MODIFIED RELEASE PREPARATIONS CONTAINING OXCARBAZEPINE AND DERIVATIVES THEREOF

• US 20120232060A1
• Filed: 05/21/2012
• Published: 09/13/2012
• Est. Priority Date: 04/26/2006
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Bhatt, Padmanabh P., Kidane, Argaw, Edwards, Kevin
• Granted Patent: US 8,617,600 B2
• Time in Patent Office: Days
• US Class Current: 514/217
• CPC Class Codes: A61K 2800/56 Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• 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 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants

Abstract

Controlled-release preparations of oxcarbazepine and derivatives thereof for once-a-day administration are disclosed. The inventive compositions comprise solubility- and/or release enhancing agents to provide tailored drug release profiles, preferably sigmoidal release profiles. Methods of treatment comprising the inventive compositions are also disclosed.

Claims

1. A pharmaceutical formulation for once-a-day administration of oxcarbazepine comprising:

(a) oxcarbazepine;

(b) at least one agent that enhances the solubility of oxcarbazepine;

(c) at least one release promoting agent comprising a polymer having pH-dependent solubility, and (d) a carrier matrix comprising a water-swellable polymer, wherein components (a)-(c) are distributed in the carrier matrix.

2. The formulation of claim 1, wherein the agent that enhances the solubility of oxcarbazepine is selected from the group consisting of surface active agents, complexing agents, cyclodextrins, pH modifying agents, and hydration promoting agents.

3. The formulation of claim 2, wherein the surface active agents comprise sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene oxide (PEO) modified sorbitan monoesters, fatty acid sorbitan esters, polyethylene oxide-polypropylene oxide-(poly(ethylene oxide)) block copolymers, or combinations thereof.

4. The formulation of claim 1, wherein the water-swellable polymer is selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol.

5. The formulation of claim 4, wherein the cellulosic polymers are selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, and ethylcellulose.

6. The formulation of claim 1, wherein the release-promoting agent is selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1:

1)), and methyl acrylate-methacrylic acid copolymers.

7. The pharmaceutical formulation of claim 1, wherein total amount of the release promoting agent and the agent that enhances the solubility of oxcarbazepine is up to 90% by weight of the formulation.

8. The pharmaceutical formulation of claim 7, wherein the agent that enhances the solubility of oxcarbazepine is incorporated in an amount from 1% to 80% by weight of the formulation.

9. The pharmaceutical formulation of claim 1, wherein the amount of oxcarbazepine is effective to produce a steady state blood level of monohydroxy derivative of oxcarbazepine in the range of about 2 μ

g/ml to about 10 μ

g/ml.

10. The pharmaceutical formulation of claim 1, wherein the formulation is effective in minimizing fluctuations between C_min and C_max of monohydroxy derivative of oxcarbazepine.

11. The pharmaceutical formulation of claim 10, which provides C_max levels of monohydroxy derivative of oxcarbazepine in the range of about 6 μ

g/ml to about 10 μ

g/ml and C_min levels of monohydroxy derivative of oxcarbazepine in the range of about 2 μ

g/ml to about 5 μ

g/ml.

12. The formulation of claim 1, wherein the amount of oxcarbazepine is 600 mg.

13. The pharmaceutical formulation of claim 1 in the form of pellets, tablets, granules or capsules.

14. The formulation of claim 13 in the form of tablets.

15. The formulation of claim 14, wherein each tablet comprises 600 mg of oxcarbazepine.

16. The formulation of claim 1, wherein the water-swellable polymer is present in the amount of from 1% to 50% by weight of the formulation.

17. The formulation of claim 1, further comprising a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, sodium stearyl fumarate, hydrogenated vegetable oils, and waxes.

18. The formulation of claim 17, wherein the wax is selected from the group consisting of beeswax, camuba wax, cetyl alcohol, glyceryl stearate, glyceryl palmitate, and stearyl alcohol.

19. The formulation of claim 17, wherein the lubricant is incorporated in the amount of from 0.1% to 20% by weight of the formulation.

20. The pharmaceutical formulation of claim 1, wherein the polymer having pH-dependent solubility remains intact at pH values of below 4 and dissolves at pH values of more than 4.

21. The pharmaceutical formulation of claim 1, wherein the polymer having pH-dependent solubility dissolves at pH values of more than 5.

22. The pharmaceutical formulation of claim 1, wherein the polymer having pH-dependent solubility dissolves at pH values of more than 6.

23. The formulation of claim 1, further comprising a tabletting aid selected from the group consisting of magnesium stearate, talc, cabosil, and silicified microcrystalline cellulose.

24. The formulation of claim 23, wherein the tabletting aid is incorporated in the amount of up to 25% by weight of the formulation.

25. The formulation of claim 14, wherein each tablet comprises a homogeneous admixture of oxcarbazepine with HPMC and methacrylic acid-ethyl acrylate copolymer.

26. The formulation of claim 6, further comprising a surfactant and a tabletting aid.