Modified release formulations containing drug-ion exchange resin complexes

• US 8,337,890 B2
• Filed: 03/12/2010
• Issued: 12/25/2012
• Est. Priority Date: 03/16/2006
• Status: Active Grant

• Current Assignee: Tris Pharma Incorporated
• Original Assignee: Tris Pharma Incorporated
• Inventors: Mehta, Ketan, Tu, Yu-Hsing
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): CRAIGO, WILLIAM A
• Application Number:
  US12/722,857
• Publication Number:
  US 20100166858A1
• Time in Patent Office: 1,019 Days
• Field of Search: None
• US Class Current: 424/469
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• 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 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 47/6933 the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/14 : Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1635 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1664 : Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/1617
• CPC Class Codes: A61K 9/167 : with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/2013 : Organic compounds, e.g. phospholipids, fats
• 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 9/2077 : Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 : with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/4866 : Organic macromolecular compounds
• CPC Class Codes: A61K 9/5021 : Organic macromolecular compounds
• 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: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/26 : Psychostimulants, e.g. nicotine, cocaine

Abstract

A coated drug-ion exchange resin complex comprising a core composed of a drug complexed with a pharmaceutically acceptable ion-exchange resin is provided. The drug-ion exchange resin complex is in admixture with a release retardant. The coating is a polyvinyl acetate polymer and a plasticizer. Methods of making and products containing this coated complex are described.

Claims

1. An orally ingestable, modified release, solid composition comprising particulates which provide at least an 8 hour release profile, said composition comprising:

(i) a particulate matrix comprising a particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer, or a hydrophilic polymer, said particulate matrix capable of passing through a number 40 mesh screen,

said drug-ion exchange resin complex comprising a pharmaceutically acceptable drug bound to a pharmaceutically acceptable water insoluble ion exchange resin to form said drug-ion exchange resin complex, said ion exchange resin being irregularly shaped and selected from

(A) a copolymer comprising styrene and divinylbenzene and

(B) a copolymer comprising sytrene and divinylbenzene having quaternary ammonium functional groups,

wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in an amount of about 3% to about 30% by weight, based on the weight of said drug-ion exchange resin complex defined in (i), and

(ii) a cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric diffusion modified release barrier coating over said particulate drug-ion exchange resin complex—

water insoluble polymer or copolymer, or hydrophilic polymer matrix defined in (i), said cured barrier coating applied as an aqueous dispersion and comprising

(a) about 75% w/w to about 90% w/w polyvinylacetate polymer

(b) a stabilizer, and

(c) about 2.5 to about 20% w/w of plasticizer effective to enhance the tensile strength of said cured barrier coating, whereby said cured coating provides a modified release profile to the drug in said drug-ion exchange resin complex in said matrix.

2. The composition according to claim 1, wherein said water insoluble polymer or copolymer or the hydrophilic polymer matrix is present in an amount of about 5 to about 20% by weight, based on the weight of said drug-ion exchange resin complex defined in (i).

3. The composition according to claim 1 wherein said cured high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating has an elongation factor of between about 125% and about 400%.

4. The composition according to claim 1, wherein said ion exchange resin is a sulfonated copolymer comprising styrene and divinylbenzene.

5. The composition according to claim 1, wherein said ion exchange resin is a copolymer comprising styrene and divinylbenzene having quaternary ammonium functional groups.

6. The composition according to claim 1, which further includes in said solid composition an uncoated orally ingestable drug, bound to a pharmaceutically acceptable, water insoluble ion exchange resin to form an uncoated particulate drug-ion exchange resin complex, said uncoated ion exchange resin being selected form a copolymer comprising styrene and divinylbenzene and a copolymer comprising styrene and divinylbenzene having quaternary ammonium functional groups and wherein said drug in said uncoated drug-ion exchange resin complex is either the same drug or a different drug as the drug included in the matrix in (ii) and said uncoated drug ion exchange resin complex being of a size capable of passing through a number 40 mesh screen.

7. The composition according to claim 6, wherein said drug in said uncoated drug-ion exchange matrix is the same drug as the drug in said coated drug-ion exchange resin matrix defined in (ii).

8. The composition according to claim 1, wherein said drug-ion exchange resin complex matrix includes a hydrophilic polymer.

9. The composition according to claim 8, wherein said hydrophilic polymer comprises a polyvinylpyrrolidone.

10. The composition according to claim 1, wherein said aqueous based coating dispersion comprises about 30% solids comprising polyvinylacetate, polyvinylpyrrolidone and an effective amount of a surfactant, said polyvinylacetate and polyvinylpyrrolidone being in a dry weight ratio about 10:

1.

