Composition for delivering bioactive agents for immune response and its preparation

• US 6,024,983 A
• Filed: 09/07/1993
• Issued: 02/15/2000
• Est. Priority Date: 10/24/1986
• Status: Expired due to Fees

• Current Assignee: Southwest Research Institute, UAB Research Foundation (University of Alabama System)
• Original Assignee: Southwest Research Institute, UAB Research Foundation (University of Alabama System)
• Inventors: Eldridge, John H., Staas, Jay K., Gilley, Richard M., Tice, Thomas R.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US08/116,802
• Time in Patent Office: 2,352 Days
• Field of Search: 428/402.21, 428/402.24, 424/237.1, 424/256.1, 424/434, 424/439, 424/497, 424/499, 424/810, 424/501, 514/885, 514/889, 514/958, 530/403
• US Class Current: 424/501
• CPC Class Codes: A61K 2039/541 Mucosal route
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• 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
• CPC Class Codes: Y10S 424/81 involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, immunotolerance, or anergy
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

A method, and compositions for use therein capable, of delivering a bioactive agent to an animal entailing the steps of encapsulating effective amounts of the agent in a biocompatible excipient to form microcapsules having a size less than approximately ten micrometers and administering effective amounts of the microcapsules to the animal. A pulsatile response is obtained, as well as mucosal and systemic immunity.

Claims

1. A composition for potentiating the immune response of an animal, comprising a mixture of effective amounts of first biocompatible microcapsules having a size between approximately 1 micrometer and approximately 10 micrometers and containing a bioactive agent encapsulated in a first biocompatible excipient and second biocompatible microcapsules containing a bioactive agent encapsulated in a second biocompatible excipient, said first microcapsules providing a primary immunological response and said second microcapsules releasing said agent contained in said second microcapsules in a pulsed manner to potentiate a subsequent immunological response.

2. The composition of claim 1, wherein said first biocompatible microcapsules have a size of between approximately 1 micrometer and approximately 5 micrometers.

3. The composition of claim 1, wherein said first biocompatible microcapsules have a size of between approximately 5 micrometers and approximately 10 micrometers.

4. The composition of claim 1, wherein said second biocompatible microcapsules have a size of between approximately 1 micrometer and approximately 10 micrometers.

5. The composition of claim 1, wherein said second biocompatible microcapsules have a size of between approximately 1 micrometer and approximately 5 micrometers.

6. The composition of claim 1, wherein said second biocompatible microcapsules have a size of between approximately 5 micrometers and approximately 10 micrometers.

7. The composition of claim 1, wherein said second biocompatible microcapsules have a size greater than approximately 10 micrometers.

8. The composition of claim 1, wherein said second biocompatible microcapsules have a size of between approximately 10 and approximately 250 micrometers.

9. The composition of claim 1, wherein said bioactive agents are independently an immunomodulator, lymphokine, monokine, cytokine, or antigen.

10. The composition of claim 1, wherein said bioactive agents are independently antigens.

11. The composition of claim 10, wherein said antigens are independently an allergen, viral antigen, bacterial antigen, protozoan antigen, or a fungal antigen.

12. The composition of claim 10, wherein said antigens are independently an influenzae antigen, Staphylococcus antigen, respiratory syncytial antigen, parainfluenza virus antigen, Hemophilus influenza antigen, Bordetella pertussis antigen, Neisseria gonorrhoea antigen, Streptococcus pneumoniae antigen, Plasmodium falciparum antigen, helminthic pathogen antigen, or an antigen to vaccinate against allergies.

13. The composition of claim 10, wherein said antigens are independently an influenza virus or staphylococcal enterotoxin B.

14. The composition of claim 1, wherein said bioactive agents independently comprise a peptide, protein or nucleic acid.

15. The composition of claim 1, wherein said bioactive agents are the same.

16. The composition of claim 1, wherein said first and said second biocompatible excipients are independently a poly(lactide-co-glycolide), poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, poly(β

-hydroxybutyric acid), polyanhydride, or a mixture thereof.

17. A composition for potentiating the immune response of an animal, comprising a mixture of effective amounts of a priming bioactive agent and first microcapsules having a size between approximately 1 micrometer and approximately 10 micrometers and containing a bioactive agent encapsulated in a first biocompatible excipient, said priming bioactive agent providing a primary immunological response and said first microcapsules releasing said bioactive agent contained in said first microcapsules in a pulsed manner to potentiate a subsequent immune response.

