially the same or lower than the rate of drug released when the pharmaceutical composition is administered in an intact form.

18. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition in configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the amount of drug released from the composition within a time period selected from the group consisting of 2 hours, 4 hours, 8 hours, and 16 hours, is substantially the same or lower than the amount of drug released when the pharmaceutical composition is administered in an intact form.

19. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the amount of drug released from the composition within a time period selected from the group consisting of 2 hours, 4 hours, 8 hours, and 16 hours, is no more than 75% of the amount of drug released when the pharmaceutical composition is administered in an intact form.

20. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition in configured such that when the pharmaceutical composition is contacted with an alcohol or consumed with an alcohol, the rate of drug released from the composition within a time period selected from the group consisting of 2 hours, 4 hours, 8 hours, and 16 hours, is substantially the same or lower than the rate of drug released when the pharmaceutical composition is administered without an alcohol.

21. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in an intact form at least 50% of the amount of drug is released after 8 hours and when the pharmaceutical composition is administered in physically compromised form no more than 40% of the amount of drug is released after 1 hour.

22. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in an intact form at least 90% of the amount of drug is released after 1 hour and when the pharmaceutical composition is administered in physically compromised form no more than 75% of the amount of drug is released after 1 hour.

23. The oral pharmaceutical composition of claim 21, wherein when the pharmaceutical composition is administered in physically compromised form no more than 35% of the amount of drug is released after 15 minutes.

24. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in a pharmaceutical dosage form selected from the group consisting of a tablet, a capsule, a micro tablet, granules, pellets, a lozenge, a lollipop, and a coated capsule.

25. The oral pharmaceutical composition of claim 24, wherein the pharmaceutical dosage form is a tablet.

26. The oral pharmaceutical composition of claim 1, wherein the drug is selected from the group consisting of central nervous system stimulants and central nervous system depressants.

27. The oral pharmaceutical composition of claim 1, wherein the drug is selected from the group consisting of opioids, barbiturates, benzodiazepines, and amphetamines.

28. The oral pharmaceutical composition of claim 1, wherein the drug is an opioid selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts thereof.

29. The oral pharmaceutical composition of claim 28, wherein the opioid is selected from the group consisting of:

oxycodone or a pharmaceutically acceptable salt thereof, which is present in an amount of about 5 mg to about 400 mg;

morphine or a pharmaceutically acceptable salt thereof, which is present in an amount of about 15 mg to about 800 mg;

hydromorphone or a pharmaceutically acceptable salt thereof, which is present in an amount of about 1 mg to about 64 mg;

hydrocodone or a pharmaceutically acceptable salt thereof, which is present in an amount of about 5 mg to about 400 mg; and

oxymorphone or a pharmaceutically acceptable salt thereof, which is present in an amount of about 4 mg to about 80 mg.

30. The oral pharmaceutical composition of claim 1, wherein the pharmaceutical composition is configured such that when the pharmaceutical composition is administered in physically compromised form to a subject, the intensity of the euphoria is substantially the same or lower than the intensity of the euphoria achieved after administration of a physically compromised bioequivalent composition not comprising means for deterring abuse.

31. The oral pharmaceutical composition of claim 1, wherein the expansion layer comprises a polymer present in the range of 5 to 90% by weight based on the total weight of the dosage form.

32. The oral pharmaceutical composition of claim 1, wherein the second polymer of the diffusion layer provides a timed release of drug over a period of about 6 to about 24 hours.

33. A method of making the oral pharmaceutical composition of claim 1 comprising:

forming the expansion layer;

applying the barrier layer over the expansion layer to substantially cover the expansion layer;

applying the diffusion layer over the barrier layer to substantially cover the barrier layer; and

bonding the diffusion layer to the barrier layer.

34. The method of claim 33, comprising applying the barrier layer onto the expansion layer by spraying.

35. The method of claim 33, comprising applying the diffusion layer over the barrier layer immediately after forming the barrier layer.

36. The method of claim 33, comprising curing the barrier layer and the diffusion layer together after applying the diffusion layer over the barrier layer.

37. The method of claim 33, comprising the step of curing the diffusion layer after applying the diffusion layer over the barrier layer.