Drug Delivery System

• US 20090081278A1
• Filed: 09/19/2008
• Published: 03/26/2009
• Est. Priority Date: 09/21/2007
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme BV (Merck & Co., Inc.)
• Original Assignee: N.V. Organon (Merck & Co., Inc.)
• Inventors: Zeeman, Raymond, De Graaff, Wouter
• Granted Patent: US 8,741,329 B2
• Time in Patent Office: Days
• US Class Current: 424/430
• CPC Class Codes: A61F 6/06 for use by females A61F6/20 takes precedence
• 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 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• 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 9/0039 Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

The subject invention provides a drug delivery system comprising at least one compartment comprising (i) a drug-loaded thermoplastic polymer core layer, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said core layer is loaded with crystals of a first (pharmaceutically) active compound and said intermediate layer is loaded with, crystals of the second (pharmaceutically) active compound.

Claims

1. A drug delivery system comprising at least one compartment, which comprises (i) a drug-loaded thermoplastic polymer core layer, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein the core layer is loaded with crystals of a first compound compound, and wherein the intermediate layer is loaded with crystals of a second compound.

2. The drug delivery system according to claim 1, wherein the core layer forms the core of the drug delivery system.

3. The drug delivery system according to claim 1, wherein an additional non-medicated core is covered by the core layer.

4. The drug delivery system according to claim 1, wherein an additional non-medicated intermediate layer is between the core layer and the drug-loaded intermediate layer.

5. The drug delivery system according to claim 1, wherein the delivery system has the form of a ring, an implant, an intrauterine system (IUS), a helical coil or a spring.

6. The drug delivery system according to claim 5, wherein the delivery system has a substantially ring-shaped form and is intended for vaginal administration.

7. The drug delivery system according to claim 1, wherein the first compound is a steroid and the second compound is a steroid.

8. The drug delivery system according to claim 1, wherein the first compound is a progestogen and the second compound is an estrogen.

9. The drug delivery system according to claim 1, wherein the first compound is an estrogen and the second compound is a progestogen.

10. The drug delivery system according to claim 8, wherein the progestogen is selected from the group consisting of nomegestrol acetate (NOMAc), natural progesterone, Dydrogesterone, Medrogestone, Medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, Gestonorone caproate, Demegestone, promegestone, nestorone, trimegestone, Norethisterone (=norethindrone), norethisterone acetate, lynestrenol, ethinodiol acetate, norethinodrel, Norgestrel, norgestimate, Dienogest, Drospirenone, and any other suitable steroidal compound with progestogenic activity.

11. The drug delivery system according to claim 8, wherein the estrogen is selected from the group consisting of estradiol, ethinyl estradiol, estriol, estetrol, esters thereof, pseudopolymorphs thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, hemihydrates thereof and any other suitable steroidal compound with estrogenic activity.

12. The drug delivery system according to claim 10, wherein the progestogen is nomegestrol acetate.

13. The drug delivery system according to claim 11, wherein the estrogen is estradiol or estradiol hemihydrate.

14. The drug delivery system according to claim 8, wherein the progestogen is nomegestrol acetate and the estrogen is estradiol or estradiol hemihydrate.

15. The drug delivery system according to claim 9, wherein the progestogen is selected from the group consisting of nomegestrol acetate (NOMAc), natural progesterone, Dydrogesterone, Medrogestone, Medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, Gestonorone caproate, Demegestone, promegestone, nestorone, trimegestone, Norethisterone (=norethindrone), norethisterone acetate, lynestrenol, ethinodiol acetate, norethinodrel, Norgestrel, norgestimate, Dienogest, Drospirenone, and any other suitable steroidal compound with progestogenic activity.

16. The drug delivery system according to claim 9, wherein the estrogen is selected from the group consisting of estradiol, ethinyl estradiol, estriol, estetrol, esters thereof, pseudopolymorphs thereof, pharmaceutically acceptable solvates thereof, hydrates thereof, hemihydrates thereof and any other suitable steroidal compound with estrogenic activity.

17. The drug delivery system according to claim 15, wherein the progestogen is nomegestrol acetate.

18. The drug delivery system according to claim 16, wherein the estrogen is estradiol or estradiol hemihydrate.

19. The drug delivery system according to claim 9, wherein the progestogen is nomegestrol acetate and the estrogen is estradiol or estradiol hemihydrate.

20. A drug delivery system according to claim 1, wherein at least the skin but optionally also the core layer and the intermediate layer comprise ethylene-vinyl acetate copolymer as the thermoplastic polymer.

21. A drug delivery system according to claim 20, wherein the core layer and the intermediate layer comprise the same grade of ethylene-vinyl acetate copolymer.

22. A drug delivery system according to claim 20, wherein the core and the intermediate layer comprise a different grade of ethylene-vinyl acetate copolymer.

