Modified release formulations containing drug-ion exchange resin complexes

• US 8,597,684 B2
• Filed: 01/22/2013
• Issued: 12/03/2013
• 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:
  US13/746,654
• Publication Number:
  US 20130136797A1
• Time in Patent Office: 315 Days
• Field of Search: None
• US Class Current: 424/486
• 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. The coating is a polyvinyl acetate polymer and a plasticizer. Methods of making the coated complex and the liquid suspension are described.

Claims

1. An orally ingestible aqueous liquid suspension composition comprising:

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

(i) a particulate matrix comprising a particulate amphetamine—

cation exchange resin complex and a water insoluble polymer or copolymer or a hydrophilic polymer, said particulate amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or hydrophilic) matrix capable of passing through a number 40 mesh screen,

said particulate amphetamine—

cation exchange resin complex comprising amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in the matrix in an amount of about 3% to about 30% by weight, based on the weight of said particulate amphetamine—

cation exchange resin complex defined in (A)(i), and

(ii) a cured high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating over said amphetamine—

cation exchange resin complex—

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

(a) about 70% 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 about a twelve hour release profile to the amphetamine in said amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or hydrophilic polymer) matrix), wherein the weight percentage is based on the weight of the cured barrier coating layer; 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 a dextro-amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, and (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 thereof which is not complexed with an ion exchange resin; and

(C) a pharmaceutically acceptable aqueous suspension base, wherein said barrier coated particulate amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or said hydrophilic polymer) matrix defined in (A) and said at least one additional component defined in (B) are suspended in said base.

2. The orally ingestible aqueous liquid suspension composition according to claim 1 which comprises the uncoated particulate dextro-amphetamine—

cation exchange resin of (B)(iiia).

3. The orally ingestible aqueous liquid suspension composition according to claim 1 which comprises the dextroamphetamine or amphetamine or pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin as defined in (B).

4. The orally ingestible aqueous liquid suspension composition according to claim 1 which comprises a combination of the uncoated particulate dextro-amphetamine—

cation exchange resin of (B) and the uncomplexed dextro-amphetamine or amphetamine or pharmaceutically acceptable salt of amphetamine or dextro-amphetamine of (B).

5. The orally ingestible aqueous liquid suspension 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%.

6. The orally ingestible aqueous liquid suspension composition according to claim 1, wherein said cured high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating is applied as an aqueous dispersion comprising 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.

7. The orally ingestible aqueous liquid suspension composition according to claim 1, wherein said plasticizer comprises about 5% to about 10% w/w of solids in said cured coating.

8. The orally ingestible aqueous liquid suspension composition according to claim 1 wherein said plasticizer comprises triacetin.

9. The orally ingestible aqueous liquid suspension composition according to claim 1 wherein said cured high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating further comprises a surfactant comprising sodium lauryl sulfate.

10. The orally ingestible aqueous liquid suspension composition according to claim 1, 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 amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or hydrophilic polymer) matrix defined in A.

11. The orally ingestible aqueous liquid suspension composition according to claim 1, wherein said water insoluble polymer or copolymer or the hydrophilic polymer in said matrix 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.

12. The orally ingestible aqueous liquid suspension 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 strong pharmaceutically acceptable cation resins.

13. The orally ingestible aqueous liquid suspension 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.

14. The orally ingestible aqueous liquid suspension composition according to claim 1, wherein said amphetamine—

cation exchange resin complex matrix includes a hydrophilic polymer.

15. The orally ingestible aqueous liquid suspension composition according to claim 14, wherein said hydrophilic polymer comprises a polyvinylpyrrolidone.

16. The orally ingestible aqueous liquid suspension composition according to claim 1, wherein said particulate matrix comprises said particulate amphetamine—

cation exchange resin complex and a water insoluble polymer or copolymer.

17. The orally ingestible aqueous liquid suspension composition according to claim 16, wherein said particulate matrix comprises polyvinylacetate with a stabilizer comprising polyvinylpyrrolidone and an effective amount of a surfactant.

18. The orally ingestible aqueous liquid suspension composition according to claim 16, wherein said particulate matrix is prepared by a process comprising mixing said particulate amphetamine—

cation 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 in 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.

19. The orally ingestible aqueous liquid suspension composition according to claim 1, wherein said water insoluble polymer or copolymer comprises an acrylate polymer or copolymer.

20. The orally ingestible aqueous liquid suspension composition according to claim 19, wherein said water insoluble polymer or copolymer comprises a copolymer comprising ethyl acrylate and methyl methacrylate.

