Submicron emulsions for delivery of peptides

• US 5,514,670 A
• Filed: 08/13/1993
• Issued: 05/07/1996
• Est. Priority Date: 08/13/1993
• Status: Expired due to Fees

• Current Assignee: Pharmos Corporation
• Original Assignee: Pharmos Corporation
• Inventors: Friedman, Doron, Schwarz, Joseph, Amselem, Shimon
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Prickril, Benet
• Application Number:
  US08/106,107
• Time in Patent Office: 998 Days
• Field of Search: 514/2, 514/3, 514/8, 514/11, 514/12, 514/13, 514/14, 514/15, 514/18, 514/19, 424/78.08, 424/78.31, 424/78.33
• US Class Current: 424/185.1
• CPC Class Codes: A61K 38/03 Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/24 Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• 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

Abstract

The present invention provides emulsions comprising a plurality of submicron particles, a bioactive peptide, and an aqueous continuous phase or that effect enhanced oral bioavailability of the peptide. Another aspect of the invention provides compositions and methods of administering peptides in an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, a bioactive peptide, and an aqueous continuous phase, which promotes absorption of the bioactive peptide through mucosal surfaces by achieving mucoadhesion of the emulsion particles. Mucous surfaces suitable for application of the emulsions of the present invention may include corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, stomachic, intestinal, and rectal routes of administration.

Claims

1. A lipid-in-water emulsion for administration of a biologically active peptide, said emulsion comprising a plurality of submicron particles each having a hydrophobic core, a surfactant, a biologically active peptide, and an aqueous continuous phase.

3. The emulsion of claim 1 further comprising a mucoadhesive macromolecule selected from the group consisting of acidic naturally occurring polymers;

acidic synthetically modified natural polymers;

acidic nonnatural polymers;

basic polymers;

neutral nonnatural polymers; and

neutral naturally occurring polymers.

4. The emulsion of claim 1 further comprising a mucoadhesive macromolecule selected from the group of acidic nonnatural polymers consisting of polymers and copolymers containing acrylic acid units, polymers and copolymers containing methacrylic acid units, and poly(methylvinylether/maleic anhydride) copolymer.

5. The emulsion of claim 4 wherein said polymer is polyacrylic acid.

6. The emulsion of claim 3 wherein said mucoadhesive macromolecule is carboxymethylcellulose.

7. The emulsion of claim 3 wherein said mucoadhesive macromolecule is hydroxypropylmethylcellulose.

8. The emulsion of claim 1 further comprising a mucoadhesive macromolecule of a naturally occurring acidic polymer selected from the group consisting of pectin, alginic acid, hyaluronic acid, gum tragacanth, and karaya gum.

9. The emulsion of claim 1 wherein said hydrophobic core comprises a triglyceride.

10. The emulsion of claim 1 wherein said hydrophobic core comprises paraffin or mineral oil.

11. The emulsion of claim 1 wherein said hydrophobic core comprises silicone oil.

12. The emulsion of claim 1 wherein said hydrophobic core comprises an ester of a fatty acid.

13. The emulsion of claim 1 wherein said hydrophobic core contains less than 1% (w/w) cholesterol.

14. The emulsion of claim 1 wherein said emulsion further comprises a cryoprotectant.

15. The emulsion of claim 14 wherein said cryoprotectant is an amino acid or oligopeptide.

16. The emulsion of claim 14 wherein said cryoprotectant is polyvinylpyrrolidone.

17. The emulsion of claim 1 wherein said surfactant is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cholates, phosphatidic acid, and cardiolipin.

18. The emulsion of claim 17 wherein said surfactant comprises phosphatidylcholine.

19. The emulsion of claim 1 wherein said surfactant is selected from the group consisting of fatty alcohols, polyethylene glycol esters of fatty acids, polyethoxylated fatty acids, polyethoxylated fatty alcohol ethers, polyethoxylated alkylphenyl ethers, SDS, polysorbates, and poloxamers.

