Method of treating seizures using modified release formulations of oxcarbazepine

DC CAFC

US 7,910,131 B2
Filed: 08/27/2008
Issued: 03/22/2011
Est. Priority Date: 04/26/2006
Status: Active Grant

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1. A method of treating seizures comprising administering to a subject in need thereof a pharmaceutical formulation comprising a homogeneous matrix comprising:

(a) oxcarbazepine;

(b) a matrix-forming polymer selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol;

(c) at least one 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; and

(d) 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, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1;

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

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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.

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24 Claims

1. A method of treating seizures comprising administering to a subject in need thereof a pharmaceutical formulation comprising a homogeneous matrix comprising:
- (a) oxcarbazepine;
  
  (b) a matrix-forming polymer selected from the group consisting of cellulosic polymers, alginates, gums, cross-linked polyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol;
  
  (c) at least one 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; and
  
  (d) 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, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1;
  
  1)), and methyl acrylate-methacrylic acid copolymers.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
- - 2. The method of claim 1, 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.
  - 3. The method of claim 1, 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 method of claim 1, wherein the release promoting agent is incorporated in an amount from 10% to 90% 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.
  - 5. The method of claim 4, wherein the release promoting agent is incorporated in an amount from 30% to 70% 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.
  - 6. The method 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.
  - 7. The method of claim 1, wherein the formulation is effective in minimizing fluctuations between C_minand C_maxof monohydroxy derivative of oxcarbazepine.
  - 8. The method of claim 7, which provides C_maxlevels of monohydroxy derivative of oxcarbazepine in the range of about 6 μ
    - g/ml to about 10 μ
      
      g/ml and C_minlevels of monohydroxy derivative of oxcarbazepine in the range of about 2 μ
      
      g/ml to about 5 μ
      
      g/ml.
  - 9. The method of claim 1, wherein the amount of oxcarbazepine in the formulation is 600 mg.
  - 10. The method of claim 1, wherein the formulation is in the form of pellets, tablets, granules or capsules.
  - 11. The method of claim 10, wherein the formulation is in the form of tablets.
  - 12. The method of claim 11, wherein each tablet comprises 600 mg of oxcarbazepine.
  - 13. The method of claim 1, wherein the matrix-forming polymer is present in the amount of 1% to 50% by weight of the formulation.
  - 14. The method of claim 1, wherein the formulation further comprises 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.
  - 15. The method of claim 14, wherein the wax is selected from the group consisting of beeswax, carnuba wax, cetyl alcohol, glyceryl stearate, glyceryl palmitate, and stearyl alcohol.
  - 16. The method of claim 14, wherein the lubricant is incorporated in the formulation in an amount of from 0.1% to 20% by weight of the formulation.
  - 17. The method 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.
  - 18. The method of claim 1, wherein the polymer having pH-dependent solubility dissolves at pH values of more than 5.
  - 19. The method of claim 1, wherein the polymer having pH-dependent solubility dissolves at pH values of more than 6.
  - 20. The method of claim 1, wherein the formulation comprises HPMC and polyvinyl pyrrolidone as matrix-forming polymers;
    - sodium lauryl sulfate as the agent that enhances the solubility of oxcarbazepine, and Eudragit L100-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1;
      
      1)) as the release promoting agent.
  - 21. The method of claim 1, wherein the formulation is administered once a day.
  - 22. The method of claim 1, wherein the seizure is an epileptic seizure.
  - 23. The method of claim 22, wherein the epileptic seizure is a partial seizure or a generalized tonic-clonic seizure.
  - 24. The method of claim 1, wherein the patient is an adult or child.

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Current Assignee
Supernus Pharmaceuticals Incorporated
Original Assignee
Supernus Pharmaceuticals Incorporated
Inventors
Kidane, Argaw, Edwards, Kevin, Bhatt, Padmanabh P.
Primary Examiner(s)
Hartley; Michael G
Assistant Examiner(s)
Dickinson; Paul

Application Number

US12/230,276
Publication Number

US 20090004263A1
Time in Patent Office

937 Days
Field of Search

None
US Class Current

424/464
CPC Class Codes

A61K 2800/56   Compounds, absorbed onto or...

A61K 31/55   having seven-membered rings...

A61K 9/0073   Sprays or powders for inhal...

A61K 9/2013   Organic compounds, e.g. pho...

A61K 9/2027   obtained by reactions only ...

A61K 9/2031   obtained otherwise than by ...

A61K 9/205   Polysaccharides, e.g. algin...

A61K 9/2054   Cellulose; Cellulose deriva...

A61P 25/08   Antiepileptics; Anticonvuls...

Method of treating seizures using modified release formulations of oxcarbazepine

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Abstract

15 Citations

24 Claims

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Method of treating seizures using modified release formulations of oxcarbazepine

First Claim

2 Assignments

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Abstract

15 Citations

24 Claims

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