Modified release formulations containing drug-ion exchange resin complexes

• US 8,790,700 B2
• Filed: 10/02/2013
• Issued: 07/29/2014
• 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:
  US14/044,105
• Publication Number:
  US 20140030334A1
• Time in Patent Office: 300 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. A modified release aqueous oral liquid suspension comprising:

(A) a particulate diffusion barrier coated, drug-ion exchange resin complex-matrix which comprises

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

said particulate drug-ion exchange resin complex comprising multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in said particulate drug-ion exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix in an amount of about 3% to about 30% by weight, based on the weight of said particulate drug-ion exchange resin complex, and

(ii) a cured high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating over said particulate drug-ion exchange resin complex (water insoluble polymer or copolymer or said hydrophilic polymer) matrix in (i), said cured aqueous based 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 drug in said particulate drug-ion 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, wherein said multiple drugs in said coated drug-ion exchange resin complex-matrix comprise (i) codeine and (ii) chlorpheniramine or dexchlorpheniramine and optionally (iii) pseudoephedrine;

(B) an uncoated particulate drug-ion exchange resin complex which comprises multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said multiple drugs in said uncoated drug-ion exchange resin complex comprise (i) codeine and (ii) chlorpheniramine or dexchlorpheniramine and optionally (iii) pseudoephedrine;

(C) multiple drugs which are not complexed with an ion exchange resin, wherein said multiple drugs comprise (i) codeine, (ii) chlorpheniramine or dexchlorpheniramine and optionally (iii) pseudoephedrine; and

(D) a pharmaceutically acceptable aqueous suspension base, wherein said components (A), (B) and (C) are in said aqueous base.

2. The modified release aqueous oral liquid suspension according to claim 1, wherein the uncoated drug-ion exchange resin complex (B) is of a size capable of passing through a number 40 mesh screen.

3. The modified release aqueous oral liquid suspension according to claim 1, wherein the ion exchange resin of each (A) and (B) is

a sulfonated copolymer comprising styrene and divinylbenzene.

4. The modified release aqueous oral liquid suspension according to claim 1, wherein multiple drugs of (A) comprises (i) codeine and (ii) chlorpheniramine.

5. The modified release aqueous oral liquid suspension according to claim 4, wherein said multiple drugs of (B) comprise (i) codeine and (ii) chlorpheniramine.

6. The modified release aqueous oral liquid suspension according to claim 1, wherein said drugs of (C) comprise (i) codeine and (ii) chlorpheniramine.

7. 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%.

8. The modified release aqueous oral liquid suspension 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.

9. The modified release aqueous oral liquid suspension according to claim 1, wherein said plasticizer comprises about 5% to about 10% w/w of solids in said cured coating.

10. The modified release aqueous oral liquid suspension according to claim 1, wherein said plasticizer comprises triacetin.

11. The modified release aqueous oral liquid suspension according to claim 1, wherein said cured high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating further comprises sodium lauryl sulfate.

12. The modified release aqueous oral liquid suspension 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 said drug-ion exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix of (A).

13. The modified release aqueous oral liquid suspension 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 drug-ion exchange resin complex of (A).

14. The modified release aqueous oral liquid suspension according to claim 1, wherein said ion exchange resin used to form the complex of (A) and said ion exchange resin used to form the complex of (B) are independently selected from among strong pharmaceutically acceptable ion resins.

15. The modified release aqueous oral liquid suspension according to claim 1, wherein said coated drug-ion exchange resin complex-matrix of (A) includes a hydrophilic polymer.

16. The modified release aqueous oral liquid suspension according to claim 15, wherein said hydrophilic polymer comprises a polyvinylpyrrolidone.

17. The modified release aqueous oral liquid suspension according to claim 1, wherein said particulate matrix comprises said particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer.

18. The modified release aqueous oral liquid suspension according to claim 17, wherein said water insoluble polymer or copolymer comprises polyvinylacetate with a stabilizer comprising polyvinylpyrrolidone and an effective amount of a surfactant.

19. A modified release aqueous oral liquid suspension comprising:

(A) a particulate diffusion barrier coated, drug-ion exchange resin complex-matrix which comprises

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

said particulate drug-ion exchange resin complex comprising multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in said particulate drug-ion exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix in an amount of about 3% to about 30% by weight, based on the weight of said particulate drug-ion exchange resin complex, and

(ii) a cured high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating over said particulate drug-ion exchange resin complex (water insoluble polymer or copolymer or said hydrophilic polymer) matrix of (i), said cured aqueous based 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 drug in said particulate drug-ion 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, wherein said multiple drugs comprise (i) hydrocodone, (ii) chlorpheniramine or dexchlorpheniramine; and

(iii) pseudoephedrine;

(B) an uncoated particulate drug-ion exchange resin complex which comprises multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said multiple drugs comprise (i) hydrocodone, (ii) chlorpheniramine or dexchlorpheniramine; and

(iii) pseudoephedrine;

(C) multiple drugs which are not complexed with an ion exchange resin, wherein said multiple drugs comprise (i) hydrocodone, (ii) chlorpheniramine or dexchlorpheniramine; and

(iii) pseudoephedrine; and

(D) a pharmaceutically acceptable aqueous suspension base, wherein said components (A), (B) and (C) are in said aqueous base.

