Active/passive immunization of the internal female reproductive organs

• US 4,756,907 A
• Filed: 01/24/1986
• Issued: 07/12/1988
• Est. Priority Date: 10/17/1978
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Stolle Research & Development Corporation
• Inventors: Flowers, Charles F. Jr., Cowsar, Donald R., Beck, Lee R., Tanquary, Albert C.
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US06/822,236
• Time in Patent Office: 900 Days
• Field of Search: 424/85, 424/86, 424/87, 424/88, 424/89, 424/92, 424/489, 424/490, 424/491, 514/170, 514/171, 514/841, 514/843, 514/885, 514/899
• US Class Current: 424/178.1
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• 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 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres

Abstract

Antibody or antigen containing microparticles for the active or passive immunization of the internal female reproductive organs, comprising: microparticles of an antigen or antibody incorporated in a matrix material which is biocompatible and biologically degradable, said microparticles capable of being transported after deposition in the vagina by the natural transport mechanism of the internal female reproductive organs across the cervix into the uterus.

Claims

1. A method of duplicating the menstrual cycle of a host female while administering an antibody or antigen to the internal female reproductive organs, comprising:

depositing estrogen containing microparticles in the vagina where estrogen is steadily released thereby duplicating days 1 to 14 of the estrogenic phase of the menstrual cycle and rendering the cervix increasingly capable of microparticle transport;

depositing progestin containing microparticles in the vagina where said progestin is released after day 1 to day 28 of said menstrual cycle, thereby duplicating the progestational phase of said cycle; and

depositing microparticles containing said antigen or antibody in the vagina in time sufficient for the maximum transport of said antibody or antigen containing microparticles between days 12 and 16 of said cycle across the cervix into the uterus and fallopian tubes where said antigen or antibody is released so as to elicit an antibody response or passive immunization within the uterus.

2. The method of claim 1, wherein said microparticles are of a monolithic structure in which said antigen is dispersed throughout a matrix material.

3. The method of claim 1, wherein said microparticles are of a layered structure comprising a core of said antigen surrounded by a matrix material.

4. The method of claim 1, wherein said microparticles are of a layered structure comprising a core of said antigen dispersed in a matrix material surrounded by said matrix material free of antigen.

5. The method of claim 1, wherein said antigen induces a contraceptive response and is derived from the blastocyst, the ovum, sperm, is a non-hormonal placental antigen or is a trophobactic hormone.

6. The method of claim 1, wherein said estrogen is estradiol and said progestin is progesterone.

7. The method of claim 1, wherein said estrogen is released from said microparticles at a rate of 0.1 to 1 mg per day and wherein said progestin is released at a rate of 0.5 and 2 mg per day.

8. The method of claim 1, wherein said estrogen and antigen or antibody are both incorporated in said microparticles structured such that the microparticles have a core containing antigen or antibody in a matrix material and an outer shell of matrix material throughout which is dispersed said estrogen.

9. The method of claim 1, wherein said estrogen and antibody or antigen containing microparticles are dispersed in the vagina such that estrogen is steadily released from said outer shell of said microparticles during the estrogenic phase of said menstrual cycle thereby stimulating the cervix to convey said antigen or antibody containing microparticles across the cervix into the uterus, said antigen or antibody being released from said microparticles as the cores thereof are exposed by deterioration of said shell, and thereafter said progestin containing microparticles are deposited in the vagina for the progestational phase of said cycle.

10. The method of claim 1, wherein said estrogen, progestin and antibody or antigen are each administered separately in microparticles containing the same, each of said microparticles being of a monolithic structure throughout the matrix material of which antibody or antigen, estrogen and progestin are dispersed.

11. Antigen containing microparticles for the active immunization of the internal female reproductive organs, which comprises:

microparticles containing an amount of antigen sufficient to elicit an antibody response incorporated in a matrix material which is biocompatible and biologically degradable, said microparticles capable of being transported after deposition in the vagina by the natural mechanism of the internal female reproductive organs across the cervix into the uterus wherein an antibody response is elicited within the uterus.

12. The microparticles of claim 11, wherein said microparticles further contain a menstrual cycle regulatory hormone.

13. The microparticles of claim 12, wherein said menstrual cycle regulatory hormone is estradiol or progesterone.

14. The microparticles of claim 11, wherein said microparticles are of a size ranging from 20 to 70 μ

m.

15. The microparticles of claim 11, wherein said matrix material is polylactic acid, polyglycolic acid, or copolymers of glycolic and lactic acids.

