Modified-release preparations containing oxcarbazepine and derivatives thereof

DC CAFC

US 7,722,898 B2
Filed: 04/13/2007
Issued: 05/25/2010
Est. Priority Date: 04/26/2006
Status: Active Grant

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1. A pharmaceutical formulation for once-a-day administration of oxcarbazepine 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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20 Claims

1. A pharmaceutical formulation for once-a-day administration of oxcarbazepine 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)
- - 2. The formulation 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 formulation 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 pharmaceutical formulation 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 pharmaceutical formulation 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 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.
  - 7. The pharmaceutical formulation of claim 1 wherein the formulation is effective in minimizing fluctuations between C_minand C_maxof monohydroxy derivative of oxcarbazepine.
  - 8. The pharmaceutical formulation 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 formulation of claim 1, wherein the amount of oxcarbazepine is 600 mg.
  - 10. The pharmaceutical formulation of claim 1 in the form of pellets, tablets, granules or capsules.
  - 11. The formulation of claim 10 in the form of tablets.
  - 12. The formulation of claim 11, wherein each tablet comprises 600 mg of oxcarbazepine.
  - 13. The formulation of claim 1, wherein the matrix-forming polymer is present in the amount of 1% to 50% by weight of the formulation.
  - 14. 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.
  - 15. The formulation of claim 1, wherein the wax is selected from the group consisting of beeswax, camuba wax, cetyl alcohol, glyceryl stearate, glyceryl palmitate, and stearyl alcohol.
  - 16. The formulation of claim 12 wherein the lubricant is incorporated in an amount of from 0.1% to 20% by weight of the formulation.
  - 17. 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.
  - 18. The pharmaceutical formulation of claim 1, wherein the polymer having pH-dependent solubility dissolves at pH values of more than 5.
  - 19. The pharmaceutical formulation of claim 1, wherein the polymer having pH-dependent solubility dissolves at pH values of more than 6.
  - 20. The formulation of claim 1 comprising 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.

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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 W

Application Number

US11/734,874
Publication Number

US 20070254033A1
Time in Patent Office

1,138 Days
Field of Search

None
US Class Current

424/468
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...

Modified-release preparations containing oxcarbazepine and derivatives thereof

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Modified-release preparations containing oxcarbazepine and derivatives thereof

First Claim

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Abstract

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