Drug delivery system

• US 20060280771A1
• Filed: 05/19/2004
• Published: 12/14/2006
• Est. Priority Date: 05/23/2003
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme BV (Merck & Co., Inc.)
• Original Assignee: Akzo Nobel N.V. (Nouryon BV)
• Inventors: Groenewegen, Rudolf Johannes Joseph, De Graaff, Wouter
• Granted Patent: US 8,333,983 B2
• Time in Patent Office: Days
• US Class Current: 424/426
• 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 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• 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 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/12 for climacteric disorders
• 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 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• 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 consisting of (i) a drug-loaded thermoplastic polymer core, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with (a) crystals of a first pharmaceutically active compound and with (b) a second pharmaceutically active compound in dissolved form and wherein said core is loaded with said second compound in dissolved form.

Claims

1. A drug delivery system comprising at least one compartment consisting of (i) a drug-loaded thermoplastic polymer core, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with (a) crystals of a first pharmaceutically active compound and with (b) a second pharmaceutically active compound in dissolved form and wherein said core is loaded with said second compound in dissolved form.

2. A drug delivery system according to claim 1 which is physically stable at about 18-30°

C.

3. A drug delivery system according to claim 1 wherein said second compound in the core is present in the same concentration as in the intermediate layer.

4. A drug delivery system according to claim 1, wherein the delivery system has a substantially ring-shaped form and is intended for vaginal administration.

5. A drug delivery system according to claim 1, wherein said first active compound is a steroid and said second active compound is a steroid.

6. A drug delivery system according to claim 5, wherein said first active steroid-is a proestrogen.

7. A drug delivery system according to claim 5, wherein said second active steroid is an estrogen.

8. A drug delivery system according to claim 7, wherein the estrogen is ethinyl estradiol.

9. A drug delivery system according to claim 6, wherein the proestrogen is etonogestrel.

10. A drug delivery system according to claim 1, wherein the first active compound is etonogestrel and the second active compound is ethinyl estradiol.

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

12. A drug delivery system according to claim 11, wherein the core and the intermediate layer comprise the same grade of ethylene-vinylacetate copolymer as the thermoplastic polymer.

13. A drug delivery system according to claim 11, wherein the core and the intermediate layer comprise a different grade of ethylene-vinylacetate copolymer as the thermoplastic polymer.

14. A drug delivery system according to claim 1 wherein the core is additionally loaded with the first compound.

15. A drug delivery system according to claim 8 wherein ethinyl estradiol is present in the intermediate layer and in the core at about 0.05-1.5% by weight.

16. A drug delivery system according to claim 15 wherein ethinyl estradiol is present in the intermediate layer and in the core at about 0.08-0.5% by weight.

17. A drug delivery system according to claim 16 wherein ethinyl estradiol is present in the intermediate layer and in the core at about 0.09-0.18% by weight.

18. A drug delivery system according to claim 17 wherein ethinyl estradiol is present in the intermediate layer and in the core at about 0.09-0.15% by weight.

19. A drug delivery system according to claim 16 wherein ethinyl estradiol is present in the intermediate layer and in the core at about 0.09-0.20% by weight.

20. A drug delivery system according to claim 9 wherein etonogestrel is present in the intermediate layer at about 6-80% by weight.

21. A drug delivery system according to claim 20 wherein etonogestrel is present in the intermediate layer at about 6-70% by weight.

22. A drug delivery system according to claim 21 wherein etonogestrel is present in the intermediate layer at about 10-53% by weight.

23. A drug delivery system according to claim 22 wherein etonogestrel is present in the intermediate layer at about 10-30% by weight.

24. A drug delivery system according to claim 23 wherein etonogestrel is present in the intermediate layer at about 10-15% by weight.

25. A drug delivery system according to claim 24 wherein etonogestrel is present in the intermediate layer at about 10-12% by weight.

26. A drug delivery system according to claim 1 wherein the ratio R₁/R₂ as described in FIG. 5 is between about 1.0075-2.0000 and the ratio R₂/R₃ is between about 1.0075-2.0000.

27. A drug delivery system according to claim 26 wherein the ratio R₁/R₂ as described in FIG. 5 is between about 1.0100-1.5000 and the ratio R₂/R₃ is between about 1.0200-1.5000.

28. A drug delivery system according to claim 27 wherein the ratio R₁/R₂ as described in FIG. 5 is between about 1.0300-1.3000 and the ratio R₂/R₃ is between about 1.0200-1.5000.

29. A drug delivery system according to claim 28 wherein the-ratio R₁/R₂ as described in FIG. 5 is between about 1.0400-1.1800 and the ratio R₂/R₃ is between about 1.0200-1.0500.

30. A drug delivery system according to claim 1 wherein the ratio R₁/R₂ as described in FIG. 5 is between about 1.0300-1.2000 and the ratio R₂/R₃ is between about 1.0100-1.0900.

31. A drug delivery system according to claim 5 wherein the intermediate layer additionally contains an anti-microbial agent.

32. A drug delivery system according to claim 5 wherein the core additionally contains an anti-microbial agent.

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

34. A drug delivery system according to claim 33 wherein the second compartment contains an anti-microbial agent.

36. 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 at least about 21 days.

37. 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.

38. 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 31 within the female vaginal tract and (ii) retaining the system within the vaginal tract for at least about 21 days.

39. 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 31 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.

40. A contraceptive kit comprising a drug delivery system of claim 1.

41. A medicament for hormone replacement therapy comprising the drug delivery system of claim 1.

42. A use of the drug delivery system of claim 31 which provides contraception and treats and/or prevents a sexually transmitted disease.

43. The drug delivery system of claim 42 wherein the disease is AIDS.

44. The drug delivery system of claim 42 wherein the disease is herpes.

45. The drug delivery system of claim 42 wherein the disease is chlamydia.

46. The drug delivery system of claim 42 wherein the disease is gonorrhoea.

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

(i) Producing a loaded homogeneous polymer core granulate and a loaded homogeneous polymer intermediate layer granulate;

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

48. A method according to claim 47 wherein step (i) comprises:

(a) grounding the polymer;

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

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

(d) blend extruding the resulting powder mixtures of steps (b) and (c);

(e) cutting the resulting loaded polymer strands into granules, thereby obtaining a core granulate and an intermediate layer granulate;

(f) lubricating both core granulate and intermediate granulate with a lubricant;

wherein steps (b) and (c) are interexchangeable.

35. A drug delivery system according to wherein the anti-microbial agent is mandelic acid condensation polymer.

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