Compositions for mucosal delivery of agents

• US 7,906,140 B2
• Filed: 06/16/2005
• Issued: 03/15/2011
• Est. Priority Date: 06/17/2004
• Status: Active Grant

• Current Assignee: Virun, Inc.
• Original Assignee: Virun, Inc.
• Inventors: Huang, Lee Nickols, Bromley, Philip James
• Primary Examiner(s): Wax; Robert A
• Assistant Examiner(s): Mercier; Melissa S
• Application Number:
  US11/155,262
• Publication Number:
  US 20050281772A1
• Time in Patent Office: 2,098 Days
• Field of Search: None
• US Class Current: 424/450
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 38/40 Transferrins, e.g. lactoferrins, ovotransferrins
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

Compositions and methods for mucosal delivery of agents are provided. The compositions are intended for administration to mucosal surface, such as oral and nasal mucosa. The compositions provided contain one or more mucoadhesive proteins and an agent to be delivered. Methods for delivery of agents using the compositions provided herein are also provided.

Claims

1. A composition, comprising:

a mucoadhesive protein, wherein;

the mucoadhesive protein is present at a concentration of about 1% by weight up to about 50% of the total weight of the composition; and

the mucoadhesive protein is selected from among the family of transferrins and the family of mucin proteins, whereby the composition adsorbs to the mucosa for effecting systemic delivery of the agent;

an agent for delivery; and

a delivery vehicle associated with the agent, wherein;

the composition is formulated as an emulsion and is formulated for mucosal delivery to the oral or gastrointestinal tract mucosa;

the mucoadhesive protein is associated with the delivery vehicle via a chemical or physical bond;

the composition has a viscosity of about 50,000 cps up to 500,000 cps at about 72°

F., whereby the composition is retained on a mucosal surface; and

the delivery vehicle is selected from among a micelle, inverse micelle, liposome, cubosome and a mixture thereof.

2. The composition of claim 1, wherein the emulsion is an oil in water or a water in oil emulsion.

3. The composition of claim 1, wherein the agent is dissolved in the oil phase or is dissolved in the water phase.

4. The composition of claim 1, wherein the mucoadhesive protein is a transferrin protein selected from among a lactoferrin, lactoferrin binding proteins, recombinant lactoferrin, lactoferricin, lactoferricin b, transferrin binding proteins, transferrin, ovotransferrin, neutrophil granules, apo-lactoferrin and lanthanide-lactoferrin.

5. The composition of claim 4, wherein the protein is from a human or bovine source.

6. The composition of claim 1, wherein the mucoadhesive protein is lactoferrin.

8. The composition of claim 1, wherein the agent alters a body function or alters cosmetic appearance.

9. The composition of claim 1, wherein the agent is a therapeutic agent.

10. The composition of claim 1, wherein the agent is selected from among antidiabetics, anticonvulsants, analgesics, antiparkinsons, anti-inflammatories, calcium antagonists, anesthetics, antimicrobials, antimalarials, antiparasitics, antihypertensives, antihistamines, antipyretics, alpha-adrenergic agonists, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics, hormones, hypoglycemics, hyperglycemics, muscle contractants, muscle relaxants, neoplastics, glycoproteins, nucleoproteins, lipoproteins, ophthalmics, psychic energizers, sedatives, steroids, sympathomimetics, parasympathomimetics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, vitamins, minerals, nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes, polynucleotides, polypeptides, polysaccharides, and nutritional supplements.

11. The composition of claim 1, wherein the agent is a hormone or a nutritional supplement.

12. The composition of claim 1, wherein the agent is a drug.

13. The composition of claim 1, wherein the agent is a polypeptide drug.

14. The composition of claim 1, wherein the agent is insulin, testosterone, vinpocetin, IGF-1, hexarelin or GHRP-6.

15. The composition of claim 1, comprising a second agent.

16. The composition of claim 15, wherein the two agents are testosterone and vinpocetin.

17. The composition of claim 15, wherein the two agents are hexarelin and GHRP-6.

18. The composition of claim 2, wherein the oil phase comprises oat oil, a medium chain triglyceride and propylene glycol.

19. The composition of claim 18, wherein the oil is present at a concentration of about 5% by weight up to about 30% by weight of the total weight of the composition.

20. The composition of claim 1, further comprising a surface active agent.

21. The composition of claim 20, wherein the surface active agent is polysorbate-80 or phosphatidylcholine.

22. The composition of claim 1, further comprising a cosolvent.

23. The composition of claim 22, wherein the cosolvent is selected from among polyhydric alcohol and combinations of polyhydric alcohols.

24. The composition of claim 23, wherein the cosolvent is selected from among ethylene glycol, dipropylene glycol, propylene glycol, polyethylene glycol, glycerin, butylene glycol, hexylene glycol, polyoxyethylene, polypropylene glycol, sorbitol, and mixtures thereof.

25. The composition of claim 1, further comprising one or more other additives selected from taste modifying agents, a buffering agent, a chelating agent, a colorant, an osmotic modifier, a preservative, a sterilizer, a solubilizer, a tonicifier, a trace element, and a viscomodulator.

27. The composition of claim 1 that is formulated for oral or nasal administration.

28. The composition of claim 1 that has a viscosity of about 100,000 cps up to about 500,000 cps.

29. A method for mucosal delivery of an agent, comprising:

contacting the composition of claim 1 with a mucosal surface of a subject, whereby the agent is delivered into the circulatory system of the subject.

