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Details for Patent: 6,121,313

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Details for Patent: 6,121,313

Title: Pharmaceutical composition in a form of self-emulsifying formulation for lipophilic compounds
Abstract:The present invention provides a novel pharmaceutical composition based on the use of a particular oil phase which comprises a pyranone compound as a pharmaceutically active agent, a mixture of diglyceride and monoglyceride in a ratio of from about 9:1 to about 6:4 (diglyceride:monoglyceride) wherein the diglyceride and monoglyceride are mono- or di- unsaturated fatty acid esters of glycerol having sixteen to twenty-two carbon chain length, one or more pharmaceutically acceptable solvents, and one or more pharmaceutically acceptable surfactants. The composition is in a form of a self-emulsifying formulation which provides high concentration and high oral bioavailability for lipophilic pyranone compounds.
Inventor(s): Gao; Ping (Portage, MI), Morozowich; Walter (Kalamazoo, MI)
Assignee: Pharmacia & Upjohn Company (Kalamazoo, MI)
Filing Date:Jul 27, 1998
Application Number:09/123,069
Claims:1. A pharmaceutical composition comprising:

(a) a pyranone compound of formula II as a pharmaceutically active agent, ##STR4## (b) a mixture of diglyceride and monoglyceride in a ratio of from about 9:1 to about 6:4 by weight (diglyceride:monoglyceride) wherein the diglyceride and monoglyceride are mono- or di- unsaturated fatty acid esters of glycerol having sixteen to twenty-two carbon chain length,

(c) one or more pharmaceutically acceptable solvents, and

(d) one or more pharmaceutically acceptable surfactants;

wherein R.sub.1 is H--;

R.sub.2 is C.sub.3 -C.sub.5 alkyl, phenyl-(CH.sub.2).sub.2 --, het--SO.sub.2 NH--(CH.sub.2).sub.2 --, cyclopropyl-(CH.sub.2).sub.2 --, F-phenyl-(CH.sub.2).sub.2 --, het--SO.sub.2 NH-phenyl-, or F.sub.3 C--(CH.sub.2).sub.2 --; or

R.sub.1 and R.sub.2 taken together are a double bond;

R.sub.3 is R.sub.4 --(CH.sub.2).sub.n --CH(R.sub.5)--, H.sub.3 C--[O(CH.sub.2).sub.2 ].sub.2 --CH.sub.2 --, C.sub.3 -C.sub.5 alkyl, phenyl-(CH.sub.2).sub.2 --, het--SO.sub.2 NH--(CH.sub.2).sub.2 --, (HOCH.sub.2).sub.3 C--NH--C(O)--NH--(CH.sub.2).sub.3 --, (HO.sub.2 C)(H.sub.2 N)CH--(CH.sub.2).sub.2 --C(O)--NH--(CH.sub.2).sub.3 --, piperazin-1-yl-C(O)--NH--(CH.sub.2).sub.3, HO.sub.3 S(CH.sub.2).sub.2 --N(CH.sub.3)--C(O)--(CH.sub.2).sub.6 --C(O)--NH--(CH.sub.2).sub.3 --, cyclopropyl-(CH.sub.2).sub.2 --, F-phenyl-(CH.sub.2).sub.2 --, het--SO.sub.2 NH-phenyl, or F.sub.3 C--(CH.sub.2).sub.2 --;

n is 0, 1 or 2;

R.sub.4 is phenyl, het, cyclopropyl, H.sub.3 C--[O(CH.sub.2).sub.2 ].sub.2 --, het--SO.sub.2 NH--, Br--, N.sub.3 --, or HO.sub.3 S(CH.sub.2).sub.2 --N(CH.sub.3)--C(O)--(CH.sub.2).sub.6 --C(O)--NH--;

R.sub.5 is --CH.sub.2 --CH.sub.3, or --CH.sub.2 -cyclopropyl;

R.sub.6 is cyclopropyl, CH.sub.3 --CH.sub.2 --, or t-butyl;

R.sub.7 is --NR.sub.8 SO.sub.2 --het, --NR.sub.8 SO.sub.2 -phenyl, optionally substituted with R.sub.9, --CH.sub.2 --SO.sub.2 -phenyl, optionally substituted with R.sub.9, or --CH.sub.2 --SO.sub.2 --het;

R.sub.8 is --H, or --CH.sub.3 ;

R.sub.9 is --CN, --F, --OH, or --NO.sub.2 ;

wherein het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle, optionally substituted with --CH.sub.3, --CN, --OH, --C(O)OC.sub.2 H.sub.5, --CF.sub.3, --NH.sub.2, or --C(O)--NH.sub.2 ; or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 wherein the pyranone compound of formula II is a compound of formula I ##STR5##

3. The pharmaceutical composition of claim 1 wherein the compound of formula II is in an amount of from about 1% to about 40% by weight of the total composition.

4. The pharmaceutical composition of claim 2 wherein the compound of formula I is in an amount of from about 20% to about 30% by weight of the total composition.