20. The emulsion of claim 19 wherein said surfactant comprises a polyethylene glycol ester of a fatty acid.

21. The emulsion of claim 1 wherein said biologically active peptide is selected from the group consisting of pentigetide, histamine releasing peptide antigen, and vasoactive intestinal peptide.

22. The emulsion of claim 1 wherein said biologically active peptide is selected from the group consisting of antiflammins, complement blockers, corticotropin releasing factor, interferon gamma antagonists, interleukin 6 antagonists, kinin antagonists, lymphocyte adhesion blockers, and pancreatic trypsin inhibitor.

23. The emulsion of claim 1 wherein said biologically active peptide is selected from the group consisting of calcitonin, PTH-releasing peptide, insulin, human chorionic gonadotropin, human growth hormone, and growth hormone releasing peptide.

24. The emulsion of claim 1 wherein said biologically active peptide is selected from the group consisting of hirudin;

platelet aggregation inhibitors;

platelet adhesion inhibitors;

coagulation protease inhibitors of factors VIIa, Xa, XIIa and thrombin;

kininogen-derived peptides; and

desmopressin.

25. The emulsion of claim 1 wherein said biologically active peptide is selected from the group consisting of antistasin, EGF receptor blockers, bestatin, LHRH agonists, LHRH antagonists, melanoma receptor blockers, and TGF beta.

26. The emulsion of claim 1, wherein said biologically active peptide is selected from the group consisting of atrial natriuretic peptide and analogs, auriculin, atrial peptide clearance inhibitors, brain natriuretic peptide, urodilatin, captopril, ACE inhibitor peptide, and renin inhibitor.

27. The emulsion of claim 1 wherein said biologically active peptide is erythropoietin or adrenocortico-tropic hormone.

28. The emulsion of claim 1 wherein said plurality of submicron particles have an average particle diameter of 30-500 nm.

29. The emulsion of claim 1 wherein said average particle diameter is 70-300 nm.

30. The emulsion of claim 1 wherein said emulsion contains less than 1% (w/w) of an unhalogenated aliphatic C3-C6 alcohol cosurfactant, relative to the weight of the hydrophobic core.

31. The emulsion of claim 1 wherein said emulsion contains less than 1% (w/w) of a monoglyceride cosurfactant, relative to the weight of the hydrophobic core.

32. The emulsion of claim 1 wherein said emulsion contains less than 1% (w/w) of a lysophosphatidylcholine cosurfactant, relative to the weight of the hydrophobic core.

33. The emulsion of claim 1 wherein said emulsion contains less than 1% (w/w) sorbitol, relative to the weight of the hydrophobic core.

34. The emulsion of claim 1 wherein said emulsion contains less than 1% (w/w) milk or serum apolipoprotein, relative to the weight of the hydrophobic core.

2. A lipid-in-water emulsion for administration of a biologically active peptide, said emulsion comprising a plurality of submicron particles each having a hydrophobic core, a surfactant, an aqueous continuous phase and a mucoadhesive macromolecule;

wherein said hydrophobic core comprises a biologically active peptide.

38. The emulsion of claim 2 wherein the peptide is calcitonin, the surfactant comprises a phospholipid and a non-ionic surfactant, and the mucoadhesive macromolecule contains acrylic or methacrylic acid units.

39. The emulsion of claim 38 wherein the surfactant comprises phosphatidylcholine and a polyethylene glycol ester of a fatty acid, and the mucoadhesive macromolecule is a carbomer.

35. A dehydrated emulsion for administration of a biologically active peptide, comprising a plurality of submicron particles each having a hydrophobic core, said biologically active peptide, and a surfactant, whereby a submicron lipid-in-water emulsion is generated when water is added to said dehydrated emulsion.

36. A method for administering a bioactive peptide comprising applying to a mucosal surface a lipid-in-water emulsion comprising a plurality of particles each having a hydrophobic core, a bioactive peptide, a surfactant, and an aqueous continuous phase.

37. The method of claim 36 wherein said emulsion comprises a mucoadhesive molecule.