30. The method of claim 29, wherein the composition contacts a mucosal lining for a period of time that is sufficient for quantitative delivery of the agent.

31. The method of claim 30, wherein the composition adheres to or penetrates into a mucosal lining for a period of time that is sufficient for a quantitative delivery of the agent.

32. The method of claim 30, wherein the composition adheres to and penetrates the mucosal lining for about 1 minute up to about 24 hours.

33. The method of claim 30, wherein the agent is selected from among antidiabetics, anticonvulsants, analgesics, antiparkinsons, anti-inflammatories, calcium antagonists, anesthetics, antimicrobials, antimalarials, antiparasitics, antihypertensives, antihistamines, antipyretics, alpha-adrenergic agonists, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics, hormones, hypoglycemics, hyperglycemics, muscle contractants, muscle relaxants, neoplastics, glycoproteins, nucleoproteins, lipoproteins, ophthalmics, psychic energizers, sedatives, steroids, sympathomimetics, parasympathomimetics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, vitamins, minerals, nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes, polynucleotides, polypeptides, polysaccharides, nutritional supplements and combinations thereof.

34. A method for making the composition of claim 1, comprising:

dissolving components of the composition in an oil and water phase; and

mixing the two phases at a predetermined temperature and pressure, whereby the mucoadhesive protein is associated with the delivery vehicle.

35. The method of claim 34, wherein the temperature during the dissolving and mixing step is maintained at a level that prevents denaturation of the mucoadhesive protein.

36. The method of claim 35, wherein the temperature during the dissolving and mixing step is maintained at about 115°

F. and the pressure at about 25 PSI.

37. The method of claim 34, wherein the dissolving step is carried out at about 250 rpm.

38. A method of treating diabetes comprising:

administering a composition of claim 1, to a subject, wherein the composition comprises an agent for treatment of diabetes.

39. An article of manufacture, comprising the composition of claim 1, a packaging material for the composition and a label that indicates that the composition is for altering body function or altering cosmetic appearance.

40. The composition of claim 1, wherein the mucoadhesive protein is present at a concentration of about 5% by weight up to about 50% of the total weight of the composition.

41. The composition of claim 16, wherein the agent is a hormone or a nutritional supplement.

45. The composition of claim 1, wherein the mucoadhesive protein is present at a concentration of about 1% by weight up to about 11% by weight.

7. A composition, comprising:

a mucoadhesive protein selected from among the families of mucin proteins and transferrins, whereby the composition adsorbs to mucosa for effecting systemic delivery of the agent, present at a concentration of about 9% by weight up to about 10% by weight of the total weight of the composition;

an agent for delivery; and

a delivery vehicle associated with the agent, wherein;

the composition is formulated for mucosal delivery to the oral or gastrointestinal mucosa or nasal or lung mucosa;

the mucoadhesive protein is associated with the delivery vehicle;

the mucoadhesive protein is associated with the delivery vehicle via a chemical or physical bond; and

the delivery vehicle is selected from among a micelle, inverse micelle, liposome, cubosome and a mixture thereof.

42. The composition of claim 7, wherein the agent is a drug.

43. The composition of claim 7, wherein the agent is a polypeptide drug.

44. The composition of claim 7, wherein the agent is insulin, testosterone, vinpocetin, IGF-1, hexarelin or GHRP-6.

26. A composition, comprising:

a mucoadhesive protein, wherein;

the mucoadhesive protein is present at a concentration of about 1% by weight up to about 50% of the total weight of the composition; and

the mucoadhesive protein is selected from among the family of transferrins and the family of mucin proteins, whereby the composition is retained on a mucosal surface;

an agent for delivery;

a delivery vehicle associated with the agent, wherein;

the composition is formulated as an emulsion and is formulated for mucosal delivery;

the mucoadhesive protein is associated with the delivery vehicle via a chemical or physical bond; and

the delivery vehicle is selected from among a micelle, inverse micelle, liposome, cubosome and a mixture thereof; and

a taste modifying agent, wherein the taste modifying agent is selected from flavoring agents, sweetening agents and taste masking agents.

46. A composition, comprising:

a mucoadhesive protein selected from among the families of mucin proteins and transferrins, present at a concentration of about 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 20%, 30% or 40% by weight of the total weight of the composition, whereby the composition adsorbs to mucosa for effecting systemic delivery of the agent;

an agent for delivery; and

a delivery vehicle associated with the agent, wherein;

the composition is formulated for mucosal delivery to the oral or gastrointestinal mucosa or nasal or lung mucosa;

the mucoadhesive protein is associated with the delivery vehicle;

the mucoadhesive protein is associated with the delivery vehicle via a chemical or physical bond; and

the delivery vehicle is selected from among a micelle, inverse micelle, liposome, cubosome and a mixture thereof.

47. The composition of claim 46, wherein the mucoadhesive protein is present at a concentration of about 5% by weight.

48. The composition of claim 46, wherein the mucoadhesive protein is present at a concentration of about 6%, 7%, 8%, 9% or 10% by weight.

49. The composition of claim 46, wherein the mucoadhesive protein is present at a concentration of about 12% or 15% by weight.

50. The composition of claim 46, wherein the mucoadhesive protein is present at a concentration of about 20% or 30% by weight.