21. An orally ingestible aqueous liquid suspension composition comprising:

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

(i) a particulate matrix comprising a particulate dextro-amphetamine—

cation exchange resin complex and a water insoluble polymer or copolymer or a hydrophilic polymer, said particulate dextro-amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or hydrophilic) matrix capable of passing through a number 40 mesh screen,

said particulate dextro-amphetamine—

cation exchange resin complex comprising dextro-amphetamine bound to a pharmaceutically acceptable water insoluble cation exchange resin, wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in the matrix in an amount of about 3% to about 30% by weight, based on the weight of said particulate dextro-amphetamine—

cation exchange resin complex defined in (i), and

(ii) a cured high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating over said dextro-amphetamine—

cation exchange resin complex—

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

(a) about 70% 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 about a twelve hour release profile to the dextro-amphetamine in said dextro-amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or hydrophilic polymer) matrix, wherein the weight percentage is based on the weight of the cured barrier coating layer; and

(B) at least one additional component from the group consisting of at least one of (iiia) 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, (iiib) 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, (iiic) amphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin, or (iiid) dextro-amphetamine or a pharmaceutically acceptable thereof which is not complexed with a ion exchange resin; and

(C) a pharmaceutically acceptable aqueous suspension base, wherein said barrier coated particulate dextro-amphetamine—

cation exchange resin complex—

(water insoluble polymer or copolymer or said hydrophilic polymer) matrix defined in (A) and said at least one additional component defined in (B) are suspended in said base.

22. The composition according to claim 21, wherein the suspension composition comprises the uncoated particulate amphetamine—

cation exchange resin of B(iiia).

23. The composition according to claim 22, wherein the suspension composition comprises the dextroamphetamine or amphetamine or pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin as defined in B(iiib).

24. The composition according to claim 21, wherein the suspension composition further comprises a combination of the uncoated particulate amphetamine—

cation exchange resin defined in B(iiia) and the uncomplexed amphetamine or acceptable salt thereof defined in B(iiic) or the uncomplexed dextramphetamine or pharmaceutically acceptable salt thereof defined in B(iiid).

25. An orally ingestible aqueous liquid suspension composition which provides about a twelve hour release profile, comprising a mixture of a barrier coated, modified release, drug—

cation exchange resin complex-matrix and an uncoated drug—

ion exchange resin complex comprising;

(A) (i) modified release, barrier coated, drug—

cation exchange resin complex—

(hydrophilic polymer) matrix particulates capable of passing through a number 40 mesh screen, said drug—

cation exchange resin complex—

matrix comprising a drug bound to a pharmaceutically acceptable, water insoluble cation exchange resin which is in admixture with said hydrophilic polymer, said hydrophilic polymer being present in an amount of about 3% to about 30% by weight, based on the weight of the drug—

cation exchange resin complex defined in (A)(i), and wherein said water insoluble cation exchange resin is a sulfonated copolymer comprising styrene and a divinylbenzene, and

(ii) a cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric diffusion barrier coating over said drug—

cation exchange resin complex —

(hydrophilic polymer) matrix defined in (A)(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—

matrix; and

(B) an uncoated particulate drug—

cation exchange resin complex of a size capable of passing through a number 40 mesh screen, said complex comprising a drug bound to a pharmaceutically acceptable water insoluble cation exchange resin which comprises a copolymer of styrene and a divinylbenzene;

wherein the drug of the coated drug—

cation exchange resin complex—

matrix defined in (A) and the drug of the uncoated drug—

cation exchange resin complex defined in (B) are each independently selected from the group consisting of amphetamine and dextro-amphetamine; and

(C) pharmaceutically acceptable aqueous suspension base, wherein said barrier coated particulate drug—

cation exchange resin complex—

(hydrophilic polymer) matrix defined in (A) and said uncoated particulate drug—

cation exchange resin complex defined in (B) are suspended in said base.

26. The orally ingestible aqueous liquid suspension composition according to claim 25, wherein said particulate amphetamine—

cation exchange resin complex—

(hydrophilic polymer) matrix comprises polyvinylpyrrolidone.

27. The orally ingestible aqueous liquid suspension composition according to claim 25, 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 (A)(i).

28. The orally ingestible aqueous liquid suspension composition according to claim 25, wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 50% by weight of the matrix defined in (A)(i).

29. The orally ingestible aqueous liquid suspension composition according to claim 25, wherein said composition comprises (a) amphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin or (b) dextroamphetamine or a pharmaceutically acceptable salt thereof which is not complexed with an ion exchange resin.