Methods and devices for the sustained release of multiple drugs

• US 20070196433A1
• Filed: 04/29/2004
• Published: 08/23/2007
• Est. Priority Date: 04/29/2003
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology, The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Massachusetts General Hospital (Mass General Brigham, Inc.)
• Inventors: Langer, Robert, Ron, Eyal, Crowley, William
• Granted Patent: US 7,833,545 B2
• Time in Patent Office: Days
• US Class Current: 424/432
• CPC Class Codes: A61F 6/08 Pessaries, i.e. devices worn in the vagina to support the uterus, remedy a malposition or prevent conception , e.g. combined with devices protecting against contagion
• CPC Class Codes: A61F 6/142 Wirelike structures, e.g. loops, rings, spirals
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

The invention relates to an drug delivery device and a method for delivering multiple drugs over a prolonged period of time. The drug delivery device has two or more unitary segments comprising a drug-permeable polymeric substance, wherein at least one of the segments further comprises a pharmaceutically active agent. The invention also relates to a method for the treatment of a benign ovarian secretory disorder in a female mammal, a method of contraception, and a method of relieving the symptoms associated with menopausal, perimenopausal and post-menopausal periods in a woman.

Claims

1. A drug delivery device comprising two or more segments, wherein each unitary segment comprises a drug-permeable polymeric substance, and wherein at least one unitary segment comprises a mixture of the drug-permeable polymeric substance and a drug.

2. The drug delivery device of claim 1, wherein two or more unitary segments each contain a drug.

3. The drug delivery device of claim 1, wherein the drug-permeable polymeric substance is a thermoplastic polymer.

4. The drug delivery device of claim 3, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

5. The method of claim 1, wherein the drug delivery device is in the shape of a ring, a wafer, or a suppository.

6. The drug delivery device of claim 1, wherein at least one end of the unitary segments is attached to the end of another unitary segment, and wherein the drug delivery device is in the shape of a ring.

7. The drug delivery device of claim 6, wherein the device is suitable for use as a vaginal ring.

8. The drug delivery device of claim 6, wherein the ends of the segments are attached by a coupling means.

9. The drug delivery device of claim 8, wherein the coupling means is an adhesive material.

10. The drug delivery device of claim 7, having an overall diameter of from 40 mm to 80 mm.

11. The drug delivery device of claim 7, having a cross-sectional diameter of from 0.5 mm to 12 mm.

12. The drug delivery device of claim 1, wherein the drug is a hormone replacement steroid.

13. The drug delivery device of claim 1, wherein the drug is a contraceptive agent.

14. The drug delivery device of claim 1, wherein the drug is selected from the group consisting of:

interferon, anti-angiogenesis factors, growth factors, hormones, enzymes, transferases, hydrolases, lysases, isomerases, proteases, ligases and oxidoreductases, enzyme inhibitors, steroids, anti-cancer drugs and antibiotics.

15. The drug delivery device of claim 1, wherein the drug is selected from the group consisting of:

growth hormone, polysaccharides, antigens, and antibodies.

16. A drug delivery system for the simultaneous release of two or more drugs, which system comprises two or more unitary segments, wherein each unitary segment comprises a mixture of a drug-permeable polymeric substance and a drug.

17. The drug delivery system of claim 16, wherein at least two of the segments comprise a different drug.

18. The drug delivery system of claim 16, wherein the drug-permeable polymeric substance is a thermoplastic polymer.

19. The drug delivery system of claim 18, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

20. The drug delivery system of claim 16, wherein the drug is a hormone replacement steroid.

21. The drug delivery system of claim 16, wherein the drug is a contraceptive agent.

22. The drug delivery device of claim 16, wherein the drug is selected from the group consisting of selected from the group consisting of:

interferon, anti-angiogenesis factors, growth factors, hormones, enzymes, transferases, hydrolases, lysases, isomerases, proteases, ligases and oxidoreductases, enzyme inhibitors, steroids, anti-cancer drugs and antibiotics.

23. The drug delivery device of claim 16, wherein the drug is selected from the group consisting of:

growth hormone, polysaccharides, antigens, and antibodies.

