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

• US 5,958,446 A
• Filed: 05/04/1995
• Issued: 09/28/1999
• 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:
  US08/433,754
• Time in Patent Office: 1,608 Days
• Field of Search: 424/448, 424/449
• US Class Current: 424/448
• CPC Class Codes: A61F 13/0276 Apparatus or processes for manufacturing adhesive dressings or bandages
• CPC Class Codes: A61F 2013/00646 Medication patches, e.g. transcutaneous
• 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: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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
• CPC Class Codes: C08L 83/04 Polysiloxanes

Abstract

The method of adjusting the saturation concentration of a drug in a transdermal composition for application to the dermis, which comprises mixing polymers having differing solubility parameters, so as to modulate the delivery of the drug. This results in the ability to achieve a predetermined permeation rate of the drug into and through the dermis. In one embodiment, a dermal composition of the present invention comprises a drug, an acrylate polymer, and a polysiloxane. The dermal compositions can be produced by a variety of methods known in the preparation of drug-containing adhesive preparations, including the mixing of the polymers, drug, and additional ingredients in solution, followed by removal of the processing solvents. The method and composition of this invention permit selectable loading of the drug into the dermal formulation and adjustment of the delivery rate of the drug from the composition through the dermis, while maintaining acceptable shear, tack, and peel adhesive properties.

Claims

1. A dermal composition, comprising a blend of:

(a) a polyacrylate and a second polymer selected from the group consisting of a polysiloxane and a hydrocarbon polymer; and

(b) a therapeutically effective amount of a drug for transdermal administration,

wherein the composition is a pressure-sensitive adhesive and the polyacrylate and the second polymer modulates the permeation rate of the drug through the dermis, and wherein the composition excludes a polyethylene/vinyl acetate copolymer.

2. The composition of claim 1, which further comprises a hydrophilic filler.

3. The composition of claim 2, wherein the hydrophilic filler includes aluminum silicate clay.

4. The composition of claim 1, wherein the drug is a steroid.

5. The composition of claim 4, wherein the steroid is an estrogen selected from the group consisting of, estropipate, 17β

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

6. The composition of claim 4, wherein the steroid is a progestational agent.

7. The composition of claim 6, wherein the progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chloromadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17α

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

8. The composition of claim 1, wherein the drug is a cardioactive drug.

9. The composition of claim 8, wherein said cardioactive agent is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, quinidine sulfate, procainamide, benzydroflumethiazide, bendroflumethiazide, chlorothiazide, nifedipine, nicardipine, verapamil, diltiazem, timolol, propranolol, captopril, clonidine and prazosin.

10. The composition of claim 1, wherein said composition is a reservoir device having an adhesive portion comprised of said blend.

11. The composition of claim 5, wherein the estrogen is 17β

-estradiol and the 17β

-estradiol is present in the composition in an amount of from about 1% to about 5% by weight.

12. The composition of claim 7, wherein the progestational agent is norethindrone acetate and the norethindrone acetate is present in the composition in an amount of from about 1% to about 5% by weight.

13. The composition of claim 1, wherein the drug is albuterol and the albuterol is present in the composition in an amount of up to about 30% by weight.

14. The composition of claim 9, wherein the cardioactive agent is nitroglycerin and the nitroglycerin is present in the composition in an amount of less than about 25% by weight.

15. The composition of claim 1, wherein the drug is pilocarpine and the pilocarpine is present in the composition in an amount of less than about 30% by weight.

16. The composition of claim 1, wherein the drug is a tranquilizer.

17. The composition of claim 16, wherein the tranquilizer is selected from the group consisting of alprazolam, chlordiazepoxide, clorazeptate, halazepam, oxazepam, prazepam, clonazepam, flurazepam, triazolam, lorazepam and diazepam.

18. The composition of claim 17, wherein the tranquilizer is alprazolam.

19. The composition of claim 1, wherein the drug is an antipsychotic.

20. The composition of claim 19, wherein the 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.

21. The composition of claim 20, wherein the antipsychotic is haloperidol.

22. The composition of claim 1, wherein the drug is an anesthetic.

23. The composition of claim 22, wherein the anesthetic is selected from the group consisting of lidocaine, tetracaine, dyclonine, dibucaine, cocaine, procaine, mepivacaine, bupivacaine, etidocaine, prilocaine and benzocaine.

24. The composition of claim 23, wherein the anesthetic is lidocaine.

25. The composition of claim 1, wherein the drug is an analgesic.

26. The composition of claim 25, wherein the analgesic is selected from the group consisting of fentanyl, buprenorphine and codeine.