16. The microparticles of claims 11 and 12, wherein said microparticles have a monolithic structure in which antigen is dispersed throughout the matrix material.

17. The microparticles of claim 13, wherein said microparticles comprise a core of antigen surrounded by a shell of matrix material containing a menstrual cycle regulatory hormone.

18. The microparticles of claim 11, wherein said microparticles comprise a core of antigen surrounded by a shell of matrix material.

19. The microparticles of claim 11, wherein said microparticles contain from 10 wt. % to 60 wt. % of said antigen.

20. The microparticles of claim 11, wherein said antigen is derived from a bacterial or viral pathogen.

21. The microparticles of claim 11, wherein said antigen is derived from a bacterial pathogen selected from the group consisting of Neisseria gonorrhea, Mycobacterium tuberculosis, Candida albicans, Candida tropicalis, Trichomonas vaginalis, Haemophilus vaginalis, Group B Streptococcus ecoli, Microplasma hominis, Hemophilus ducreyi, Granuloma inguinale, Lymphopathia venereum, Treponema pallidum, Brucella abortus, Brucella melitensis, Brucella suis, Brucella canis, Campylobacter fetus, Campylobacter fetus intestinalis, Leptospira pomona, Listeria monocytogenes, Brucella ovis, Chlamydia psittaci, Trichomonas foetus, Toxoplasma gondii, Escherichia coli, Actinobacillus equuli, Salmonella abortus ovis, Salmonella abortus equi, Pseudomonas aeruginosa, Corynebacterium equi, Corynebacterium pyogenes, Actinobaccilus seminis, Mycoplasma bovigenitalium, Aspergillus fumigatus, Absidia ramosa, Trypanosoma equiperdum, Babesia caballi, and Clostridium tetani.

22. The microparticles of claim 11, wherein said antigen is derived from a viral pathogen selected from the group consisting of Equine herpes virus 1, Equine arteritis virus, IBR-IBP virus, BVD-MB virus, and Herpes virus (humonis, types 1 and 2).

23. The microparticles of claim 11, wherein said antigen is an enzyme selected from the group consisting of ribonuclease, neuramidinase, trypsin, glycogen phosphorylase, sperm lactic dehydrogenase, sperm hyaluronidase, adenosinetriphosphatase, alkaline phosphatase, alkaline phosphatase esterase, amino peptidase, trypsin chymotrypsin, amylase, muramidase, acrosomal proteinase, diesterase, glutamic acid dehydrogenase, succinic acid dehydrogenase, beta-glycophosphatase, lipase, ATP-ase alpha peptate gamma-glutamylotrans peptidase, sterol-3-beta-ol-dehydrogenase, and DPN-di-aprorase.

24. The microparticles of claim 11, wherein said antigen is a hormone selected from the group consisting of human chorionic gonadotrophin, human placental lactogen, estradiol and progesterone.

25. The microparticles of claim 11, wherein said antigen induces a contraceptive response and is derived from the blastocyst, the ovum, or sperm;

is a non-hormonal placental antigen or is a trophoblastic hormone.

26. The microparticles of claim 11, wherein said microparticles are formulated in a composition as a suppository, cream, jelly, foam or a liquid with a pharmaceutically acceptable excipient.

37. The microparticles of claim 27, wherein said antibody is one which responds to a bacterial antigen from a bacterium of claim 21.

38. The microparticles of claim 27, wherein said antibody is one which responds to a viral antigen from or virus of claim 22.

39. The microparticles of claim 27, wherein said antibody is one which responds to an enzyme antigen of claim 23.

40. The microparticles of claim 27, wherein said antibody is one which responds to a hormone of claim 24.

41. The microparticles of claim 27, wherein said antibody is one which responds to an antigen derived from the source of claim 25.

27. Antibody containing microparticles for the passive immunization of the internal female reproductive organs, which comprises:

microparticles containing a biologically effective amount of an antibody incorporated in a matrix material which is biocompatible and biologically degradable, said microparticles capable of being transported after deposition in the vagina by the natural transport mechanism of the internal female reproductive organs across the cervix into the uterus wherein passive immunization is effected within the uterus.

28. The microparticles of claim 27, wherein said microparticles further contain a menstrual cycle regulatory hormone which stimulates said natural transport mechanism.

29. The microparticles of claim 28, wherein said hormone is estradiol or progesterone.

30. The microparticles of claim 27, wherein said microparticles are of a size ranging from 20 to 70 μ

m.

