Micellar colloidal pharmaceutical composition containing a lipophilic active principle

• US 20040052824A1
• Filed: 06/25/2003
• Published: 03/18/2004
• Est. Priority Date: 12/28/2000
• Status: Abandoned Application

• Current Assignee: CCL Pharma
• Original Assignee: CCL Pharma
• Inventors: Toselli, Dominique, Laruelle, Claude, Abou Chacra-Vernet, Marie-Line
• Application Number:
  US10/465,923
• Publication Number:
  US 20040052824A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

The invention concerns novel pharmaceutical compositions capable of comprising micelles containing at least a very lipophilic principle, enabling to enhance bioavailability of active principles insoluble in aqueous solvents called MIDDS® (Micellar Improved Drug Delivery Solutions).

Claims

1. A self-micro emulsifying pharmaceutical composition for oral use comprising:

at least one lipophilic active principle,

at least one surfactant having a hydrophilic/lipophilic balance of less than 16,

at least one cosurfactant,

at least one lipophilic phase, characterized in that;

the lipophilic active principle(s) have a log P greater than 2,

the surfactant(s) represent at least 50% by weight of the total weight of said composition,

the cosurfactant(s) are chosen from the good solvents for said active principle(s),

the lipophilic phase is optionally surface-active and represents less than 0.5 to 4.5% by weight of the total weight of said composition and has an HLB of less than or equal to 6, and

when the active principle is different from a retinoid, then said composition additionally comprises a nonsurfactant oily phase representing from 1 to 12% of the total weight of said composition.

2. The composition as claimed in claim 1, characterized in that the active principle(s) have a log P greater than 4.

3. The composition as claimed in claim 1 or 2, characterized in that the active principle(s) are chosen from retinoids, hypolipidemic agents, steroid hormones, steroid anti-inflammatories, nonsteroid anti-inflammatories (NSAIDs), antiretrovirals, protease inhibitors (“

navirs”

), antiacids, proton pump inhibitors, antiemetics, fat-soluble vitamins, cardiovascular system drugs, platelet aggregation inhibitors, cancer drugs, certain plant extracts and their isolated or derived APs, immunosuppressants, central nervous system drugs, antimigraines, antibiotics, antifungals and antiparasitics.

4. The composition as claimed in claim 3, characterized in that the active principle(s) are chosen from retinoids, hypolipidemic agents and steroid hormones.

5. The composition as claimed in claim 3 or 4, characterized in that it contains isotretinoin in a quantity of between 1 and 2.5% by weight relative to the total weight of the composition.

6. The composition as claimed in claim 3 or 4, characterized in that it contains fenofibrate in a quantity of between 5 and 10% by weight relative to the total weight of the composition.

7. The composition as claimed in claim 2 or 3, characterized in that it contains progesterone in a quantity of between 3 and 7% by weight relative to the total weight of the composition.

8. The composition as claimed in any one of the preceding claims, characterized in that the surfactant(s) are chosen from polyglycolized C₈-C₁₈ glycerides, polysorbates or polyethylene glycols (PEG)-esters of C₁₂-C₁₈ fatty acids, macrogol and propylene glycol esters of C₈-C₁₈ fatty acids, macrogol-glyceride esters of C₁₂-C₁₈ fatty acids, polyglyceric esters of C₁₂-C₁₈ fatty acids, and mixtures thereof.

9. The composition as claimed in any one of the preceding claims, characterized in that the surfactant(s) represent from 70 to 85% of the total weight of the composition.

10. The composition as claimed in any one of the preceding claims, characterized in that the cosurfactant(s) are chosen from diethylene glycol monoethyl ether;

N-methyl-2-pyrrolidone;

the triester of glycerol and acetic acid;

dimethyl isosorbate;

polyethylene glycols;

alcohols and glycols;

mono- and diesters of propylene glycol and of caprylic, capric, lauric fatty acids;

mono- and diglycerides of caprylic, capric, lauric, oleic, stearic fatty acids; and

mixtures thereof.

11. The composition as claimed in any one of the preceding claims, characterized in that the cosurfactant(s) represent from 5% to 20% of the total weight of the composition.

12. The composition as claimed in claim 5, characterized in that the cosurfactant concentration is between 10 and 15% of the total weight of the composition.

13. The composition as claimed in claim 6, characterized in that the CoS concentration is between 5 and 10% of the total weight of the composition.

14. The composition as claimed in any one of the preceding claims, characterized in that the lipophilic phase has an HLB of less than or equal to 4, and is chosen from fatty acid esters;

sorbitan esters of saturated or unsaturated fatty acids and their derivatives;

glycerol, propylene or butylene glycol esters of fatty acids;

medium chain triglycerides of caprylic, capric or lauric fatty acids; and

mixtures thereof.

15. The composition as claimed in claim 14, characterized in that the fatty acid esters are chosen from macrogol (or polyethylene glycol) glycerides, in other words polyglycolized glycerides of fatty acids.

16. The composition as claimed in claim 5, characterized in that it contains a lipophilic phase in a proportion of between 3 and 4.5% by weight relative to the total weight of the composition.

17. The composition as claimed in claim 5, characterized in that it contains a nonsurfactant oily phase representing from 1 to 12% of the total weight of said composition and at least one thickening agent.

18. The composition as claimed in any one of the preceding claims, characterized in that the oily phase is chosen from oils of natural and synthetic origin.

19. The composition as claimed in claim 18, characterized in that the natural oils are chosen from almond, peanut, rapeseed, cotton seed, linseed, corn, olive, borage, evening primrose, fish, palm, palm kernel, grapeseed, sesame, soybean and sunflower oils.

20. The composition as claimed in claim 18, characterized in that the synthetic oils are chosen from fatty acid esters whose HLB value is between 1 and 3.

21. The composition as claimed in claim 6, characterized in that it contains an oily phase in a proportion of between 2 and 15% by weight.

22. The composition as claimed in any one of the preceding claims, characterized in that it leads, in the presence of a hydrophilic phase, to the formation of a microemulsion in which the size of the micelles is less than 500 nm, and more particularly between 1 and 200 nm.

23. The composition as claimed in any one of the preceding claims, characterized in that it is packaged in hard gelatin capsules or in soft gelatin capsules.