18. The composition of claim 17, wherein said first biocompatible microcapsules have a size of between approximately 1 micrometer and approximately 5 micrometers.

19. The composition of claim 17, wherein said first biocompatible microcapsules have a size of between approximately 5 micrometers and approximately 10 micrometers.

20. The composition of claim 17, wherein said priming bioactive agent is encapsulated in a second biocompatible excipient to form second microcapsules having a size greater than approximately 10 micrometers.

21. The composition of claim 17, wherein said second microcapsules have a size of between approximately 10 micrometers and approximately 250 micrometers.

22. The composition of claim 17, wherein said bioactive agents are independently an immunomodulator, lymphokine, monokine, cytokine, or antigen.

23. The composition of claim 17, wherein said bioactive agents are independently antigens.

24. The composition of claim 23, wherein said antigens are independently an allergen, viral antigen, bacterial antigen, protozoan antigen, or a fungal antigen.

25. The composition of claim 23, wherein said antigens are independently an influenzae antigen, Staphylococcus antigen, respiratory syncytial antigen, parainfluenza virus antigen, Hemophilus influenza antigen, Bordetella pertussis antigen, Neisseria gonorrhoea antigen, Streptococcus pneumoniae antigen, Plasmodium falciparum antigen, helminthic pathogen antigen, or an antigen to vaccinate against allergies.

26. The composition of claim 23, wherein said antigens are independently an influenza virus or staphylococcal enterotoxin B.

27. The composition of claim 17, wherein said bioactive agents independently comprise a peptide, a protein, or nucleic acid.

28. The composition of claim 17, wherein said bioactive agents are the same.

29. The composition of claim 17, wherein said first and said second biocompatible excipients are independently a poly(lactide-co-glycolide), poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, poly(β

-hydroxybutyric acid), polyanhydride, or a mixture thereof.

30. The composition of claim 17, wherein said priming bioactive agent is a free bioactive agent.

31. A composition for potentiating the immune response of an animal, comprising a mixture of effective amounts of a priming bioactive agent and first microcapsules having a size less than approximately 10 micrometers and containing a bioactive agent encapsulated in a first biocompatible excipient, said priming bioactive agent providing a primary immunological response and said first microcapsules releasing said bioactive agent contained in said first microcapsules in a pulsed manner to potentiate a subsequent immune response.

32. A composition for delivering a bioactive agent that provides or potentiates an immune response to the mucosally associated lymphoreticular tissues of an animal or for parenterally delivering a bioactive agent that provides or potentiates an immune response to an animal, comprising an effective amount of said bioactive agent encapsulated in a biocompatible excipient to form microcapsules having a size between approximately 1 micrometer and approximately 10 micrometers, wherein said biocompatible excipient is a poly(lactide-co-glycolide), poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, poly(β

-hydroxybutyric acid), polyanhydride, or a mixture thereof.

33. The composition of claim 32, wherein said microcapsules have a size between approximately 5 micrometers and approximately 10 micrometers.

34. The composition of claim 32, wherein said microcapsules have a size between approximately 1 micrometer and approximately 5 micrometers.

35. The composition of claim 32, wherein said bioactive agent is a nutrient, immunomodulator, lymphokine, monokine, cytokine, or antigen.

36. The composition of claim 32, wherein said bioactive agent is an antigen.

37. The composition of claim 36, wherein said antigen is an allergen, viral antigen, bacterial antigen, protozoan antigen, or a fungal antigen.

38. The composition of claim 36, wherein said antigen is an influenzae antigen, Staphylococcus antigen, respiratory syncytial antigen, parainfluenza virus antigen, Hemophilus influenza antigen, Bordetella pertussis antigen, Neisseria gonorrhoea antigen, Streptococcus pneumoniae antigen, Plasmodium falciparum antigen, helminthic pathogen antigen, or an antigen to vaccinate against allergies.

