Pharmaceutical formulations

• US 5,665,700 A
• Filed: 08/15/1994
• Issued: 09/09/1997
• Est. Priority Date: 03/29/1990
• Status: Expired due to Fees

• Current Assignee: SKUA Investments Limited
• Original Assignee: SKUA Investments Limited
• Inventors: Cho, Young W., Shepherd, Thomas Smith, Flynn, Michael John
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): Gupta, Anish
• Application Number:
  US08/290,293
• Time in Patent Office: 1,121 Days
• Field of Search: 514/21, 514/12, 514/8, 514/4, 514/3, 514/2, 514/937
• US Class Current: 514/6.5
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

A Pharmaceutical formulation comprises a biologically active material such as insulin, erythropoietin, calcitonin and growth hormone, and, associated with it, a phospholipid for forming a material which participates in the alpha-glycerol or other pathways for the formation of lecithins which are found in the intestinal epithelial cell. Biologically active protein orally administered in such a formulation are bioavailable and bioactive.

Claims

1. A water-in-oil pharmaceutical formulation for oral or rectal administration comprising a hydrophilic phase dispersed in a lipophilic phase to form an emulsion,

wherein said hydrophilic phase comprises (a) water, (b) a biologically active material and (c) in association with the biologically active material, lecithin or a lecithin precursor,

wherein said lipophilic phase comprises (a) one or more oils, (b) a phospholipid and (c) a lipophilic surfactant,

and wherein an emulsion is formed from said hydrophilic phase dispersed in said lipophilic phase.

2. The formulation as claimed in claim 1, wherein said biologically active material comprises a protein.

3. The formulation as claimed in claim 2, wherein said protein is insulin, erythropoietin, porcine somatotropin, human growth hormone or calcitonin.

4. The formulation as claimed in claim 1, wherein said lecithin precursor is a phospholipid.

5. The formulation as claimed in claim 4, wherein said phospholipid has the general formula:

##STR2## and wherein each of R1 and R2 independently represents an acyl group and X represents a hydrogen atom or a phospholipid headgroup.

6. The formulation as claimed in claim 5, wherein said phospholipid headgroup contains a residue of ethanolamine, choline, serine or glycerol.

7. The formulation as claimed in claim 6, wherein said phospholipid comprises:

dimyristoryl phosphatidyl glycerol (DMPG);

dipalmitoyl phosphatidyl glycerol (DPPG);

distearoyl phosphatidyl glycerol (DSPG);

dimyristoyl phosphatidylcholine (DMPC);

dipalmitoyl phosphatidylcholine (DPPC);

distearoyl phosphatidylcholine (DSPC);

dimyristoyl phosphatidic acid (DMPA);

dipalmitoyl phosphatidic acid (DPPA);

or

distearoyl phosphatidic acid (DSPA).

8. The formulation as claimed in claim 6, wherein said phospholipid comprises:

dimyristoyl phosphatidyl ethanolamine (DMPE);

dipalmitoyl phosphatidyl ethanolamine (DPPE);

or

distearoyl phosphatidyl ethanolamine (DSPE).

9. The formulation as claimed in claim 1, comprising a lecithin.

10. The formulation as claimed in claim 1, comprising a hydrophilic liquid.

11. The formulation as claimed in claim 1, wherein said hydrophilic phase further comprises a hydrophilic surfactant.

12. The formulation as claimed in claim 1, further comprising a protease inhibitor.

13. The formulation as claimed in claim 1, further comprising a stabilizer for the biologically active material.

14. The formulation as claimed in claim 1, further comprising an emulsification aid.

15. The formulation as claimed in claim 1, further comprising a stabilizer or a plasticizer or both.

16. The formulation as claimed in claim 1, further comprising a preservative.

17. The formulation as claimed in claim 16, wherein said preservative comprises an antioxidant.

18. The formulation as claimed in claim 1, wherein said formulation is coated on a solid core.

19. A method for the treatment or prophylaxis of a human or other animal with a disorder treatable or controllable by a normally parenterally administered biologically active material comprising the oral or rectal administration of a formulation as claimed in claim 1.

20. A water-in-oil pharmaceutical formulation for oral or rectal administration comprising a hydrophilic phase dispersed in a lipophilic phase to form an emulsion,

wherein said hydrophilic phase comprises (a) water, (b) a biologically active material and (c) in association with the biologically active material lecithin or a lecithin precursor,

wherein said lipophilic phase comprises (a) materials that can be used to form a chylomicron matrix, (b) a phospholipid and (c) a lipophilic surfactant,

and wherein an emulsion is formed from said hydrophilic phase dispersed in said lipophilic phase.

21. The formulation as claimed in claim 20, wherein said chylomicron matrix comprises cholesterol or cholesterol ester, or both.

22. The formulation as claimed in claim 21, wherein said phospholipid is lecithin.

23. The formulation as claimed in claim 20, wherein said biologically active material is insulin, erythropoietin, porcine somatotropin, human growth hormone or calcitonin.