27. The composition of claim 1, wherein the drug has an action on the central nervous system.

28. The composition of claim 27, wherein the drug is nicotine.

29. The composition of claim 1, comprising a mixture of at least two drugs.

30. The composition of claim 29, comprising a mixture of a progestational agent and an estrogen.

31. The composition of claim 30, wherein said progestational agent is selected from the group consisting of progesterone, 19-norprogesterone, norethindrone, norethindrone acetate, melengestrol, chloromadinone, ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate, ethynodiol diacetate, norethynodrel, 17α

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

32. The composition of claim 31, wherein said progestational agent is norethindrone acetate.

33. The composition of claim 30, wherein said estrogen is selected from the group consisting of conjugated estrogens, esterified estrogens, estropipate, 17β

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

34. The composition of claim 33, wherein said estrogen is 17β

-estradiol.

35. The composition of claim 1, wherein said composition achieves an increased permeation rate of the drug through the dermis of a subject relative to the permeation rate achieved by a composition comprising one of said polyacrylate or said second polymer as the sole polymer.

36. The composition of claim 1, wherein said composition achieves a decreased permeation rate of the drug through the dermis of a subject relative to the permeation rate achieved by a composition comprising said one of said polyacrylate or said second polymer as the sole polymer.

37. The composition of claim 1, further comprising one or more additives selected from the group consisting of one or more enhancers, a filler, a co-solvent and an excipient.

38. The composition of claim 1, wherein the polymers of the blend consist essentially of the polyacrylate and second polymer.

39. The composition of claim 1, wherein the polymers of the blend consist essentially of the polysiloxane and the polyacrylate.

40. The composition of claim 39, wherein the polyacrylate is present in an amount ranging from about 2% to about 96% by weight of the composition and the polysiloxane is present in an amount ranging from about 98% to about 4% by weight of the composition.

41. The composition of claim 39, which comprises based on the weight of the composition, about 0.3 to about 50% by weight of albuterol, about 14 to about 97% by weight of polysiloxane, about 2 to about 85% by weight of polyacrylate, 0 up to about 20% by weight of enhancers, and about 0 up to about 30% by weight of cosolvents.

42. The composition of claim 1, wherein the blend includes additional polymers.

46. A composition as claimed in claim 1, wherein the polyacrylate and the second polymer are pressure-sensitive adhesives.

47. The dermal composition as claimed in claim 38, wherein the polymers of the blend consist essentially of the polyacrylate and the hydrocarbon polymer.

48. The composition as claimed in claim 47, wherein the hydrocarbon polymer is selected from the group consisting of polyethylene, polystyrene, polyisobutylene, polybutadiene and the copolymer of polyethylene/butylene.

49. The composition as claimed in claim 48, wherein the hydrocarbon polymer is polyisobutylene.

52. The composition of claim 40, wherein the composition further comprises dipropylene glycol, and wherein the drug is estradiol.

53. The composition of claim 52, wherein the drug is 17β

-estradiol.

54. The composition of claim 40, wherein the composition further comprises dipropylene glycol and oleic acid, and wherein the drug includes a further drug, wherein said drug and further drug selected from the group of an estrogen and a progestational agent.

55. The composition of claim 54, wherein the estrogen is 17β

-estradiol.

56. The composition of claim 55, wherein the progestational agent is one or more norethindrone and norethindrone acetate.

57. A composition according to claim 1, wherein the composition consists essentially of the polyacrylate, the second polymer and one or more drugs.

61. The composition of claim 1, wherein the drug is an androgenic steroid.

62. The composition of claim 1, wherein the drug is an Parkinsonian agent.

63. The composition of claim 62, wherein the Parkinsonian agent is selegiline (deprenyl).

64. The composition of claim 1, wherein the drug is an anti-inflamatory.

65. The composition of claim 64, wherein the anti-inflammatory agent is selected from the group consisting of fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, peroxicam, fludrocortisone, betamethasone, flucinolone, flurandrenolide, prednisolone and prednisone.

66. The composition of claim 1, wherein the drug is an anorectic.

67. The composition of claim 66, wherein the anorectic is selected from the group consisting of fenfluramine, mazindol and phentermine.

68. The composition of claim 1, wherein the drug is selected from the group consisting of misoprostol, baclofen, scopolamine, tetracycline, albuterol, alprazolam, and haloperidol.

69. The composition of claim 29, wherein the first drug is an anesthetic and the second drug is elected from the group consisting of analgesics, anesthetics and anti-inflammatories.