31. The microparticles of claim 27, wherein said matrix material is polylactic acid, polyglycolic acid or copolymers of glycolic and lactic acids.

32. The microparticles of claim 27, wherein said microparticles are of a monolithic structure in which antibody is dispersed throughout the matrix material.

33. The microparticles of claim 28, wherein said microparticles comprise a core of antibody surrounded by a shell of matrix material containing dispersed menstrual cycle regulatory hormone.

34. The microparticles of claim 27, wherein said microparticles comprise a core of antibody surrounded by a shell of matrix material.

35. The microparticles of claim 27, wherein said microparticles contain from 10 wt. % to 60 wt. % of said antibody.

36. The microparticles of claim 27, wherein said antibody is one which responds to an antigen from a viral or bacterial pathogen.

42. The microparticles of claim 27, wherein said microparticles are formulated in a composition as suppository, cream, jelly, foam or a liquid with a pharmaceutically acceptable excipient.

43. A method of passively immunizing the internal female reproductive organs, comprising:

depositing microparticles containing an antibody in the vagina; and

allowing the natural transport mechanism of said organs to convey said microparticles across the cervix into the uterus and fallopian tubes, whereby said antibody is released by said microparticles so as to elict a passive immunization within the uterus.

44. The method of claim 43, wherein said microparticles are of a monolithic structure in which said antibody is dispersed throughout the matrix material.

45. The method of claim 43, wherein said microparticles are of a layered structure comprising a core of said antibody surrounded by a matrix material.

46. The method of claim 43, wherein said microparticles are of a layered structure comprising a core of said antibody dispersed in a matrix material surrounded by said matrix material free of antibody.

47. The method of claim 43, wherein said microparticles are of a size ranging from 20 to 70 μ

m.

48. The method of claim 43, wherein said matrix material is polylactic acid, polyglycolic acid or mixtures thereof.

49. The method of claim 43, wherein said antibody is responsive to a challenge from a bacterial or viral antigen.

50. A method of passively immunizing the internal female reproductive organs, comprising:

depositing microparticles containing an antibody and a menstrual cycle regulatory hormone in the vagina;

stimulating the natural transport mechanism of said internal reproductive organs by absorption of said hormone released from said microparticles; and

allowing said transport mechanism to convey said microparticles across the cervix into the uterus and fallopian tubes by sperm surrogate forces, whereby said antibody is released from said microparticles so as to elicit immunization within the uterus.

51. The method of claim 50, wherein said microparticles are of a monolithic structure in which said hormone and said antibody are dispersed throughout the matrix material of said microparticles.

52. The method of claim 50, wherein said menstrual cycle regulatory hormone is a progestin or an estrogen.

53. The method of claim 52, wherein said estrogen is estradiol and said progestin is progesterone.

54. The method of claim 50, wherein said menstrual cycle regulatory hormone and said antibody are incorporated in separate microparticle populations, said microparticles having a monolithic structure in which said antibody and said hormone are dispersed throughout the matrix material of the respective microparticles.

55. The method of claim 50, wherein said antibody is responsive to a challenge by an antigen of bacterial or viral origin.

57. The method of claim 52, wherein said microparticles are of a monolithic structure in which said hormone and said antigen are dispersed throughout the matrix material of said microparticles.

58. The method of claim 52, wherein said menstrual cycle regulatory hormone is a progestin or an estrogen.

59. The method of claim 52, wherein said estrogen is estradiol and said progestin is progesterone.

60. The method of claim 52, wherein said menstrual cycle regulatory hormone and said antigen are incorporated in separate microparticle populations, said microparticles having a monolithic structure in which said antigen and said hormone are dispersed throughout the matrix material of the respective microparticles.

56. A method of eliciting an active immunization response of the internal female reproductive organs, comprising:

depositing microparticles containing an antigen and a menstrual cycle regulatory hormone in the vagina;

stimulating the natural transport mechanism of said internal reproductive organs by absorption of said hormone released from said microparticles; and

allowing said transport mechanism to convey said microparticles across the cervix into the uterus and fallopian tubes by sperm surrogate forces, whereby said antigen is discharged from said microparticles by diffusion from or deterioration of said microparticles wherein an antibody response is elicited within the uterus.

61. The method of claim 56, wherein said antigen is of viral or bacterial origin.

62. The method of claim 56, wherein said antigen induces a contraceptive response by said organs and is derived from the blastocyst, the ovum, sperm, is a non-hormonal placental antigen or is a trophoblastic hormone.