Composition

• US 20040096494A1
• Filed: 09/09/2003
• Published: 05/20/2004
• Est. Priority Date: 03/15/2001
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Siekmann, Britta, Thoring, Barbo
• Application Number:
  US10/471,378
• Publication Number:
  US 20040096494A1
• Time in Patent Office: Days
• US Class Current: 424/450
• 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: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A new pharmaceutical composition in the form of lipoglobules which comprises (a) one or more NO-releasing NSAID(s); (b) one or more surfactant(s); and (c) an aqueous phase, as well as a process for the preparation of such composition and the use of such composition in the treatment of pain and inflammation.

Claims

1. A pharmaceutical composition in form of lipoglobules comprising

(a) one or more NO-releasing NSAID(s);

(b) one or more surfactant(s); and

(c) an aqueous phase

wherein the NO-releasing NSAD(s) is a lipophilic core surrounded by one or more layers of surfactant(s), which NO-releasing NSAID(s) and surfactant(s) are dispersed in an aqueous phase.

2. A pharmaceutical composition according to claim 1 wherein the NO-releasing NSAID is a compound of the formula I

3. A pharmaceutical composition according to claim 2, wherein the spacer X of the NO-releasing NSAID is selected from a linear, branched or cyclic alkylene group —

(CH₂)—

_n wherein n is an integer of from 2 to 10;

—

(CH₂)_m—

O—

(CH₂)_p—

wherein m and p are integers of from 2 to 10; and

—

CH₂—

pC₆H₄—

CH₂—

.

4. A pharmaceutical composition according to any one of the preceding claims, wherein the NO-releasing NSAID is any one compound selected from

5. A pharmaceutical composition according to claim 4 wherein the NO-releasing NSAID is a compound according to formula Ia.

6. A pharmaceutical composition according to claim 4 wherein the NO-releasing NSAID is a compound according to formula Ic, If, Ig or IL.

11. A pharmaceutical composition according to any one of claims 1-10 wherein the NO-releasing NSAID lipophilic core further comprises one or more lipophilic water-immiscible solvent(s).

12. A pharmaceutical composition according to claim 11 wherein the lipophilic water-immiscible solvent is a vegetable oil;

a fractionated oil;

a marine oil;

an ester of a medium or long-chain fatty acid;

a chemically modified or manufactured material;

or a mixture of two or more of the above water-immiscible solvents.

13. A pharmaceutical composition according to claim 11 wherein the lipophilic, water immiscible solvent is fractionated coconut oil.

20. Use of a pharmaceutical composition according to claims 1-18 for use in therapy.

21. Use according to claim 20 in the treatment of pain.

22. Use according to claim 20 in the treatment of inflammation.

23. A method for the treatment of pain which method comprises treating a subject suffering from said condition with a pharmaceutical composition according to any one of claims 1-18.

24. A method for the treatment of inflammation which method comprises treating a subject suffering from said condition with a pharmaceutical composition according to any one of claims 1-18.

25. A process for the preparation of a composition according to any one of claims 1-20 wherein

i) one or more surfactant(s) is added to an aqueous phase whereupon one or more NO-NSAID(s) is dispersed in the aqueous phase by using conventional dispersion techniques such as high shear mixing, sonication or high pressure homogenisation;

or

ii) one or more NO-NSAID(s) is mixed with one or more surfactant(s), whereupon the mixture is dispersed in an aqueous phase by using conventional dispersion techniques such as high shear mixing, sonication or high pressure homogenisation;

or

iii) one or more surfactant(s) is added to an aqueous phase and one or more NO-NSAID(s) is mixed with one or more lipophilic water-immiscible solvent(s), whereupon the mixture of NO-NSAID(s) and lipophilic water-immiscible solvent(s) is dispersed in the aqueous phase by using conventional dispersion techniques such as high shear mixing, sonication or high pressure homogenisation;

or

iv) one or more NO-NSAID(s) is mixed with one or more surfactant(s) and one or more lipophilic water-immiscible solvent(s), whereupon the mixture is dispersed in an aqueous phase by using conventional dispersion techniques such as high shear mixing, sonication or high pressure homogenisation;

or

v) one or more surfactant(s) is added to the aqueous phase, and one or more surfactant(s) is mixed with one or more NO-NSAID(s), whereupon the mixture of NO-NSAID(s) and surfactant(s) is dispersed in the aqueous phase by using conventional dispersion techniques such as high shear mixing, sonication or high pressure homogenisation;

or

vi) one or more surfactant(s) is added to the aqueous phase, and one or more surfactant(s) as well as one or more lipophilic water-immiscible solvent(s) is mixed with one or more NO-NSAID(s), whereupon the mixture of NO-NSAID(s), surfactant(s) and lipophilic water-immiscible solvent(s) is dispersed in the aqueous phase by using conventional dispersion techniques such as high shear mixing, sonication or high pressure homogenisation.

26. A process according to claim 25 wherein the NO-releasing NSAID(s) is heated above its melting point prior to dispersion in the aqueous phase.

7. A pharmaceutical composition according to any one of the preceeding claims wherein the surfactant is selected from phospholipids, e.g. naturally occurring phospholipids;

synthetic or semisynthetic phospholipids;

ethoxylated phospholipids;

galactolipids and other glycolipids;

bile acids and their salts;

sterols and esters therof;

ethoxylated sterols;

fatty acids and their salts;

mono- and diglyceride esters of fatty acids;

fatty acid esters and alcohols;

ethoxylated fatty acids, ethers and esters;

ethoxylated castor oil;

ethoxylated sorbitan esters;

polypropylenepolyethylene block copolymers such as poloxamers and poloxamines;

or mixtures of two or more of these surfactants.

8. A pharmaceutical composition according to claim 7 wherein the surfactant is one of a naturally occurring, synthetic or semi-synthetic phospholipid;

a polypropylene polyethylene block copolymer;

an ethoxylated sorbitan ester;

or a mixture of two or more of these surfactants.

9. A pharmaceutical composition according to claim 7 wherein the surfactant is a naturally occurring phospholipid from soya in combination with a poloxamer.

10. A pharmaceutical formulation according to claim 7 wherein the surfactant is polysorbate 80.

14. A pharmaceutical composition according to any one of the preceeding claims wherein the aqueous phase contains water and one or more of buffering agents;

salts;

pH adjusting agents;

tonicity modifiers;

water miscible solvents;

density modifiers;

viscosity modifiers agents;

preservatives;

antioxidants; and

taste modifiers.

15. A pharmaceutical composition according any one of the preceeding claims wherein the amount of NO-releasing NSAID or mixtures of NO-releasing NSAID and water-immiscible solvent is up to 30% by weight of the composition.

16. A pharmaceutical composition according to claim 15 wherein the amount of NO-releasing NSAID or mixtures of NO-releasing NSAID and water-immiscible solvent is 0.5-20% by weight of the composition.

17. A pharmacutical composition according to any one of the preceeding claims wherein the amount of surfactant is up to 20% by weight of the composition.

18. A pharmaceutical composition according to claim 17 wherein the amount of surfactant is 0.1-10% by weight of the composition.

19. A pharmaceutical composition according to any one of the preceeding. claims for oral, rectal, parenteral, nasal or topical administration to a human or an animal.