11. The composition according to claim 1, wherein said particulate matrix comprises said particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer.

12. The composition according to claim 11, wherein said matrix comprises polyvinylacetate with a stabilizer comprising polyvinylpyrrolidone and an effective amount of a surfactant.

13. The composition according to claim 12, wherein said particulate matrix is prepared by a process comprising mixing said particulate drug-ion exchange resin complex with an aqueous dispersion comprising polyvinylacetate, polyvinylpyrrolidone and a sodium lauryl sulfate surfactant to form a mass, drying said mass and milling through a 40 mesh screen, and wherein said polyvinylacetate is present in an amount of about 27% w/w of the solids of said aqueous dispersion, said polyvinylpyrrolidone is present in an amount of about 2.7% w/w of the solids, and said sodium lauryl sulfate is present in an amount of about 0.3% w/w of the solids in said aqueous dispersion which comprises 30% solids.

14. The composition according to claim 1, wherein said water insoluble polymer or copolymer comprises an acrylate polymer or copolymer.

15. The composition according to claim 14, wherein said water insoluble polymer or copolymer comprises a copolymer comprising ethyl acrylate and methyl methacrylate.

16. The composition according to claim 1, wherein said plasticizer comprises about 5% to about 10% w/w of solids in said cured coating.

17. The composition according to claim 16 wherein said plasticizer comprises triacetin.

18. The composition according to claim 1 wherein said barrier coating further comprises a surfactant comprising sodium lauryl sulfate.

19. The composition according to claim 1, wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 5% to about 200% by weight of the matrix defined in (i).

20. The composition according to claim 19, wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 35% to about 50% by weight of the matrix defined in (i).

21. The composition according to claim 19, wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 30% to about 45% by weight of the matrix defined in (i).

22. The composition according to claim 1, wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises 50% by weight of the matrix defined in (i).

23. The composition according to claim 1, wherein said drug in said drug-ion exchange resin matrix defined in (ii) is selected form the group consisting of morphine, oxycodone, albuterol, dextromethorphan, codeine, tramadol, pseudoephedrine, phenylephrine, hydrocodone, venlafaxine, ibuprofen, oxybutynin, clonidine, dexchlorpheniramine, fexofenadine, diphenhydramine, oxymorphone, carbinoxamine, dicylomine, chlorpheniramine, amphetamine, naproxene, diclofenac, paroxetine, amoxicillin and pharmaceutically acceptable salts thereof.

24. The composition according to claim 1, wherein said drug in said drug-ion exchange resin matrix defined in (i) is diphenhydramine.

25. The composition according to claim 1, wherein said drug in said drug-ion exchange resin matrix in (i) is dextromethorphan.

26. The composition according to claim 1, which comprises a finished unit dose in tablet form, wherein the particulates are compressed into the tablet.

27. An orally ingestable, modified release, powder composition comprising particulates which provide at least an 8 hour release profile, said composition comprising:

(i) a particulate matrix comprising a particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer, or a hydrophilic polymer, said particulate matrix capable of passing through a number 40 mesh screen,

said drug-ion exchange resin complex comprising a pharmaceutically acceptable drug bound to a pharmaceutically acceptable water insoluble ion exchange resin to form a said drug-ion exchange resin complex, said ion exchange resin being irregularly shaped and selected from

(A) a copolymer comprising styrene and divinylbenzene and

(B) a copolymer comprising sytrene and divinylbenzene having quaternary ammonium functional groups,

wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in an amount of about 3% to about 30% by weight, based on the weight of said drug-ion exchange resin complex defined in (i), and

(ii) a cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric diffusion modified release barrier coating over said particulate drug-ion exchange resin complex—

water insoluble polymer or copolymer, or hydrophilic polymer matrix defined in (i), said cured barrier coating applied as an aqueous dispersion and comprising

(a) about 75% w/w to about 90% w/w polyvinylacetate polymer

(b) a stabilizer, and

(c) at least an amount of plasticizer effective to enhance the tensile strength of said cured barrier coating, whereby said cured coating provides a modified release profile to the drug in said drug-ion exchange resin complex in said matrix.

28. The composition according to claim 27, in which the powder is loaded into a capsule.

29. The composition according to claim 27, wherein said plasticizer comprises about 5% to about 10% w/w of solids in said cured coating.