23. A drug delivery system according to claim 8, wherein the progestogen is present at about 5-70% by weight.

24. A drug delivery system according to claim 23, wherein the progestogen is nomegestrol acetate.

25. A drug delivery system according to claim 24, wherein nomegestrol acetate is present at about 5-35% by weight.

26. A drug delivery system according to claim 25, wherein nomegestrol acetate is present at about 35% by weight.

27. A drug delivery system according to claim 9, wherein the estrogen is present at about 3-70% by weight.

28. A drug delivery system according to claim 27, wherein the estrogen is estradiol or estradiol hemihydrate.

29. A drug delivery system according to claim 8, wherein the estradiol is present at about 3-27% by weight.

30. A drug delivery system according to claim 29, wherein the estradiol is present at about 9-27% by weight.

31. A drug delivery system according to claim 27, wherein the estradiol is present at about 3-20% by weight.

32. A drug delivery system according to claim 31, wherein the estradiol is present at about 4.5-9% by weight.

33. A drug delivery system according to claim 9, wherein the progestogen is present at about 10-70% by weight.

34. A drug delivery system according to claim 33, wherein the progestogen is nomegestrol acetate.

35. A drug delivery system according to claim 34, wherein the nomegestrol acetate is present at about 20-60% by weight.

36. A drug delivery system according to claim 35, wherein the nomegestrol acetate is present at about 35-60% by weight.

37. A drug delivery system according to claim 1, wherein the intermediate layer additionally contains an anti-microbial agent.

38. A drug delivery system according to claim 1, wherein the core additionally contains an anti-microbial agent.

39. A drug delivery system according to claim 1, wherein the device contains two compartments.

40. A drug delivery system according to claim 39, wherein the second compartment contains an anti-microbial agent.

41. A method of contraception which comprises the steps of (i) positioning the drug delivery system of claim 1 within the female vaginal tract and (ii) retaining the system within the vaginal tract for prolonged period of time.

42. The method of claim 41, wherein the prolonged period of time is about 21 days.

43. The method of claim 41, wherein the prolonged period of time is about 24 days.

44. A method of contraception which comprises the step of (i) positioning the drug delivery system of claim 1 within the female vaginal tract on numerical date ‘

n+x’

of a month and (ii) retaining the system within the vaginal tract until numerical date ‘

n’

of the following month, wherein ‘

n’

is a numerical date of a month from 1-28, ‘

x’

is 3, 4, 5, 6 or 7 and wherein the method is carried out for at least two cycles.

45. The method of claim 44, wherein when ‘

x’

is 4 ‘

n’

is 24, 25, 26 or 27 depending on whether the calendar month has 28, 29, 30 or 31 days.

46. The method of claim 44, wherein when ‘

x’

is 7 ‘

n’

is 21, 22, 23 or 24 depending on whether the calendar month has 28, 29, 30 or 31 days.

47. A method of contraception which comprises the steps of (i) positioning the drug delivery system of claim 1 within the female vaginal tract (ii) retaining the system within the vaginal tract for at least about 21 days and (iii) removing the system for an approximate one week period to permit menstruation.

48. A method of contraception which comprises the steps of (i) positioning the drug delivery system of claim 1 within the female vaginal tract (ii) retaining the system within the vaginal tract for at least about 24 days and (iii) removing the system for an approximate 4 day period to permit menstruation.

49. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 37 within the female vaginal tract and (ii) retaining the system within the vaginal tract for at least about 21 days.

50. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 37 within the female vaginal tract (ii) retaining the system within the vaginal tract for at least about 21 days and (iii) removing the system for an approximate one week period to permit menstruation.

51. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 38 within the female vaginal tract and (ii) retaining the system within the vaginal tract for at least about 21 days.

52. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 38 within the female vaginal tract (ii) retaining the system within the vaginal tract for at least about 21 days and (iii) removing the system for an approximate one week period to permit menstruation.

53. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 37 within the female vaginal tract and (ii) retaining the system within the vaginal tract for at least about 24 days.

54. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 38 within the female vaginal tract and (ii) retaining the system within the vaginal tract for at least about 24 days.

55. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 37 within the female vaginal tract (ii) retaining the system within the vaginal tract for at least about 24 days and (iii) removing the system for an approximate 4 day period to permit menstruation.

56. A method of concomitantly providing contraception and treating or preventing a sexually transmitted disease which comprises the steps of (i) positioning the drug delivery system of claim 38 within the female vaginal tract (ii) retaining the system within the vaginal tract for at least about 24 days and (iii) removing the system for an approximate 4 day period to permit menstruation.

57. The method according to claim 49, wherein the disease is selected from the group consisting of AIDS, Chlamydia, gonorrhea and herpes.

58. The method according to claim 51, wherein the disease is selected from the group consisting of AIDS, Chlamydia, gonorrhea and herpes.

59. A method of manufacturing the three-layered drug delivery system of claim 1 comprising:

(i) producing a loaded homogenous polymer core granulate;

(ii) producing a loaded homogenous polymer intermediate layer granulate; and

(iii) co-extruding the core granulate and the intermediate layer granulate with a polymer skin granulate to form the three-layered drug delivery system.

60. The method according to claim 59, wherein step (i) comprises:

a) grounding the core polymer;

b) dry powder mixing the grounded polymer with the active compound to be loaded in the core;

c) blend extruding the resulting powder mixture of step (b);

d) cutting the resulting loaded polymer strands into granules, thereby obtaining a core granulate;

e) lubricating the core granulate with a lubricant.

61. The method according to claim 59, wherein step (ii) comprises:

a) grounding the intermediate layer polymer;

b) dry powder mixing the grounded polymer with the active compound to be loaded in the intermediate layer;

c) blend extruding the resulting powder mixture of steps (b);

d) cutting the resulting loaded polymer strands into granules, thereby obtaining an intermediate layer granulate;

e) lubricating the intermediate granulate with a lubricant.