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Claims for Patent: 6,231,887

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Claims for Patent: 6,231,887

Title: Pharmaceutical composition for acidic lipophilic compounds in a form of a self-emulsifying formulation
Abstract:The present invention provides a novel pharmaceutical composition based on the use of a particular amount of basic amine which comprises a pyranone compound as a pharmaceutically active agent, a basic amine in an amount of from about 0.1% to about 10% by weight of the total composition, one or more pharmaceutically acceptable solvents, and one or more pharmaceutically acceptable surfactants. In addition, the composition may further comprises one or more pharmaceutically acceptable oils. The composition is in a form of 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)
Application Number:09/122,927
Patent Claims: 1. A pharmaceutical composition comprising:

(a) a pyranone compound of formula II as a pharmaceutically active agent, ##STR4##

(b) an amine in an amount of from about 0.1% to about 10% by weight of the total composition,

(c) one or more pharmaceutically acceptable solvents, and

(d) one or more pharmaceutically acceptable surfactants;

wherein said solvent is propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, dimethyl acetamide or a mixture thereof;

wherein said surfactant is Polyoxyl 40 hydrogenated castor oil, Polyoxyl 35 castor oil, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, polyethylene glycol 12-hydroxy stearate, polyoxyethylene glyceryl trioleate, Polyoxyethylene stearates, Saturated Polyglycolyzed Glycerides, or Poloxamers;

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. A pharmaceutical composition comprising:

(a) a pyranone compound of formula III or IV as a pharmaceutically active agent, ##STR6##

(b) an armine in an amount of from about 0.1% to about 10% by weight of the total composition,

(c) one or more pharmaceutically acceptable solvents, and

(d) one or more pharmaceutically acceptable surfactants;

wherein said solvent is propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, dimethyl acetamide or a mixture thereof;

wherein said surfactant is Polyoxyl 40 hydrogenated castor oil, Polyoxyl 35 castor oil, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, polyethylene glycol 12-hydroxy stearate, polyoxyethylene glyceryl trioleate, Polyoxyethylene stearates, Saturated Polyglycolyzed

Glycerides, or Poloxamers;

wherein R.sub.10 is H--, CH.sub.3 O--, or CH.sub.3 O--[(CH.sub.2).sub.2 O].sub.3 --;

R.sub.11 is cyclopropyl, or --CH.sub.2 --CH(CH.sub.3).sub.2 ;

R.sub.12 is --NR.sub.14 SO.sub.2 -phenyl, optionally substituted with R.sub.15, --NR.sub.14 SO.sub.2 -het, --CH.sub.2 --SO.sub.2 -phenyl, optionally substituted with R.sub.15, or --CH.sub.2 --SO.sub.2 -het;

R.sub.13 is --H, --(CH.sub.2).sub.2 --CH.sub.3, --CH.sub.2 -cyclopropyl, or --CH.sub.2 -phenyl;

R.sub.14 is --H, or --CH.sub.3 ; R.sub.15 is --CN, --F, --CH.sub.3, --COOH, or --OH; 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 one or two --CH.sub.3, --CN, --C(O)OC.sub.2 H.sub.5, or --OH; or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 1 or 3 wherein a compound of formula II, III or IV is in an amount of from about 1% to about 50%.

5. The pharmaceutical composition of claim 2 wherein a compound of formula I is in an amount of from about 20% to about 30%.

6. The pharmaceutical composition of claim 1 or 3 wherein the amine is lower alkylamine, basic amino acid, or choline hydroxide.

7. The pharmaceutical composition of claim 6 wherein the lower alkylamine is ethanolamine, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, ethylenediamine, or dimethylaminoethanol.

8. The pharmaceutical composition of claim 6 wherein the lower alkylamine is dimethylaminoethanol or tris(hydroxymethyl)aminomethane.

9. The pharmaceutical composition of claim 6 wherein the basic amino acid is arginine, lysine or guanidine.

10. The pharmaceutical composition of claim 1 or 3 wherein the amine is in an amount of from about 0.1% to about 7% by weight of the total composition.

11. The pharmaceutical composition of claim 1 or 3 wherein the amine is in am amount of from about 0.1% to about 5% by weight of the total composition.

12. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable solvent is propylene glycol.

13. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable solvent is a mixture solution comprising propylene glycol and 95% (v/v) ethanol in a ratio of about 1:1.

14. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable solvent is in an amount of from about 10% to about 30% by weight of the total composition.

15. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable solvent is in an amount of from about 15% to about 25% by weight of the total composition.

16. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable surfactant is Polyoxyl 40 hydrogenated castor oil, Polyoxyl 35 castor oil, or Polysorbate 80.

17. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable surfactant is Polyoxyl 40 hydrogenated castor oil.

18. The pharmaceutical composition of claim 1 or 3 wherein the pharmaceutically acceptable surfactant is Polyoxyl 35 hydrogenated castor oil.

19. The pharmaceutical composition of claim 1 or 3 wherein the surfactant is in an amount of from about 10% to about 50% by weight of the total composition.

20. The pharmaceutical composition of claim 1 or 3 wherein the surfactant is in an amount of from about 30% to about 45% by weight of the total composition.

21. The pharmaceutical composition of claim 1 or 3 wherein the composition further comprises one or more oils.

22. The pharmaceutical composition of claim 21 wherein said oil is soybean oil, avocado oil, squalene oil, sesame oil, olive oil, canola oil, corn oil, rapeseed oil, safflower oil, sunflower oil, fish oils, flavored oils, or a mixture thereof.

23. The pharmaceutical composition of claim 21 wherein said oil is monoolein, diolein, triolein, monolinoleate, dilinoleate, or trilinoleate.

24. The pharmaceutical composition of claim 21 wherein said oil is monoolein, diolein, monolinoleate, or dilinoleate.

25. The pharmaceutical composition of claim 21 wherein said oil is in an amount from about 5% to about 35% by weight of the total composition.

26. A pharmaceutical composition comprising:

(a) a pyranone compound of formulas I as when in claim 1 in an amount of from about 20% to about 30% by weight of the total composition,

(b) a dimethylaminoethanol or tnis(hydroxymethyl)aminomethane in an amount of from about 0.1% to about 5% by weight of the total composition,

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

(d) a surfactant comprising Polysorbate 80 in an amount of from about 30% to about 45% by weight of the total composition.

27. The pharmaceutical composition of claim 26 wherein the mixture solution of propylene glycol and ethanol is in a ratio of about 1:1.

28. The pharmaceutical composition of claim 1, 3 or 26 which is a self-emulsifying formulation capable of generating emulsions or microemulsions upon mixing with sufficient aqueous media.

29. The pharmaceutical composition of claim 1, 3, or 26 which is in a form of liquid for soft elastic capsules.
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