20. The modified release aqueous oral liquid suspension according to claim 19, wherein said ion exchange resin used to form the complex of each of (A) and (B) is a sulfonated copolymer comprising styrene and a divinylbenzene.

21. The modified release aqueous oral liquid suspension according to claim 19, wherein said particulate drug-ion exchange resin complex-(hydrophilic polymer) matrix comprises polyvinylpyrrolidone.

22. The modified release aqueous oral liquid suspension 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 of (A)(i).

23. The modified release aqueous oral liquid suspension according to claim 19, wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 50% by weight of the matrix of (A)(i).

24. A modified release aqueous oral liquid suspension comprising:

(A) a particulate diffusion barrier coated, drug-ion exchange resin complex-matrix which comprises

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

said particulate drug-ion exchange resin complex comprising multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in said particulate drug-ion exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix in an amount of about 3% to about 30% by weight, based on the weight of said particulate drug-ion exchange resin complex, and

(ii) a cured high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating over said particulate drug-ion exchange resin complex (water insoluble polymer or copolymer or said hydrophilic polymer) matrix defined in (i), said cured aqueous based 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 drug in said particulate drug-ion 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, wherein said multiple drugs in said particulate drug-ion exchange resin complex comprise (i) codeine, (ii) chlorpheniramine or dexchlorpheniramine, and optionally (iii) pseudoephedrine; and

(B) an uncoated particulate drug-ion exchange resin complex which comprises multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said multiple drugs in said uncoated particulate drug-ion exchange resin complex comprise (i) codeine, (ii) chlorpheniramine or dexchlorpheniramine, and optionally (iii) pseudoephedrine; and

a pharmaceutically acceptable aqueous suspension base, wherein said components (A) and (B) are in said aqueous base.

25. The modified release aqueous oral liquid suspension according to claim 24, wherein said drug-ion exchange resin complex-matrix includes a hydrophilic polymer which comprises polyvinylpyrrolidone.

26. The modified release aqueous oral liquid suspension according to claim 24, wherein said multiple drugs in the coated drug-ion exchange resin complex-matrix of (A) comprises (i) codeine and (ii) chlorpheniramine and said multiple drugs in the coated drug-ion exchange resin complex-matrix of (B) comprises (i) codeine and (ii) chlorpheniramine.

27. A modified release aqueous oral liquid suspension comprising:

(A) a particulate diffusion barrier coated, drug-ion exchange resin complex-matrix which comprises

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

said particulate drug-ion exchange resin complex comprising multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in said particulate drug-ion exchange resin complex-(water insoluble polymer or copolymer or hydrophilic polymer) matrix in an amount of about 3% to about 30% by weight, based on the weight of said particulate drug-ion exchange resin complex, and

(ii) a cured high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating over said particulate drug-ion exchange resin complex (water insoluble polymer or copolymer or said hydrophilic polymer) matrix in (i), said cured aqueous based 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 drug in said particulate drug-ion 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, wherein said multiple drugs in said coated drug-ion exchange resin complex-matrix comprise (i) hydrocodone, (ii) chlorpheniramine or dexchlorpheniramine, and (iii) pseudoephedrine; and

(B) an uncoated particulate drug-ion exchange resin complex which comprises multiple drugs bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein said multiple drugs comprise (i) hydrocodone, (ii) chlorpheniramine or dexchlorpheniramine, and (iii) pseudoephedrine; and

a pharmaceutically acceptable aqueous suspension base, wherein said components (A) and (B) are in said aqueous base.

28. The modified release aqueous oral liquid suspension according to claim 27, wherein said drug-ion exchange resin complex-matrix includes a hydrophilic polymer which comprises a polyvinylpyrrolidone.

29. The modified release aqueous oral liquid suspension according to claim 27, wherein said multiple drugs in the coated drug-ion exchange resin complex-matrix of (A) comprises (i) hydrocodone, (ii) chlorpheniramine and (iii) pseudoephedrine, and said multiple drugs in the coated drug-ion exchange resin complex-matrix of (B) comprises (i) hydrocodone, (ii) chlorpheniramine, and (iii) pseudoephedrine.