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Claims for Patent: 5,071,643

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Claims for Patent: 5,071,643

Title: Solvent system enhancing the solubility of pharmaceuticals for encapsulation
Abstract:This invention relates to a solvent system for enhancing the solubility of an acidic, basic, or amphoteric pharmaceutical agent to produce a highly concentrated solution suitable for softgel filling or two piece encapsulation. The solvent system comprises polyethylene glycol containing 0.2-1.0 mole equivalents of an ionizing agent per mole equivalent pharmaceutical agent and 1-20% water. Glycerin or polyvinylpyrrolidone may be added to further enhance the solubility of certain drugs. The disclosed solvent system is capable of enhancing solubilities of pharmaceutical agents 40-400%. The ionizing agent functions by causing partial ionization (neutralization) of the free pharmaceutical agent. When the pharmaceutical agent is acidic, the ionizing agent is preferably a hydroxide ion species, whereas when the pharmaceutical agent is basic, the ionizing agent is preferably a hydrogen ion species. For amphoteric pharmaceutical agents, either hydroxide ion or hydrogen ion sources may be utilized to effect partial ionization. The disclosed solvent system is useful because it not only provides for the enhancement or improvement of bioavailability of acidic, basic and amphoteric pharmaceutical agents by delivering them already in solution, but it also provides for a highly concentrated solution capable of encapsulation in a small enough vessel to permit easy swallowing. The highly concentrated solid solutions of the present invention are also useful for conversion into tablets and as veterinary spot and pour on preparations.
Inventor(s): Yu; Man S. (Rochester, NY), Hom; Foo S. (Safety Harbor, FL), Chakrabarti; Sibaprasanna (Oldsmer, FL), Huang; Chong-Heng (Madison, NJ), Patel; Mahendra (Swindon, GB2)
Assignee: R. P. Scherer Corporation (Troy, MI)
Application Number:07/104,911
Patent Claims: 1. A pharmaceutically acceptable highly concentrated solution of an acidic pharmaceutical agent suitable for filling softgels or for two-piece encapsulation or for tablet formation for subsequent oral administration, comprising the acidic pharmaceutical agent and a solvent system, the solvent system comprising 10% to 80% polyethylene glycol by weight of the solvent system, 1% to 20% water by weight of the solvent system and a hydroxide species, the hydroxide species being capable of dissociating in the solvent system into pharmaceutically acceptable cations and hydroxide ions, the hydroxide species being present in an amount such that between 0.1 and less than one mole of hydroxide ions per mole of acidic groups in the acidic pharmaceutical agent is present in the solution, the hydroxide species partially ionizing the acidic pharmaceutical agent such that the acidic pharmaceutical agent is present in a dissolved state in the solution as both a free acid and a cationic salt in a total amount of 20% to 80% by weight of the solution.

2. The pharmaceutically acceptable solution according to claim 1 further containing 4-12% glycerin by weight of the solvent system.

3. The pharmaceutically acceptable solution according to claim 1 wherein the hydroxide species is selected from the group consisting of sodium hydroxide, ammonium hydroxide and potassium hydroxide.

4. The pharmaceutically acceptable solution according to claim 1 wherein said polyethylene glycol has an average molecular weight of between about 200-100,000.

5. The pharmaceutically acceptable solution according to claim 2 wherein said polyethylene glycol has an average molecular weight of between about 200-100,000.

6. A highly concentrated solution of ibuprofen suitable for filling softgels or for two-piece encapsulation or for conversion into tablets for subsequent oral administration, comprising ibuprofen, an hydroxide ion species capable of dissociating in the solution into pharmaceutically acceptable cations and hydroxide ions, the hydroxide ion species being present in an amount such that between 0.1 and less than one mole of hydroxide ions per mole of ibuprofen is present in the solution, 1% to 20% by weight water, and 10% to 80% by weight polyethylene glycol, the hydroxide ion species partially ionizing the ibuprofen such that the ibuprofen is present in a dissolved state in the solution as both a free acid and a cationic salt in a total amount of 20% to 80% by weight.

7. A highly concentrated solution of ibuprofen suitable for filling softgels for subsequent oral administration, comprising ibuprofen, an hydroxide ion species capable of dissociating in the solution into pharmaceutically acceptable cations and hydroxide ions, the hydroxide ion species being present in an amount such that 0.2 to 0.5 mole of hydroxide ions per mole of ibuprofen is present in the solution, 1% to 20% by weight water, 3% to 12% by weight glycerin or propylene glycol, and 18% to 50% by weight polyethylene glycol, said polyethylene glycol having an average molecular weight in the range between about 200 and about 800, the hydroxide ion species partially ionizing the ibuprofen such that the ibuprofen is present in a dissolved state in the solution as both a free acid and a cationic salt in a total amount of 40% to 80% by weight.

8. A pharmaceutically acceptable highly concentrated solution of a basic pharmaceutical agent suitable for filling softgels or for two-piece encapsulation or for tablet formation for subsequent oral administration, comprising the basic pharmaceutical agent and a solvent system, the solvent system comprising 10% to 80% polyethylene glycol by weight of the solvent system, 1% to 20% water by weight of the solvent system and a hydrogen ion species, the hydrogen ion species being capable of dissociating in the solvent system into hydrogen ions and pharmaceutically acceptable anions, the hydrogen ion species being present in an amount such that between 0.1 and less than one mole of hydrogen ions per mole of basic groups in the basic pharmaceutical agent is present in the solution, the hydrogen ion species partially ionizing the basic pharmaceutical agent such that the basic pharmaceutical agent is present in a dissolved state in the solution as both a free base and an anionic salt in a total amount of 20% to 80% by weight of the solution.

9. The solution according to claim 8 wherein said polyethylene glycol has an average molecular weight of between about 200-800.

10. The solution according to claim 8 wherein 50-95% of the polyethylene glycol has an average molecular weight between about 800 to about 10,000.

11. The solution according to claim 8 wherein the polyethylene glycol has an average molecular weight between about 10,000 to about 100,000.

12. A pharmaceutically acceptable highly concentrated solution of an amphoteric pharmaceutical agent suitable for filling softgels or for two-piece encapsulation or for tablet formation for subsequent oral administration, comprising the amphoteric pharmaceutical agent and a solvent system, the solvent system comprising 10% to 80% polyethylene glycol by weight of the solvent system, 1% to 20% water by weight of the solvent system and an ion species selected from the group consisting of cationic hydroxide species and anionic hydrogen ion species, the ion species being capable of dissociating in the solvent system into pharmaceutically acceptable ions, the ion species being present in an amount such that between 0.1 and less than one mole of ions selected from the group consisting of hydrogen ions and hydroxide ions per mole of ionizable groups in the amphoteric pharmaceutical agent is present in the solution, the ion species partially ionizing the amphoteric pharmaceutical agent such that the amphoteric pharmaceutical agent is present in a dissolved state in the solution both in a free form and a salt form in a total amount of 20% to 80% by weight of the solution.
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