Modified release formulations containing drug-ion exchange resin complexes

• US 8,747,902 B2
• Filed: 10/29/2013
• Issued: 06/10/2014
• 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): Tran, Susan
• Assistant Examiner(s): CRAIGO, WILLIAM A
• Application Number:
  US14/065,842
• Publication Number:
  US 20140056984A1
• Time in Patent Office: 224 Days
• US Class Current: 424/490
• 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

An aqueous liquid suspension containing a coated drug-ion exchange resin complex comprising a core composed of an amphetamine complexed with a pharmaceutically acceptable ion-exchange resin and an uncoated amphetamine-ion exchange resin complex is provided. The coated amphetamine-ion exchange resin complex is in admixture with a polymer to form a matrix. Methods of making the coated complex and the liquid suspension are described.

Claims

1. An orally ingestible composition comprising:

(A) barrier coated particulates which provide about a twelve hour release profile which comprise;

(i) a particulate drug-cation exchange resin complex-matrix comprising at least one drug bound to a pharmaceutically acceptable water insoluble cation exchange resin, and further comprising a water insoluble polymer or copolymer, or hydrophilic polymer, said particulate drug-cation exchange resin complex-(water insoluble polymer or copolymer or a hydrophilic polymer) matrix being capable of passing through a number 40 mesh screen, and

(ii) a high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating which provides about a twelve hour release profile to the drug in said drug-cation exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix, said barrier coating having an elongation factor of about 125% to about 400%, wherein said at least one drug in part (A) is amphetamine or dextro-amphetamine; and

(B) at least one additional component selected from the group consisting of at least one of (iiia) an uncoated particulate dextro-amphetamine-cation exchange resin complex of a size capable of passing through a number 40 mesh screen, wherein said uncoated dextro-amphetamine-cation exchange resin complex is dextro-amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, (iiib) an uncoated particulate amphetamine-cation exchange resin complex of a size capable of passing through a number 40 mesh screen, wherein said uncoated amphetamine-cation exchange resin complex is amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, (iiic) amphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin, or (iiid) dextroamphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin.

2. The orally ingestible composition according to claim 1, which is a solid dose form.

3. The orally ingestible composition according to claim 2, which is a tablet or capsule.

4. The orally ingestible composition according to claim 3, in which said tablet is an orally dissolving tablet.

5. The orally ingestible composition according to claim 1, wherein the barrier coated particulate comprises a water insoluble polymer or copolymer.

6. The orally ingestible composition according to claim 5, wherein said barrier coated drug-cation exchange resin particulate comprises an acrylate polymer or copolymer.

7. The orally ingestible composition according to claim 6, wherein said acrylate polymer or copolymer is a copolymer comprising ethyl acrylate and methyl methacrylate.

8. The orally ingestible composition according to claim 1 which comprises the uncoated particulate dextro-amphetamine-cation exchange resin of (B)(iiia).

9. The orally ingestible composition according to claim 1 which comprises at least one of said dextroamphetamine or amphetamine or pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin as defined in (B).

10. The orally ingestible composition according to claim 1 which comprises said at least one said uncoated particulate dextro-amphetamine-cation exchange resin of (B) and said uncomplexed dextro-amphetamine or amphetamine or pharmaceutically acceptable salt of amphetamine or dextro-amphetamine of (B).

11. The orally ingestible composition according to claim 1 wherein said high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating further comprises a plasticizer in an amount of about 2 to about 20% of the coating layer.

12. The orally ingestible composition according to claim 11 wherein said plasticizer comprises about 5% to about 20% w/w of the coating.

13. The orally ingestible composition according to claim 12, wherein said high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 35% to about 50% by weight of the drug-cation exchange resin complex and water insoluble polymer or copolymer or hydrophilic polymer particulate defined in A.

14. The orally ingestible composition according to claim 1, wherein said water insoluble polymer or copolymer or hydrophilic polymer is present in an amount of about 5 to about 20% by weight, based on the weight of said amphetamine-cation exchange resin complex defined in A.

15. The orally ingestible composition according to claim 1 wherein said cation exchange resin used to form the complex of A and said cation exchange resin used to form the complex of B(iiia) are independently selected from among strongly acidic pharmaceutically acceptable cation exchange resins.