24. A method for delivering a drug to a female mammal, said method comprising the steps of:

(a) preparing a drug delivery device comprising two or more unitary segments, wherein each unitary segment comprises a drug-permeable polymeric substance, and wherein at least one unitary segment comprises a mixture of the drug-permeable polymeric substance and a drug;

(b) positioning in the vaginal tract of the female mammal the drug delivery device of step (a); and

(c) maintaining the drug delivery device in the vaginal tract of the female mammal for a period of time sufficient to deliver an effective amount of the drug to the female mammal.

25. The method of claim 24, wherein the drug-permeable polymeric substance is a thermoplastic polymer.

26. The method of claim 25, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

27. The method of claim 24, wherein the drug is a hormone replacement steroid.

28. The method of claim 24, wherein the drug is a contraceptive agent.

29. The drug delivery device of claim 24, wherein the drug is selected from the group consisting of:

interferon, anti-angiogenesis factors, growth factors, hormones, enzymes, transferases, hydrolases, lysases, isomerases, proteases, ligases and oxidoreductases, enzyme inhibitors, steroids, anti-cancer drugs and antibiotics.

30. The drug delivery device of claim 24, wherein the drug is selected from the group consisting of:

growth hormone, polysaccharides, antigens, and antibodies.

31. A method of making a ring-shaped drug delivery device, comprising the steps of:

(a) mixing a first drug-permeable polymeric substance with a first drug to form a first polymeric mixture;

(b) molding the first polymeric mixture of step (a) to form a first ring;

(c) cutting the first ring of step (b) to form a first unitary segment;

(d) repeating steps (a) to (c) with a second drug-permeable polymeric substance and a second drug to form a second unitary segment; and

(e) connecting an end of a first unitary segment with an end of a second unitary segment to form a ring-shaped drug delivery device.

32. The method of claim 31, further comprising repeating step (d) with a third drug-permeable polymeric substance and a third drug to form a third unitary segment, and connecting said first unitary segment, second unitary segment, and third unitary segment to form a ring-shaped drug delivery device.

33. The method of claim 32, further comprising repeating step (d) with at least one additional drug-permeable polymeric substance and one additional drug to form two or more additional unitary segments, and connecting said first unitary segment, second unitary segment, third unitary segment, and an additional unitary segment to form a ring-shaped drug delivery device.

34. The method of claim 31, wherein the first and second drug-permeable polymeric substances are a thermoplastic polymer.

35. The method of claim 34, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

36. The method of claim 31, wherein the first and second drug-permeable polymeric substances are the same.

37. The method of claim 31, wherein the connecting step is performed using an adhesive material.

38. A method of making a ring-shaped drug delivery device, comprising the steps of:

(a) mixing a first drug-permeable polymeric substance with a first drug to form a first polymeric mixture;

(b) molding the first polymeric mixture of step (a) to form a first unitary segment;

(c) repeating steps (a) and (b) with a second drug-permeable polymeric substance and a second drug to form a second unitary segment; and

(d) connecting an end of a first unitary segment with an end of a second unitary segment to form a ring-shaped drug delivery device.

39. The method of claim 38, further comprising repeating step (c) with a third drug-permeable polymeric substance and a third drug to form a third unitary segment, and connecting said first unitary segment, second unitary segment, and third unitary segment to form a ring-shaped drug delivery device.

40. The method of claim 39, further comprising repeating step (c) with at least one additional drug-permeable polymeric substance and one additional drug to form at least one additional unitary segment, and connecting said first unitary segmenet, second unitary segment, third unitary segment, and at least one additional unitary segment to form a ring-shaped drug delivery device.

41. The method of claim 38, wherein the first and second drug-permeable polymeric substances are a thermoplastic polymer.

42. The method of claim 41, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

43. The method of claim 38, wherein the first and second drug-permeable polymeric substances are the same.

44. The method of claim 38, wherein the connecting step is performed using an adhesive material.

45. A method of making a drug delivery device, comprising the steps of:

(a) mixing a first drug-permeable polymeric substance with a first drug to form a first polymeric mixture;

(b) injecting the first polymeric mixture of step (a) into a mold to form a first unitary segment; and

(c) repeating steps (a) and (b) with a second drug-permeable polymeric substance and a second drug to form a second unitary segment to form the drug delivery device.