5. The pharmaceutical composition of claim 1 wherein said diglyceride is diolein, dilinoleate or a mixture thereof.

6. The pharmaceutical composition of claim 1 wherein said diglyceride is diolein.

7. The pharmaceutical composition of claim 1 wherein said monoglyceride is monoolein, monolinoleate or a mixture thereof.

8. The pharmaceutical composition of claim 1 wherein said monoglyceride is monoolein.

9. The pharmaceutical composition of claim 1 wherein the mixture of diglyceride and monoglyceride is in an amount of from about 5% to about 35% by weight of the total composition.

10. The pharmaceutical composition of claim 1 wherein the mixture of diglyceride and monoglyceride is in an amount of from about 5% to about 20% by weight of the total composition.

11. The pharmaceutical composition of claim 1 wherein the mixture of diglyceride and monoglyceride is in a ratio of about 8:2 by weight (diglyceride:monoglyceride) and in an amount of from about 5% to about 35% by weight of the total composition.

12. The pharmaceutical composition of claim 1 wherein the mixture of diglyceride and monoglyceride is in a ratio of about 8:2 by weight (diglyceride:monoglyceride) and in an amount of from about 5% to about 20% by weight of the total composition.

13. The pharmaceutical composition of claim 1 wherein the mixture of diglyceride and monoglyceride is in a ratio of about 9:1 by weight (diglyceride:monoglyceride) and in an amount of from about 5% to about 20% by weight of the total composition.

14. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable solvent is propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, water, dimethyl acetamide, or a mixture thereof.

15. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable solvent is propylene glycol.

16. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable solvent is a mixture comprising propylene glycol and 95% (v/v) ethanol in a ratio of about 1:1.

17. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable solvent is in an amount of from about 10% to about 30% by weight of the total composition.

18. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable solvent is in an amount of from about 15% to about 25% by weight of the total composition.

19. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable surfactant is Polyoxyl 40 hydrogenated castor oil, Polyoxyl 35 castor oil, Solutol HS-15, Tagat TO, Peglicol 6-oleate, Polyoxyethylene stearates, Poloxamers, Polysorbates, or Saturated Polyglycolyzed Glycerides.

20. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable surfactant is Polyoxyl 40 hydrogenated castor oil or Polyoxyl 35 castor oil.

21. The Polyoxyl 40 hydrogenated castor oil of claim 20 which is Cremophor RH40.

22. The Polyoxyl 35 hydrogenated castor oil of claim 20 which is Cremophor EL, or Cremophor EL-P.

23. The pharmaceutical composition of claim 1 wherein the surfactant is in an amount of from about 10% to about 50% by weight of the total composition.

24. The pharmaceutical composition of claim 1 wherein the surfactant is in an amount of from about 30% to about 45% by weight of the total composition.

25. The pharmaceutical composition of claim 1 wherein the composition further comprises a basic amine.

26. The pharmaceutical composition of claim 25 wherein the basic amine is lower alkylamine, basic amino acid, or choline hydroxide.

27. The pharmaceutical composition of claim 26 wherein the lower alkylamine is ethanolamine, diethanolamine, triethanolamine, ethylenediamine, dimethylaminoethanol or tris(hydroxymethyl)aminomethane.

28. The pharmaceutical composition of claim 26 wherein the basic amino acid is arginine, lysine, or guanidine.

29. The pharmaceutical composition of claim 25 wherein the basic amine is in an mount from about 0.1% to about 10% by weight of the total composition.

30. A pharmaceutical composition comprising: (a) a pyranone compound of formula I in an amount of from about 20% to about 30% by weight of the total composition,

(b) a mixture of diolein and monoolein in a ratio of about 9:1 by weight (diolein:monoolein) and in an amount of from about 5% to about 20% by weight of the total composition,

(c) a solvent comprising propylene glycol or a mixture of propylene glycol and 95% (v/v) ethanol in a ratio of about 1:1 and in an amount of from about 15% to about 25% by weight of the total composition, and

(d) a surfactant comprising Cremophor RH40 or Cremophor EL in an amount of from about 30% to about 45% by weight of the total composition.

31. A pharmaceutical composition comprising:

(a) a pyranone compound of formula I in an amount of from about 20% to about 30% by weight of the total composition,

(b) a mixture of diolein and monoolein in a ratio of about 8:2 by weight (diolein:mono-olein) and in an amount of from about 5% to about 20% by weight of the total composition,

(c) a solvent comprising propylene glycol or a mixture solution of propylene glycol and 95% (v/v) ethanol in a ratio of about 1:1 in an amount of from about 15% to about 25% by weight of the total composition, and

(d) a surfactant comprising Cremophor RH40 or Cremophor EL in an amount of from about 30% to about 45% by weight of the total composition.

32. The pharmaceutical composition of claim 30 or 31 which further comprises a dimethylaminoethanol or tris(hydroxymethyl)aminomethane in an amount of from about 0.1% to 7% by weight of the total composition.

33. The pharmaceutical composition of claim 1, or 31 which is a self-emulsifying formulation capable of generating emulsions or microemulsions upon mixing with sufficient aqueous media.

34. The pharmaceutical composition of claim 1, 31 or 32 which is in a form of liquid for soft elastic capsules.
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