Modified release preparations containing oxcarbazepine and derivatives thereof
View Patent ↗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.
1. A pharmaceutical formulation for once-a-day administration of oxcarbazepine comprising a homogeneous matrix comprising:
(a) oxcarbazepine;
(b) 1-50%, by weight of the formulation, a matrix-forming polymer;
(c) 1-80%, by weight of the formulation, at least one agent that enhances the solubility of oxcarbazepine; and
(d) 10-90%, by weight of the formulation, at least one release promoting agent comprising a polymer having pH-dependent solubility 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, Eudragit L100-55 (Methacrylic Acid—Ethyl Acrylate Copolymer (1:1)), and methyl acrylate-methacrylic acid copolymers.
2. The formulation of claim 1 , wherein the matrix-forming polymer is selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol.
3. The formulation of claim 2 , 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.
4. The formulation of claim 1 , wherein the agent that enhances the solubility of oxcarbazepine selected from the group consisting of surface active agents, complexing agents, cyclodextrins, pH modifying agents, and hydration promoting agents.
5. The formulation of claim 4 , 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.
6. The 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.
7. The formulation of claim 6 , wherein the polymer having pH dependent solubility dissolves at pH values of more than 5.
8. The formulation of claim 7 , wherein the polymer having pH dependent solubility dissolves at pH values of more than 6.
9. The formulation of claim 1 , wherein the rate of release of oxcarbazepine from the formulation in vitro over time is sigmoidal.
10. The formulation of claim 1 , wherein the matrix-forming polymer is incorporated in an amount from 1% to 50% by weight of the formulation, and the agent that enhances the solubility of oxcarbazepine is incorporated in an amount from 1% to 80% by weight of the formulation.
11. 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.
12. The formulation of claim 11 , wherein the wax is selected from the group consisting of beeswax, carnuba wax, cetyl alcohol, glyceryl stearate, glyceryl palmitate, and stearyl alcohol.
13. The formulation of claim 11 , wherein the lubricant is incorporated in an amount of from 0.1% to 20% by weight of the formulation.
14. The 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 μg/ml to about 10 μg/ml.
15. The formulation of claim 1 , wherein the formulation is effective in minimizing fluctuations between C min and C max of monohydroxy derivative of oxcarbazepine.
16. The formulation of claim 15 , which provides C max levels of monohydroxy derivative of oxcarbazepine in the range of about 6 μg/ml to about 10 μg/ml and C min levels of monohydroxy derivative of oxcarbazepine in the range of about 2 μg/ml to about 5 μg/ml.
17. The formulation of claim 1 , wherein the amount of oxcarbazepine is 600 mg.
18. The formulation of claim 1 , in the form of pellets, tablets, granules or capsules.
19. The formulation of claim 18 , in the form of tablets.
20. The formulation of claim 19 , wherein each tablet comprises 600 mg of oxcarbazepine.