Solubility parameter based drug delivery system and method for altering drug saturation concentration

• US 5,656,286 A
• Filed: 01/07/1994
• Issued: 08/12/1997
• Est. Priority Date: 03/04/1988
• Status: Expired due to Term

• Current Assignee: Noven Pharmaceuticals Inc (Hisamitsu Pharmaceutical Company Incorporated)
• Original Assignee: Noven Pharmaceuticals Inc (Hisamitsu Pharmaceutical Company Incorporated)
• Inventors: Miranda, Jesus, Sablotsky, Steven
• Primary Examiner(s): VENKAT, JYOTHSNA A
• Application Number:
  US08/178,558
• Time in Patent Office: 1,313 Days
• Field of Search: 424/448, 424/449
• US Class Current: 424/449
• CPC Class Codes: A61F 13/0276 Apparatus or processes for manufacturing adhesive dressings or bandages
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61K 9/7069 obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• CPC Class Codes: A61L 15/18 containing inorganic materials
• CPC Class Codes: A61L 15/58 Adhesives
• CPC Class Codes: A61L 15/585 Mixtures of macromolecular compounds
• CPC Class Codes: B26F 1/384 using rotating drums
• CPC Class Codes: C08L 31/04 Homopolymers or copolymers of vinyl acetate
• CPC Class Codes: C08L 33/00 Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers

Abstract

A blend of at least two polymers, or at least one polymer and a soluble polyvinylpyrrolidone, in combination with a drug provides a pressure-sensitive adhesive composition for a transdermal drug delivery system in which the drug is delivered from the pressure-sensitive adhesive composition and through dermis when the pressure-sensitive adhesive composition is in contact with human skin. According to the invention, soluble polyvinylpyrrolidone can be used to prevent crystallization of the drug, without affecting the rate of drug delivery from the pressure-sensitive adhesive composition.

Claims

1. A transdermal drug delivery system comprising a pressure-sensitive adhesive composition, wherein said composition comprises a blend of

(a) a pressure-sensitive adhesive selected from the group consisting of

(i) polyisoprene, polystyrene, polyethylene, polybutadiene , polyethylene/butylene, styrene/butadiene, styrene-butadiene-styrene, styrene-isoprene-styrene, styrene-ethylene/butylene-styrene block copolymers, butyl rubber, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychloroprene, polyacrylonitrile and polychlorodiene, and mixtures thereof, in an amount from about 14% to about 94% by weight of the total pressure-sensitive adhesive composition;

(ii) polyisobutylene and mixtures thereof in an amount from about 10% to about 90% by weight of the total pressure-sensitive adhesive composition; and

(iii) polysiloxane and mixtures thereof in an amount from about 5% to about 95% by weight of the total pressure-sensitive adhesive composition;

(b) a soluble polyvinylpyrrolidone in an amount from about 1% to about 20% by weight of the total pressure-sensitive adhesive composition;

(c) one drug or a mixture of two or more drugs; and

(d) optionally, an enhancer in an amount up to about by weight of the total pressure-sensitive adhesive composition.

2. The transdermal drug delivery system according to claim 1, wherein the pressure-sensitive adhesive is a polysiloxane.

3. A transdermal drug delivery system according to claim 1, wherein said blend further contains at least one enhancer.

12. The transdermal drug delivery system according to claim 1, wherein the soluble polyvinylpyrrolidone has a molecular weight from about 7,000 to about 54,000.

69. A transdermal drug delivery system according to claim 1 made by a process comprising blending

(a) a pressure-sensitive adhesive selected from the group consisting of

(i) polyisoprene, polystyrene, polyethylene, polybutadiene, polyethylene/butylens, styrone/butadiene, styrene-butadiene-styrene, styrene-isoprene-styrene, styrene-ethylene/butylene-styrene block copolymers butyl rubber, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychloroprene, polyacrylonitrile and polychlorodiene, and mixtures thereof, in an amount from about 14% to about 94% by weight of the total pressure-sensitive adhesive composition;

(ii) polyisobutylene and mixtures thereof in an amount from about 10% to about 90% by weight of the total pressure-sensitive adhesive composition; and

(iii) polysiloxane and mixtures thereof in an amount from about 5% to about 95% by weight of the total pressure-sensitive adhesive composition;

(b) a soluble polyvinylpyrrolidone in an amount from about 1% to about 20% by weight of the total pressure-sensitive adhesive composition;

(c) one drug or a mixture of two or more drugs; and

(d) optionally, an enhancer in an amount up to about 20% by weight of the total pressure-sensitive adhesive composition.

