Pharmaceutical compositions comprising cyclosporins

• US 6,024,978 A
• Filed: 11/02/1998
• Issued: 02/15/2000
• Est. Priority Date: 09/16/1988
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Meinzer, Armin, Richter, Friedrich, Hauer, Birgit, Posanski, Ulrich
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/184,546
• Time in Patent Office: 470 Days
• Field of Search: 424/455, 424/450, 424/400, 514/11, 514/1, 514/937, 514/938-945
• US Class Current: 424/450
• CPC Class Codes: A61K 38/13 Cyclosporins
• 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
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Pharmaceutical compositions comprising a cyclosporin, e.g. Ciclosporin or [Nva]² -Ciclosporin, in "microemulsion pre-concentrate" and microemulsion form. The compositions typically comprise (1.1) a C_1-5 -alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkane diol, e.g. Transcutol or Glycofurol, as hydrophilic component. Compositions are also provided comprising a cyclosporin and (1.1) and, suitably, also a saccharide monoester, e.g. raffinose or saccharose monolaurate. Dosage forms include topical formulations and, in particular, oral dosage forms.

Claims

1. A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy a composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component other than the hydrophilic surfactant, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the composition, the relative proportion of said cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant being such that upon dilution of the composition with adequate water, an oil-in-water microemulsion having particles of less than 2,000 Å

is spontaneously formed.

2. The method of claim 1 wherein the particles have a maximum size of less than 1,500 Å

.

3. The method of claim 1 wherein the maximum size of the particles is from 100 to 1,000 Å

.

4. The method of claim 1 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

5. The method of claim 1 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

6. The method of claim 1 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component and about 20 to about 90% by weight of hydrophilic surfactant, all weights based on the total weight of the composition.

40. The method of claim 1 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

7. A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy a composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component other than the hydrophilic surfactant, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the composition, the relative proportion of said cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant being such that upon dilution of the composition with adequatewater, an oil-in-water microemulsion having an average particle size of less than about 1,500 Å

is spontaneously formed.

8. The method of claim 7 wherein the average particle size is less than about 1,000 Å

.

9. The method of claim 7 wherein the average particle size is from about 150 to less than about 1,000 Å

.

10. The method of claim 7 comprising about 20 to about 90% by weight of hydrophilic surfactant, based on the total weight of the composition.

11. The method of claim 7 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component and about 20 to about 90% by weight of hydrophilic surfactant, all weights based on the total weight of the composition.

39. The method of claim 7 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

12. A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering a pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component other than the hydrophilic surfactant, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the composition, the relative proportion of said cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant being such that upon dilution of the composition with adequate water, an oil-in-water microemulsion having particles of less than 2,000 Å

is spontaneously formed.

13. The method of claim 12 wherein the particles have a maximum size of less than 1,500 Å

.

14. The method of claim 12 wherein the maximum size of the particles is from 100 to 1,000 Å

.

15. The method of claim 12 comprising about 20 to about 90% by weight of hydrophilic surfactant, based on the total weight of the composition.

16. The method of claim 12 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component and about 20 to about 90% by weight of hydrophilic surfactant, all weights based on the total weight of the composition.

38. The method of claim 12 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

17. A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method compromising orally administering a pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component other than the hydrophilic surfacant, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the composition, the relative proportion of said cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfacant being such that upon dilution of the composition with adequate water, an oil-in-water microemulsion having an average particle size of less than about 1,500 Å

spontaneously formed.

18. The method of claim 17 wherein the average particle size is less than about 1,000 Å

.

19. The method of claim 17 wherein the average particle size is from about 150 to less than about 1,000 Å

.

20. The method of claim 18 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

21. The method of claim 18 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

22. The method of claim 17 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component and about 20 to about 90% by weight of hydrophilic surfactant, all weights based on the total weight of the composition.

37. The method of claim 17 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

23. An oral pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component other than the hydrophilic surfactant, 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the composition, the relative proportion of said cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant being such that upon dilution of the compostion with adequate water, an oil-in-water microemulsion having particles of less than 2,000 Å

is spontanteously formed.

24. The composition of claim 23 wherein the particles have a maximum size of less than 1,500 Å

.

25. The composition of claim 23 wherein the maximum size of the particles is from 100 to 1,000 Å

.

26. The composition of claim 23 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

27. The composition of claim 23 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

28. The compostion of claim 23 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component and about 20 to about 90% by weight of hydrophilic surfactant, all weights based on the total weight of the composition.

36. The composition of claim 23 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

29. An oral pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component other than the hydropohilic surfactant, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the composition, the relative proportion of said cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant being such that upon dilution of the composition with adequate water, an oil-in-water microemulsion having an average particle size of less than about 1,500 Å

is spontaneously formed.

30. The composition of claim 29 wherein the average particle size is less than about 1,000 Å

.

31. The composition of claim 29 wherein the average particle size is from about 150 to less than about 1,000 Å

.

32. The composition of claim 29 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

33. The composition of claim 29 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

34. The composition of claim 29 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

35. The composition of claim 29 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component and about 20 to about 90% by weight of hydrophilic surfactant, all weight based on the total weight of the compositon.