70. The composition of claim 1, which further comprises:

a backing layer which is in contact with a first surface of the dermal composition; and

a release layer which is in contact with and which releasably covers the opposite surface of the dermal composition.

74. The composition of claim 37, wherein the drug is for Parkinson'"'"'s disease, the co-solvent is selected from the group consisting of propylene glycol, saturated fatty acids and unsaturated fatty acids, and the one or more enhancers are selected from the group consisting of a polyhydric alcohol, a polar solvent, a higher molecular weight aliphatic surfactant and oleic acid.

75. The composition of claim 74, wherein the drug for Parkinson'"'"'s disease is levodopa, and the enhancer is propylene glycol and lauryl sulfate.

43. A pressure-sensitive adhesive composition for dermal administration of a drug comprising a blend of:

(a) two polymers consisting essentially of about 2% to about 96% by weight of a polyacrylate and about 98% to about 4% by weight of a polysiloxane, the two polymers being in an amount of about 99% to about 50% by weight of said composition;

(b) a drug in the amount of about 0.3% to about 50% by weight of said composition;

(c) an effective amount of a co-solvent for the drug, said amount being up to about 30% by weight of said composition; and

(d) an effective amount of an enhancer, said amount being up to about 20% by weight of said composition.

44. The composition of claim 43, further comprising fillers and excipients in an amount of about 1% to about 15% by weight of the dermal adhesive composition.

45. A process for transdermally administering to a mammal a therapeutically effective amount of a drug, comprising the steps of applying a composition for transdermal administration of the drug to the skin of said mammal, and maintaining said composition in contact with said skin until said effective amount of said preselected drug is transdermally administered, wherein said composition comprises a blend of

(a) two or more polymers which includes a polyacrylate and one or more of a polysiloxane, polyvinylchloride, polyvinylidene chloride, polychloroprene, polyacrylonitrile, nylon-6,6, epoxy resin, a copolymer of polybutadiene/acrylonitrile and a hydrocarbon polymer, said at least two polymers have corresponding solubility parameters and are blended in a proportion, resulting in a net solubility parameter of the blend;

and

(b) said preselected drug, wherein the composition is a pressure-sensitive adhesive wherein the net solubility parameter of the blend determines the solubility of the preselected drug in the blend, and wherein the composition excludes a polyethylene/vinyl acetate copolymer.

58. A process according to claim 45, wherein the one or more polymers includes polysiloxane.

59. A process according to claim 45, wherein the composition consists essentially of the polyacrylate, the second polymer and one or more drugs.

60. A proces according to claim 45, wherein the second polymer includes the hydrocarbon polymer which is selected from the group consisting of polyethylene, polystyrene, polyisobutylene, polybutadiene, and polyethylene/butylene, and mixtures thereof.

73. A process according to claim 45, wherein before administration, the composition is positioned between a backing layer which is in contact with a first surface of the composition, and a release layer which is in contact with and which releasably covers the opposite surface of the composition.

50. A dermal composition, comprising a blend of:

(a) a polyacrylate having a first solubility parameter and a second polymer selected from the group consisting of polysiloxane and hydrocarbon polymers having a second solubility parameter, wherein the first and second solubility parameters are different from one another by an increment of at least 4 (J/cm³)^1/2 ; and

(b) a therapeutically effective amount of a drug for transdermal administration,

wherein the composition is a pressure-sensitive adhesive and the polyacrylate and the second polymer modulates the permeation rate of the drug through the dermis, and wherein the composition excludes a polyethylene/vinyl acetate copolymer.

71. The composition of claim 50, which further comprises:

a backing layer which is in contact with a first surface of the dermal composition; and

a release layer which is in contact with and which releasably covers the opposite surface of the dermal composition.

51. A composition for dermal administration of a drug, comprising a blend of:

(a) a polyacrylate and a second polymer selected from the group consisting of polyvinylchloride, polyvinylidene chloride, polychloroprene, polyacrylonitrile, nylon-6,6, epoxy resin, and a copolymer of polybutadiene/acrylonitrile; and

(b) a therapeutically effective amount of a drug for transdermal administration,

wherein the composition is a pressure-sensitive adhesive and the polyacrylate and the second polymer modulates the permeation rate of the drug through the dermis, and wherein the composition excludes a polyethylene/vinyl acetate copolymer.

72. The composition of claim 51, which further comprises:

a backing layer which is in contact with a first surface of the dermal composition; and

a release layer which is in contact with and which releasably covers the opposite surface of the dermal composition.