46. The method of claim 45, further comprising repeating step (c) with a third drug-permeable polymeric substance and a third drug to form a third unitary segment and to form a drug delivery device.

47. The method of claim 46, further comprising repeating step (c) with at least one additional drug-permeable polymeric substance and one additional drug to form at least one additional unitary segment to form a drug delivery device.

48. The method of claim 45, wherein the first and second drug-permeable polymeric substances are a thermoplastic polymer.

49. The method of claim 48, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

50. The method of claim 45, wherein the first and second drug-permeable polymeric substances are the same.

51. A method for the treatment of a benign ovarian secretory disorder in a female mammal, comprising:

(a) providing a drug delivery device comprising a first segment and a second segment, wherein said first segment comprises a drug-permeable polymeric substance and a luteinizing hormone releasing hormone (LHRH), and wherein said second segment comprises the drug-permeable polymeric substance and an estrogenic steroid; and

(b) inserting into the vagina of said mammal the drug delivery device of step (a) to release a therapeutically effective amount of the LHRH and an effective amount of the estrogenic steroid to said female mammal.

52. The method of claim 51, wherein the drug delivery device further comprises a third segment, wherein said third segment comprises the drug-permeable polymeric substance and a progestational steroid, and wherein the drug delivery device releases an effective amount of the progestational steroid.

53. The method of claim 51, wherein the drug-permeable polymeric substance is a thermoplastic polymer.

54. The method of claim 53, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

55. The method of claim 51, wherein the drug delivery device is in the shape of a ring, a wafer, or a suppository.

56. The method of claim 51, wherein the drug delivery device is in the shape of a ring.

57. The method of claim 51, wherein said benign ovarian secretory disorder is polycystic ovarian disease.

58. The method of claim 51, wherein said benign ovarian secretory disorder is characterized by excessive ovarian progesterone secretion.

59. The method of claim 51, wherein said benign ovarian secretory disorder is characterized by excessive ovarian estrogen secretion or excessive androgen secretion.

60. The method of claim 51, wherein said benign ovarian secretory disorder is characterized by hyperthecosis, hirsutism, dysfunctional uterine bleeding, amenorrhea, or anestrus.

61. The method of claim 51, wherein said estrogen steroid is selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, conjugated equine estrogen, estriol, estrone, estrone sulfate, ethinyl estradiol, estrofurate, quinestrol and mestranol.

62. The method of claim 51, wherein said estrogenic steroid is selected from the group of selective estrogen receptor modulators consisting of tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and 19-nor-testosterone derivatives.

63. The method of claim 52, wherein said progestation steroid is selected from the group consisting of progesterone, 17-hydroxy progesterone derivatives, 19-nor-testosterone derivatives, 19-nor-progesterone derivatives norethindrone, norethindrone acetate, norethynodrel, norgestrel, norgestimate, ethynodiol diacetate, allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethisterone, cyproterone levo-norgestrel, dl-norgestrel, cyproterone acetate, gestodene, desogestrol, dydrogesterone, ethynodiol diacetate, medroxyprogesterone acetate, megestrol acetate, phytoprogestins, and animal-derived progestins and metabolic derivatives thereof.

64. The method of claim 52, wherein said progestational steroid is selected from the group of selective progestin receptor modulators consisting of RU486, CDB2914, 19-nor-progesterone derivatives, 19-nor-testosterone derivatives, 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivatives, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinoline derivatives, 5-alkyl 1,2-dihydrochomeno[3,4-f]quinoline derivatives, and 6-thiophenehydroquinoline derivatives.

65. The method of claim 51, wherein the female mammal is a human female.

66. A method for increasing the breeding rate of a female mammal, wherein said female mammal is induced to breed by the method of claim 51.

