Modified release formulations containing drug-ion exchange resin complexes

• US 10,172,958 B2
• Filed: 12/19/2016
• Issued: 01/08/2019
• 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 A
• Application Number:
  US15/383,474
• Publication Number:
  US 20170100487A1
• Time in Patent Office: 750 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. An aqueous pharmaceutical liquid suspension suitable for oral ingestion comprising:

(i) a particulate drug-ion exchange resin complex-matrix comprising a pharmaceutically acceptable drug which is cyproheptadine bound to a pharmaceutically acceptable water insoluble ion exchange resin to form said particulate drug-ion exchange resin complex, said particulate drug-ion exchange resin complex 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 drug-ion exchange resin complex-matrix, said ion exchange resin being a cation exchange resin, and

(ii) a cured, water permeable, water insoluble, non-ionic polymeric diffusion modified release barrier coating over said particulate drug-ion exchange resin complex defined in (i), said cured, water permeable, water insoluble, non-ionic polymeric, modified release, diffusion barrier coating applied as an aqueous dispersion, wherein said cured 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 said cured, water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating, whereby said cured, water permeable, water insoluble, non-ionic polymeric, modified release, diffusion barrier coating is over the particulate drug-ion exchange resin complex-matrix and provides a modified release profile to said pharmaceutically acceptable drug in said particulate drug-ion exchange resin complex-matrix.

2. The suspension according to claim 1, wherein said cured, water permeable, water insoluble, non-ionic polymeric, modified release, diffusion barrier coating has an elongation factor of between about 125% and about 400%.

3. The suspension according to claim 1, wherein said particulate drug-ion exchange resin complex-matrix of (i) is capable of passing through a number 40 mesh screen.

4. The suspension according to claim 1, wherein said particulate drug-ion exchange resin complex-matrix of (i) comprises about 5% to about 20% by weight of said water insoluble polymer or copolymer or a hydrophilic polymer.

5. The suspension according to claim 1, wherein said particulate drug-ion exchange resin complex-matrix of (i) comprises said particulate drug-ion exchange resin complex and said hydrophilic polymer.

6. The suspension according to claim 5, wherein said hydrophilic polymer in said particulate drug-ion exchange resin complex-matrix of (i) comprises a polyvinylpyrrolidone.

7. The suspension according to claim 1, wherein said particulate drug-ion exchange resin complex-matrix of (i) comprises said particulate drug-ion exchange resin complex and said water insoluble polymer or copolymer.

8. The suspension according to claim 7, wherein said water insoluble polymer in said particulate drug-ion exchange resin complex-matrix of (i) comprises polyvinylacetate, wherein said particulate matrix comprises said particulate drug-ion exchange resin complex, a stabilizer comprising polyvinylpyrrolidone and an effective amount of a surfactant.

9. The suspension according to claim 1, further comprising an orally ingestible drug bound to a pharmaceutically acceptable, water insoluble ion exchange resin to form an uncoated particulate drug-ion exchange resin complex, wherein said drug in said uncoated complex is either the same as or different from the pharmaceutically acceptable drug in (i).

10. The suspension according to claim 1, wherein said plasticizer comprises about 5% to about 10% w/w of said cured modified release barrier coating.

11. The suspension according to claim 10, wherein said plasticizer comprises triacetin.

12. The suspension according to claim 1, wherein said cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating further comprises a surfactant.

13. The suspension according to claim 1, wherein said cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating comprises about 35% to about 50% by weight of the uncoated particulate drug-ion exchange resin complex-matrix defined in (i).

14. The suspension according to claim 13, wherein said cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating comprises about 30% to about 45% by weight of the uncoated drug-ion exchange resin complex-matrix defined in (i).

15. An aqueous pharmaceutical liquid suspension suitable for oral ingestion comprising:

(A) modified release, barrier coated particulates which comprise;

(i) a particulate cyproheptadine-ion exchange resin complex comprising cyproheptadine bound to a pharmaceutically acceptable water insoluble ion exchange resin, wherein the cyproheptadine-ion 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 uncoated cyproheptadine ion exchange resin complex-matrix of (i), wherein the barrier coating is cured, has an elongation factor of about 125% to about 400%, provides a modified release to the cyproheptadine in the barrier coated particulate cyproheptadine-ion 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 cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric, modified release diffusion barrier coating is over the particulate cyproheptadine-ion exchange resin complex-matrix and provides a modified release profile to said pharmaceutically acceptable drug in said particulate cyproheptadine-ion exchange resin complex-matrix; and

(B) a pharmaceutically acceptable aqueous suspension base, wherein the barrier coated cyproheptadine-ion exchange resin complex as defined in (A) is suspended in the base.

16. The aqueous pharmaceutical liquid suspension according to claim 15, wherein the water insoluble polymer in the barrier coating comprises polyvinylacetate polymer and the barrier coating further comprises a stabilizer.

17. The aqueous pharmaceutical liquid suspension according to claim 16, wherein the stabilizer comprises polyvinylpyrrolidone.

18. The aqueous suspension according to claim 15, 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.

19. The aqueous suspension according to claim 15, wherein the matrix is present and comprises the particulate cyproheptadine-ion exchange resin complex and about 3% to about 30% by weight of the hydrophilic polymer, based on the weight of the uncoated particulate cyproheptadine-ion exchange resin complex-matrix.

20. The aqueous suspension according to claim 15, wherein the matrix is present and comprises the particulate cyproheptadine-ion exchange resin complex and about 5% to about 20% by weight of the hydrophilic polymer which comprises polyvinylpyrrolidone, based on the weight of the uncoated particulate cyproheptadine-ion exchange resin complex-matrix.

21. The aqueous suspension according to claim 15, wherein said ion exchange resin is a sulfonated copolymer comprising styrene and a divinylbenzene.

22. The aqueous suspension according to claim 15, wherein the plasticizer is present in an amount of about 5% to about 10% by weight of the coating layer.

23. The aqueous suspension according to claim 15, wherein the particulate cyproheptadine-ion exchange resin complex is of a size capable of passing through a number 40 mesh screen.