4. A transdermal drug delivery system comprising a pressure-sensitive adhesive composition, wherein said composition comprises of a blend of

(a) a pressure-sensitive adhesive selected from the group consisting of

(i) polyisoprene, polystyrene, polyethylene, polybutadiene, polyethylene/butylene, styrene/butadiene, styrene-butadiene-styrene, styrene-isoprene-styrene, styrene-ethylene/butylene-styrene block copolymers, butyl rubber, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychloroprene, polyacrylonitrile and polychlorodiene, and mixtures thereof, in an amount from about 14% to about 94% by weight of the total pressure-sensitive adhesive composition;

;

(ii) polyisobutylene and mixtures thereof in an amount from about 10% to about 90% by weight of the total pressure-sensitive adhesive composition; and

(iii) polysiloxane and mixtures thereof in an amount from about 5% to about 95% by weight of the total pressure-sensitive adhesive composition;

(b) a polyacrylate in an amount from about 5% to about 85%, wherein said polyacrylate and said pressure-sensitive adhesive (a) differ in solubility parameter by an increment of at least 2 (J/cm³)^1/2 ;

(c) a soluble polyvinylpyrrolidone in an amount from about 1% to about 20% by weight of the total pressure-sensitive adhesive composition;

(d) one drug or a mixture of two or more drugs; and

(e) optionally, an enhancer in an amount up to about 20% by weight of the total pressure-sensitive adhesive composition.

5. The transdermal drug delivery system of claim 4 which is in a defined geometric shape.

6. The transdermal drug delivery system of claim 5 which is in the form of a sheet.

7. The transdermal drug delivery system of claim 5 which is in the form of an individual dosage unit.

8. The transdermal drug delivery system of claim 4 further comprising a backing material superimposed on one surface of said pressure sensitive adhesive composition, said backing material being substantially impermeable to said drug contained therein.

9. The transdermal drug delivery system of claim 8 further comprising a release liner superimposed on a surface of said pressure sensitive adhesive composition opposite said backing material.

10. The transdermal drug delivery system of claim 4, wherein said system is a reservoir device having an adhesive portion comprised of said blend.

11. The transdermal drug delivery system according to claim 4, wherein the pressure-sensitive adhesive is a polysiloxane.

13. The transdermal drug delivery system according to claim 4, wherein said drug is present in said system from about 0.1% to about 50% by weight of the total pressure-sensitive adhesive layer.

14. The transdermal drug delivery system acoording to claim 4, wherein said blend further contains at least one enhancer.

15. The transdermal drug delivery system according to claim 14, wherein said enhancer is present in said system from about 1% to about 20% by weight of the total pressure-sensitive adhesive composition.

16. The transdermal drug delivery system of claim 4, further comprising a clay.

17. The transdermal drug delivery system of claim 16, wherein said clay is bentonite.

18. The transdermal drug delivery system of claim 4, wherein said drug is a steroid.

19. The transdermal drug delivery system of claim 18, wherein said steroid is an estrogen selected from the group consisting of colpormon, equilenin, estradiol benzoate, estradiol 17β

-cypionate, moxestrol, mytatrienediol, quinestradiol, quinestrol, estropipate, 17β

-estradiol, equilin, mestranol, estrone, estriol, ethinyl estradiol and diethylstilbestrol.

20. The transdermal drug delivery system of claim 19, wherein said estrogen is 17β

-estradiol, and wherein said 17β

-estradiol is present in said system in an amount of from about 0.1% to about 5% by weight.

21. The transdermal drug delivery system of claim 18, wherein said steroid is a progestational agent.

22. The transdermal drug delivery system of claim 21, wherein said progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxyrogesterone acetate, hdroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17α

-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone, promegestone and megestrol acetate.

23. The transdermal drug delivery system of claim 22, wherein said progestational agent is norethindrone acetate, and wherein said norethindrone acetate is present in said system in an amount of from about 1% to about 5% by weight.