67. A method for preventing pregnancy in a female mammal, comprising:

(a) providing a drug delivery device comprising a first segment comprising a drug-permeable polymeric substance and a luteinizing hormone releasing hormone (LHRH), a second segment comprising the drug-permeable polymeric substance and an estrogenic steroid, and a third segment comprising the drug-permeable polymeric substance and a progestational steroid; and

(b) inserting into the vagina of said mammal the drug delivery device of step (a) to release a therapeutically effective amount of the LHRH, an effective amount of the estrogenic steroid, and an effective amount of the progestational steroid to said female mammal.

68. The method of claim 67, wherein the drug-permeable polymeric substance is a thermoplastic polymer.

69. The method of claim 68, wherein the thermoplastic polymer is an ethylene-vinyl acetate copolymer.

70. The method of claim 67, wherein the drug delivery device is in the shape of a ring, a waffer, or a suppository.

71. The method of claim 67, wherein the drug delivery device is in the shape of a ring.

72. A method of treating a decrease in estrogen secretion in a woman exhibiting symptoms of a cessation of cyclical ovulation, which method comprises:

(a) providing a drug delivery device comprising a first segment and a second segment, wherein said first segment comprises a drug-permeable polymeric substance and a hormone replacement steroid, and wherein said second segment comprises a drug-permeable polymeric substance and progestational steroid; and

(b) inserting into the vagina of said woman the drug delivery device of step (a) to release an effective amount of the hormone replacement steroid to said woman.

73. The method of claim 72, wherein the hormone replacement steroid is an estrogenic steroid.

74. The method of claim 73, wherein the estrogenic steroid is selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, conjugated equine estrogen, estriol, estrone, estrone sulfate, ethinyl estradiol, estrofurate, quinestrol and mestranol.

75. The method of claim 73, wherein the estrogenic steroid is selected from the group of selective estrogenic receptor modulators consisting of tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and 19-nor-testosterone derivatives.

76. The method of claim 72, further comprising a third segment, wherein said third segment comprises a drug-permeable polymeric substance and an androgen or a selective androgen receptor modulator (SARM).

77. A method for relieving the symptoms associated with menopausal, perimenopausal and post-menopausal periods in a woman having said periods and in need of estrogen therapy, which method comprises:

(a) providing a drug delivery device comprising a first segment and a second segment, wherein said first segment comprises a drug-permeable polymeric substance and an estrogenic steroid; and

(b) inserting into the vagina of said woman the drug delivery device of step (a) to release an effective amount of the estrogenic steroid to said woman.

78. The method of claim 77, wherein the estrogenic steroid is selected from the group consisting of a naturally occurring estrogen, a synthetic estrogen, and a selective estrogen receptor modulator.

79. The method of claim 77, wherein the drug-permeable polymeric substance is a thermoplastic polymer.

80. The method of claim 78, wherein the thermoplastic polymer is an ethylene

81. The method of claim 77, wherein the drug delivery device is in the shape of a ring, a waffer, or a suppository.

82. The method of claim 77, wherein the drug delivery device is in the shape of a ring. A method for relieving the symptoms associated with the menopausal, perimenopausal and postmenopausal periods in a woman having said periods and in need of estrogen therapy, which method comprises:

(a) providing a drug delivery device comprising a first segment and a second segment, wherein said first segment comprises a drug-permeable polymeric substance and a hormone replacement steroid; and

(b) inserting into the vagina of said woman the drug delivery device of step (a) to release an effective amount of the hormone replacement steroid to said woman.

83. The method of claim 82, wherein the hormone replacement steroid is an estrogenic steroid.

84. The method of claim 83, wherein the estrogenic steroid is selected from the group consisting of a naturally occurring estrogen, a synthetic estrogen, and a selective estrogen receptor modulator.

85. The method of claim 83, wherein the estrogenic steroid is a member selected from the group consisting of estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, conjugated equine estrogen, estriol, estrone, estrone sulfate, ethinyl estradiol, estrofurate, quinestrol and mestranol.

86. The method of claim 83, wherein the estrogenic steroid is selected from the group of selective estrogenic receptor modulators consisting of tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and 19-nor-testosterone derivatives.