24. The formulation as claimed in claim 20, wherein said lecithin precursor is a phospholipid.

25. The formulation as claimed in claim 24, wherein said phospholipid has the general formula:

##STR3## wherein each of R1 and R2 independently represents an acyl group and X represents a hydrogen atom or a phospholipid headgroup.

26. The formulation as claimed in claim 25, wherein said phospholipid headgroup contains a residue of ethanolamine, choline, serine or glycerol.

27. The formulation as claimed in claim 26, wherein said phospholipid comprises:

dimyristoyl phosphatidyl glycerol (DMPG);

dipalmitoyl phosphatidyl glycerol (DPPG);

distearoyl phosphatidyl glycerol (DSPG);

dimyristoyl phosphatidylcholine (DMPC);

dipalmitoyl phosphatidylcholine (DPPC);

distearoyl phosphatidylcholine (DSPC);

dimyristoyl phosphatidic acid (DMPA);

dipalmitoyl phosphatidic acid (DPPA);

or

distearoyl phosphatidic acid (DSPA).

28. The formulation as claimed in claim 26, wherein said phospholipid comprises:

dimyristoyl phosphatidyl ethanolamine (DMPE);

dipalmitoyl phosphatidyl ethanolamine (DPPE);

or

distearoyl phosphatidyl ethanolamine (DSPE).

29. The formulation as claimed in claim 20, comprising a lecithin.

30. The formulation as claimed in claim 20, comprising a hydrophilic liquid.

31. The formulation as claimed in claim 20, wherein said hydrophilic phase further comprises a hydrophilic surfactant.

32. The formulation as claimed in claim 20, further comprising a protease inhibitor.

33. The formulation as claimed in claim 20, further comprising a stabilizer for the biologically active material.

34. The formulation as claimed in claim 20, further comprising an emulsification aid.

35. The formulation as claimed in claim 20, further comprising a stabilizer or a plasticizer or both.

36. The formulation as claimed in claim 20, further comprising a preservative.

37. The formulation as claimed in claim 36, wherein said preservative comprises an antioxidant.

38. The formulation as claimed in claim 20, wherein said formulation is coated on a solid core.

39. A method for the treatment or prophylaxis of a human or other animal with a disorder treatable or controllable by a normally parenterally administered biologically active material comprising the oral or rectal administration of a formulation as claimed in claim 20.

40. A water-in-oil pharmaceutical formulation for oral or rectal administration comprising a hydrophilic phase dispersed in a lipophilic phase to form an emulsion,

wherein said hydrophilic phase comprises (a) water, (b) a biologically active material and (c) in association with the biologically active material, lecithin or a lecithin precursor comprising a phospholipid,

wherein said lipophilic phase comprises (a) one or more oils, (b) a phospholipid and (c) a lipophilic surfactant,

and wherein an emulsion is formed from said hydrophilic phase dispersed in said lipophilic phase.

42. The formulation as claimed in claim 40 or 41, wherein said biologically active material comprises a protein.

43. The formulation as claimed in claim 42, wherein said protein is insulin, erythropoietin, porcine somatotropin, human growth hormone or calcitonin.

44. The formulation as claimed in claim 40 or 41, wherein said phospholipid headgroup contains a residue of ethanolamine, choline, serine or glycerol.

45. The formulation as claimed in claim 40 or 41, wherein said phospholipid comprises:

dimyristoryl phosphatidyl glycerol (DMPG);

dipalmitoyl phosphatidyl glycerol (DPPG);

distearoyl phosphatidyl glycerol (DSPG);

dimyristoyl phosphatidylcholine (DMPC);

dipalmitoyl phosphatidylcholine (DPPC);

distearoyl phosphatidylcholine (DSPC);

dimyristoyl phosphatidic acid (DMPA);

dipalmitoyl phosphatidic acid (DPPA);

or

distearoyl phosphatidic acid (DSPA).

46. The formulation as claimed in claim 40 or 41, wherein said phospholipid comprises:

dimyristoyl phosphatidyl ethanolamine (DMPE);

dipalmitoyl phosphatidyl ethanolamine (DPPE);

or

distearoyl phosphatidyl ethanolamine (DSPE).

41. A water-in-oil pharmaceutical formulation for oral or rectal administration comprising a hydrophilic phase dispersed in a lipophilic phase to form an emulsion,

wherein said hydrophilic phase comprises (a) water, (b) a biologically active material and (c) in association with the biologically active material, a phospholipid, wherein said phospholipid has the general formula:

##STR4## and wherein each of R1 and R2 independently represents an acyl group and X represents a hydrogen atom or a phospholipid headgroup,

wherein said lipophilic phase comprises (a) one or more oils, (b) a phospholipid and (c) a lipophilic surfactant,

and wherein an emulsion is formed from said hydrophilic phase dispersed in said lipophilic phase.