24. The transdermal drug delivery system of claim 18, wherein said system comprises a mixture of a progestational agent and an estrogen.

25. The transdermal drug delivery system of claim 24, wherein said progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chlormadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17α

-hydroxyprogesterone, dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone, promegestone and megestrol acetate.

26. The transdermal drug delivery system of claim 25, wherein said progestational agent is norethindrone acetate.

27. The transdermal drug delivery system of claim 24, wherein said estrogen is selected from the group consisting of colpormon, equilenin, estradiol benzoate, estradiol 17β

-cypionate, moxestrol, mytatrienediol, quinestradiol, quinestrol, estropipate, 17β

-estradiol, equilin, mestranol, estrone, estriol, ethinyl estradiol and diethylstilbestrol.

28. The transdermal drug delivery system of claim 27, wherein said estrogen is 17β

-estradiol.

29. The transdermal drug delivery system of claim 4, wherein said drug is a β

₂ -adrenergic agonist.

30. The transdermal drug delivery system of claim 29, wherein said β

₂ -adrenergic agonist is selected from the group consisting of metaproterenol, terbutaline, albuterol, carbuterol, rimiterol, salmefamol, fenoterol, soterenol, tratoquinol and quinterenol.

31. The transdermal drug delivery system of claim 30, wherein said β

₂ -adrenergic agonist is albuterol, and wherein said albuterol is present in the system in an amount of less than about 30% by weight.

32. The transdermal drug delivery system of claim 4, wherein said drug is a cardioactive agent.

33. The transdermal drug delivery system of claim 32, wherein the cardioactive agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrates, quinidine sulfate, procainamide, benzydroflumethiazide, bendroflumethiazide, chlorothiazide, nifediplne, nicardipine, verapamil, diltiazem, timolol, propranolol, captopril, clonidine, prazosin, enalapril, enalaprilat, fosinopril, indapamide, lisinopril, quinapril and ramipril.

34. The transdermal drug delivery system of claim 33, wherein the cardioactive agent is nitroglycerin, and wherein said nitroglycerin is present in said system in an amount of less than about 25% by weight.

35. The transdermal drug delivery system of claim 4, wherein said drug is a cholinergic agonist.

36. The transdermal drug delivery system of claim 35, wherein said cholinergic agonist is selected from the group consisting of choline, acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine and arecoline.

37. The transdermal drug delivery system of claim 36, wherein said cholinergic agohist is pilocarpine, and wherein said pilocarpine is present in said system in an amount of less than about 30% by weight.

38. The transdermal drug delivery system of claim 4, wherein said drug is a tranquilizer.

39. The transdermal drug delivery system of claim 38, wherein said tranquilizer is selected from the group consisting of alprazolam, chlordiazepoxide, clorazeptate, halazepam, oxazepam, prazepam, clonazepam, flurazepam, triazolam, lorazepam and diazepam.

40. The transdermal drug delivery system of claim 39, wherein said tranquilizer is alprazolam.

41. The transdermal drug delivery system of claim 4, wherein said drug is an antipsychotic.

42. The transdermal drug delivery system of claim 41, wherein said antipsychotic is selected from the group consisting of thiopropazate, chlorpromazine, triflupromazine, mesoridazine, piperacetazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprathixene, thiothixene, haloperidol, bromperidol, loxapine and molindone.

43. The transdermal drug delivery system of claim 42, wherein said antipsychotic is haloperidol.

44. The transdermal drug delivery system of claim 4, wherein said drug is an anesthetic.

45. The transdermal drug delivery system of claim 44, wherein said anesthetic is selected from the group consisting of lidocaine, tetracaine, dyclonine, dibucaine, cocaine, procaine, mepivacaine, bupivacaine, etidocaine, prilocaine and benzocaine.

46. The transdermal drug delivery system of claim 45, wherein said anesthetic is lidocaine.

47. The transdermal drug delivery system of claim 4, wherein said drug is an analgesic.

48. The transdermai drug delivery system of claim 47, wherein the analgesic is selected from the group consisting of fentanyl, buprenorphine, codeins, baclofen and sumatriptan.

