Modified release formulations containing drug-ion exchange resin complexes

• US 10,668,163 B2
• Filed: 01/07/2019
• Issued: 06/02/2020
• 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 T
• Assistant Examiner(s): Craigo, William
• Application Number:
  US16/241,287
• Publication Number:
  US 20190142952A1
• Time in Patent Office: 512 Days
• Field of Search: None
• 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. A solid pharmaceutical composition suitable for oral ingestion comprising modified release, barrier coated particulates which comprise:

(i) a particulate dextromethorphan-cation exchange resin complex-matrix comprising dextromethorphan bound to a pharmaceutically acceptable water insoluble cation exchange resin, wherein the dextromethorphan-cation exchange resin complex is in a matrix with a water insoluble polymer or copolymer or a hydrophilic polymer, and

(ii) about 25% w/w to about 50% w/w of a water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating based on the weight of the dextromethorphan-cation exchange resin complex-matrix of (i) prior to coating, wherein the barrier coating has an elongation factor of about 125% to about 400%, provides a modified release to the dextromethorphan in the barrier coated particulate dextromethorphan-cation exchange resin complex-matrix defined in (i), and comprises (a) about 70% w/w to about 90% w/w of a water-insoluble polymer based on the weight of the barrier coating layer and (b) about 2.5% w/w to about 20% w/w of a plasticizer based on the weight of the barrier coating layer, whereby the water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating is over the particulate dextromethorphan-cation exchange resin complex-matrix and provides a modified release profile to said pharmaceutically acceptable drug in said particulate dextromethorphan-cation exchange resin complex-matrix.

2. The composition according to claim 1 which is a tablet.

3. The composition according to claim 1, wherein the about 70% w/w to about 90% w/w water-insoluble polymer is polyvinylacetate.

4. The solid pharmaceutical composition according to claim 1, wherein and the barrier coating further comprises a stabilizer.

5. The solid pharmaceutical composition according to claim 1, wherein the stabilizer comprises polyvinylpyrrolidone.

6. The solid pharmaceutical composition according to claim 1, wherein the plasticizer is selected from dibutyl sebacate, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, or triacetin, or mixtures thereof.

7. The solid pharmaceutical composition according to claim 1, wherein the matrix comprises the particulate dextromethorphan-cation exchange resin complex and about 3% to about 30% by weight of the hydrophilic polymer, based on the weight of the particulate dextromethorphan-ion exchange resin complex-matrix prior to coating.

8. The solid pharmaceutical composition according to claim 1, wherein the matrix comprises the particulate dextromethorphan-cation exchange resin complex and about 5% to about 20% by weight of the hydrophilic polymer which comprises polyvinylpyrrolidone, based on the weight of the particulate dextromethorphan-cation exchange resin complex-matrix prior to coating.

9. The solid pharmaceutical composition according to claim 1 which further comprises a second active component.

10. The solid pharmaceutical composition according to claim 9, wherein the second active component is not in a drug-ion exchange resin complex.

11. The solid pharmaceutical composition according to claim 9, wherein the second active component is in a drug-ion exchange resin complex.

12. The solid pharmaceutical composition according to claim 9, wherein the further active ingredient is pseudoephedrine.

13. The solid pharmaceutical composition according to claim 1, which further comprises a dextromethorphan-cation exchange resin complex which is uncoated with a modified release barrier coating.

14. A method for oral administration of a modified release drug to a subject in need thereof, said method comprising administering to said subject a product according to claim 1.

16. The tablet according to claim 12, wherein said ion exchange resin is a sulfonated copolymer comprising styrene and a divinylbenzene.

17. The tablet according to claim 12, wherein the barrier coating layer comprises about 5% to about 10% by weight plasticizer.

18. The tablet according to claim 17, wherein the plasticizer comprises triacetin.

19. The tablet according to claim 12, wherein the particulate dextromethorphan-ion exchange resin complex is of a size capable of passing through a number 40 mesh screen.

20. The tablet according to claim 12, wherein the barrier coating is cured.

21. The tablet according to claim 12, wherein the matrix is present and comprises the particulate dextromethorphan-cation exchange resin complex and about 5% to about 20% by weight of the hydrophilic polymer which comprises polyvinylpyrrolidone, based on the weight of the particulate dextromethorphan-cation exchange resin complex-matrix prior to coating.

22. The tablet according to claim 12 which further comprises a second active component.

23. The tablet according to claim 22, wherein the second active component is not in a drug-ion exchange resin complex.

24. The tablet according to claim 22, wherein the second active component is in a drug-ion exchange resin complex.

25. The tablet according to claim 22 wherein the second active ingredient is pseudoephedrine.

26. The tablet according to claim 12, which further comprises a dextromethorphan-cation exchange resin complex which is uncoated with a modified release barrier coating.

27. A method for oral administration of a modified release drug to a subject in need thereof, said method comprising administering to said subject a product according to claim 12.

15. A pharmaceutical tablet suitable for oral ingestion comprising:

(A) a particulate dextromethorphan-ion exchange resin complex-optional matrix comprising;

(i) dextromethorphan bound to a pharmaceutically acceptable water insoluble cation exchange resin to form said particulate dextromethorphan-cation exchange resin complex-optional matrix, said particulate dextromethorphan-cation exchange resin complex optionally being in a matrix with a water insoluble polymer or copolymer or a hydrophilic polymer, which polymer or copolymer is present in an amount of about 3% to about 30% by weight, based on the weight of said particulate dextromethorphan-cation exchange resin complex-optional matrix, and

(ii) a water permeable, water insoluble, non-ionic polymeric diffusion modified release barrier coating over said particulate dextromethorphan-ion exchange resin complex-optional matrix defined in (i), the water permeable, water insoluble, non-ionic polymeric, modified release, diffusion barrier coating applied as an aqueous dispersion, wherein the barrier coating comprises;

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

(b) a stabilizer comprising polyvinylpyrrolidone, and

(c) about 2.5% w/w to about 20% w/w of plasticizer effective to enhance the tensile strength of the water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating, whereby the water permeable, water insoluble, non-ionic polymeric, modified release, diffusion barrier coating is over the particulate dextromethorphan-ion exchange resin complex-optional matrix and provides a modified release profile to said pharmaceutically acceptable dextromethorphan in the particulate dextromethorphan-cation exchange resin complex-optional matrix; and

(B) one or more pharmaceutically acceptable excipient.