16. The orally ingestible composition according to claim 1, wherein said cation exchange resin used to form the complex of A and B(iiia) is a sulfonated copolymer comprising styrene and a divinylbenzene.

17. The orally ingestible composition according to claim 1, wherein said barrier coated drug-cation exchange resin complex matrix includes a hydrophilic polymer.

18. The orally ingestible composition according to claim 17, wherein said hydrophilic polymer comprises a polyvinylpyrrolidone.

19. An orally ingestible aqueous liquid suspension comprising:

(A) barrier coated particulates which provide about a twelve hour release profile which comprise;

(i) a particulate drug-cation exchange resin complex-matrix comprising at least one drug bound to a pharmaceutically acceptable water insoluble cation exchange resin, and further comprising a water insoluble polymer or copolymer, or hydrophilic polymer, said particulate drug-cation exchange resin complex-(water insoluble polymer or copolymer or a hydrophilic polymer) being capable of passing through a number 40 mesh screen, and

(ii) a high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating which provides about a twelve hour release profile to the drug in said drug-cation exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix, said barrier coating having an elongation factor of about 125% to about 400%, wherein said at least one drug of part (A) is amphetamine or dextroamphetamine; and

(B) at least one additional component selected from the group consisting of at least one of (iiia) an uncoated particulate dextro-amphetamine-cation exchange resin complex of a size capable of passing through a number 40 mesh screen, wherein said uncoated dextro-amphetamine-cation exchange resin complex is dextro-amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, (iiib) an uncoated particulate amphetamine-cation exchange resin complex of a size capable of passing through a number 40 mesh screen, wherein said uncoated amphetamine-cation exchange resin complex is amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, (iiic) amphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin, or (iiid) dextroamphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin; and

(C) a pharmaceutically acceptable aqueous suspension base, wherein said barrier coated drug-cation exchange resin complex and water insoluble polymer or copolymer or said hydrophilic polymer particulate defined in (A) and said at least one additional component defined in (B) are suspended in said base.

20. The orally ingestible aqueous liquid suspension according to claim 19, wherein the barrier coated particulate comprises a water insoluble polymer or copolymer.

21. The orally ingestible aqueous liquid suspension composition according to claim 20, wherein said barrier coated drug-cation exchange resin particulate comprises an acrylate polymer or copolymer.

22. The orally ingestible aqueous liquid suspension composition according to claim 19 which comprises said uncoated particulate dextro-amphetamine-cation exchange resin of (B)(iiia).

23. The orally ingestible aqueous liquid suspension composition according to claim 19 which comprises said dextroamphetamine or amphetamine or pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin as defined in (B).

24. The orally ingestible aqueous liquid suspension composition according to claim 19 which comprises said uncoated particulate dextro-amphetamine-cation exchange resin of (B) and said uncomplexed dextro-amphetamine or amphetamine or pharmaceutically acceptable salt of amphetamine or dextro-amphetamine of (B).

25. The orally ingestible aqueous liquid suspension composition according to claim 19 wherein said high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating further comprises a plasticizer in an amount of about 2 to about 20% of the coating layer.

26. The orally ingestible aqueous liquid suspension composition according to claim 25 wherein said plasticizer comprises about 5% to about 20% w/w of the coating.

27. The orally ingestible aqueous liquid suspension composition according to claim 19, wherein said high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 35% to about 50% by weight of the drug-cation exchange resin complex and water insoluble polymer or copolymer or hydrophilic polymer particulate defined in A.

28. The orally ingestible aqueous liquid suspension composition according to claim 19, wherein said water insoluble polymer or copolymer or hydrophilic polymer is present in an amount of about 5 to about 20% by weight, based on the weight of said drug-cation exchange resin complex defined in A.

29. The orally ingestible aqueous liquid suspension composition according to claim 19, wherein said cation exchange resin used to form the complex of A and B(iiia) is a sulfonated copolymer comprising styrene and a divinylbenzene.

30. The orally ingestible aqueous liquid suspension composition according to claim 29, wherein said hydrophilic polymer comprises a polyvinylpyrrolidone.