49. The transdermal drug delivery system of claim 4, wherein said drug has an action on the central nervous system.

50. The transdermal drug delivery system of claim 49, wherein the drug is nicotine, methylphenidate and tacrine.

51. The transdermal drug delivery system of claim 4, wherein said drug is a vasodilator.

52. The transdermal drug delivery system of claim 51, wherein said drug is papaverine.

53. The transdermal drug delivery system of claim 4, comprising at least two drugs.

54. The transdermal drug delivery system of claim 18, wherein said steroid is selected from the group consisting of fluoxymesterone, 17-methyltestosterone, 17α

-methyltestosterone 3-cyclopentyl enol ether, oxymetholone, stanozolol, testosterone, testosterone 17β

-cypionate, testosterone enanthate, testosterone propionate.

55. The transdermal drug delivery system of claim 4, wherein the drug is an antiparkinsonian.

56. The transdermal drug delivery system of claim 55, wherein said antiparkinsonian is selected from the group consisting of pergolide and deprenyl.

57. The transdermai drug delivery system of claim 4, wherein the drug is a non-steroidal anti-inflammatory.

58. The transdermal drug delivery system of claim 57, wherein said non-steroidal anti-inflammatory is selected from the group consisting of diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nahumstone, naproxen and piroxicam.

59. The transdermal drug delivery system of claim 4, wherein the drug is an anorectic.

60. The transdermal drug delivery system of claim 59, wherein said anorectic is selected from the group consisting of fenfluramine, mazindol and phentermine.

61. The transdermal drug delivery system of claim 4, wherein the drug is a glucocorticoid selected from the group consisting of aclometasone, beclomethasone, betamethasone, clobetasol, cortisone, desonide, desoximetasone, flunisolide, fluocinolone acetonide, flurandrenolide, mometasone furdate, prednisolone and prednisone.

62. The transdermal drug delivery system of claim 4, wherein the drug is an antinauseant selected from the group consisting of granisetron, ondanseteron and scopolamine.

63. The transdeal drug delivery. system of claim 4, wherein the drug is an antibiotic selected from the group consisting of tetracyclines.

64. The transdermal drug delivery system of claim 63, wherein said tetracycline is doxycyline.

65. The transdermal drug delivery system of claim 4, wherein the drug is selected from the group consisting of chlorhexidine and metronidazole.

66. The transdermal drug delivery system of claim 4, wherein the drug is a prostaglandin selected from the group consisting of prostaglandin E₁ and prostaglandin E₂.

67. The transdermal drug delivery system of claim 4, wherein the drug is misoprostol.

68. The transdermal drug delivery system of claim 4, wherein the drug is an antidiabetic selected from the group consisting of glypinamide.

70. A transdermal drug delivery system according to claim 4 made by a process comprising blending

(a) a pressure-sensitive adhesive selected from the group consisting of

(i) polyisoprene, polystyrene, polyethylene, polybutadiene, polyethylene/butylene, styrene/butadiene, styrene-butadiene-styrene, styrene-isoprene-styrene, styrene-ethylene/butylene-styrene block copolymers, butyl rubber, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, polychloroprene, polyacrylonitrile and polychlorodiene, and mixtures thereof, in an amount from about 14% to about 94% by weight of the total pressure-sensitive adhesive composition;

(ii) polyisobutylene and mixtures thereof in an amount from about 10% to about 90% by weight of the total pressure-sensitive adhesive composition; and

(iii) polysiloxane and mixtures thereof in an amount from about 5% to about 95% by weight of the total pressure-sensitive adhesive composition;

(b) a polyacrylate in an amount from about 5% to about 85%, wherein said polyacrylate and said pressure-sensitive adhesive (a) differ in solubility parameter by an increment of at least 2 (J/cm³)^1/2 ;

(c) a soluble polyvinylpyrrolidone in an amount from about 1% to about 20% by weight of the total pressure-sensitive adhesive composition;

(d) one drug or a mixture of two or more drugs; and

(e) optionally, an enhancer in an amount up to about 20% by weight of the total pressure-sensitive adhesive composition.

71. The transdermal drug delivery system according to claim 4, wherein the soluble polyvinylpyrrolidone has a molecular weight from about 5,000 to 100,000.

72. The transdermal drug delivery system of claim 4, wherein the drug is a mineralcorticoid.

73. The transdermal drug delivery system of claim 72, wherein said mineralcorticoid is fludrocortisone.