39. The composition of claim 36, wherein said antigen is an influenza virus or staphylococcal enterotoxin B.

40. The composition of claim 36, wherein said bioactive agent further includes a cytokine.

41. The composition of claim 40, wherein said bioactive agent further includes an adjuvant.

42. The composition of claim 32, wherein said bioactive agent is a mixture of a cytokine and an adjuvant.

43. The composition of claim 32, wherein said bioactive agent comprises a peptide, protein, or nucleic acid.

44. The composition of claim 32, wherein the composition is for delivery to the mucosally associated lymphoreticular tissues of an animal, the mucosally associated lymphoreticular tissues are the Peyer'"'"'s patch, the excipient is biodegradable, the microcapsules are capable of passing through the gastrointestinal tract without degradation, and the excipient is a poly(lactide-co-glycolide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, or a poly(β

-hydroxybutyric acid).

45. A composition for potentiating the immune response of an animal, comprising a mixture of effective amounts of first biocompatible microcapsules having a size less than approximately 10 micrometers and containing a bioactive agent encapsulated in a first biocompatible excipient and second biocompatible microcapsules containing a bioactive agent encapsulated in a second biocompatible excipient, said first microcapsules providing a primary immunological response and said second microcapsules releasing said agent contained in said second microcapsules in a pulsed manner to potentiate a subsequent immunological response.

46. A composition for delivering a bioactive agent to the mucosally associated lymphoreticular tissues of an animal, comprising an effective amount of said bioactive agent encapsulated in a biocompatible excipient to form microcapsules having a size between approximately 1 micrometer and approximately 10 micrometers, wherein said microcapsules comprise a mixture of a plurality of first microcapsules having a size between approximately 1 micrometer and approximately 5 micrometers and a plurality of second microcapsules having a size between approximately 5 micrometers and approximately 10 micrometers for providing both a systemic immunity and a mucosal immunity to said animal.

47. A method of preparing a composition for delivering a bioactive agent that provides or potentiates an immune response to the mucosally associated lymphoreticular tissues of an animal, comprising the step of encapsulating effective amounts of said bioactive agent in a biocompatible excipient to form microcapsules having a size between approximately 1 micrometer and approximately 10 micrometers, wherein the excipient is a poly(lactide-co-glycolide), poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, poly(β

-hydroxybutyric acid), polyanhydride, or a mixture thereof.

48. The method of claim 47, wherein said microcapsules have a size between approximately 5 micrometers and approximately 10 micrometers so that said microcapsules can be retained in said mucosally associated lymphoreticular tissues.

49. The method of claim 47, wherein said microcapsules have a size between approximately 1 micrometer and approximately 5 micrometers so that said microcapsules can pass through said mucosally associated lymphoreticular tissues.

50. The method of claim 47, wherein said bioactive agent is a nutrient, immunomodulator, lymphokine, monokine, cytokine, or antigen.

51. The method of claim 47, wherein said bioactive agent comprises a peptide, protein or nucleic acid.

52. A method of preparing a composition for delivering a bioactive agent to the mucosally associated lymphoreticular tissues of an animal, comprising the step of encapsulating effective amounts of said bioactive agent in a biocompatible excipient to form microcapsules having a size between approximately 1 micrometer and approximately 10 micrometers, wherein said microcapsules are comprised of a plurality of first microcapsules having a size between approximately 1 micrometer and approximately 5 micrometers and a plurality of second microcapsules having a size between approximately 5 micrometers and approximately 10 micrometers, said first and second microcapsules can be administered to said animal to provide both a systemic immunity and a mucosal immunity.

53. A method of preparing a composition for providing systemic immunity in an animal, comprising the step of encapsulating effective amounts of a bioactive agent in a biocompatible excipient to form microcapsules having a size between approximately 1 micrometer and approximately 5 micrometers, wherein the excipient is a poly(lactide-co-glycolide), poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, poly(β

-hydroxybutyric acid), polyanhydride, or a mixture thereof.

54. A method of preparing a composition for providing mucosal immunity in an animal, comprising the step of encapsulating effective amounts of a bioactive agent in a biocompatible excipient to form microcapsules having a size between approximately 5 micrometers and approximately 10 micrometers, wherein the excipient is a poly(lactide-co-glycolide), poly(lactide), poly(glycolide), copolyoxalate, polycaprolactone, poly(lactide-co-caprolactone), poly(esteramide), polyorthoester, poly(β

-hydroxybutyric acid), polyanhydride, or a mixture thereof.