Therapeutic system for administering clonidine transdermally

• US 4,201,211 A
• Filed: 07/12/1977
• Issued: 05/06/1980
• Est. Priority Date: 07/12/1977
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim GmbH (C.H. Boehringer Sohn AG & Co. KG), ALZA Corporation (Johnson & Johnson)
• Original Assignee: Boehringer Ingelheim GmbH (C.H. Boehringer Sohn AG & Co. KG), ALZA Corporation (Johnson & Johnson)
• Inventors: Michaels, Alan S., Chandrasekaran, Santosh K., Cleary, Gary W., Darda, Siegfried
• Primary Examiner(s): Michell, Robert W.
• Assistant Examiner(s): Rosenbaum, C. F.
• Application Number:
  US05/815,033
• Time in Patent Office: 1,029 Days
• Field of Search: 128/156, 128/260, 128/268, 424/19, 424/20, 424/28
• US Class Current: 424/448
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• 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 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: B32B 2323/10 Polypropylene
• CPC Class Codes: B32B 2556/00 Patches, e.g. medical patches, repair patches
• CPC Class Codes: B32B 27/06 as the main or only constituent of a layer, which is next to another layer of the same or of a different material next to a layer of a particular substance B32B9/045; next to a bituminous or tarry layer B32B11/046; next to a water setting substance layer B32B13/12; next to a metal layer B32B15/08; next to a glass layer B32B17/10; next to a layer formed of natural mineral fibres or particles B32B19/045; next to a wood layer B32B21/08; next to a cellulosic plastic layer B32B23/08; next to a natural or synthetic rubber layer B32B25/08
• CPC Class Codes: B32B 27/32 comprising polyolefins comprising vinyl (co)polymers or acrylic (co)polymers B32B27/30

Abstract

Therapeutic system in the form of a skin patch that administers clonidine transdermally in an initial priming dose of 10 to 300 mcg/cm² of skin that brings the concentration of clonidine in the blood to a level sufficient to elicit alpha-adrenergic stimulation without intolerable side effects, followed by a substantially constant continuous dosage in the range of 0.1 to 100 mcg/hr that maintains said level. The system is a four-layer laminate of, from the top: a protective backing; a gelled, mineral oil-polyisobutene-clonidine reservoir lamina that is the source of the clonidine for the continuous constant dosage; a microporous membrane that controls the constant dosage rate; and a gelled, mineral oil-polyisobutene-clonidine contact adhesive layer that is the source of the clonidine for the priming dose and the means by which the system is attached to the skin.

Claims

1. A therapeutic system in the form of a skin patch for administering clonidine continuously and transdermally through a predetermined area of unbroken skin in a controlled manner for a prolonged time period to effect central alpha-adrenergic stimulation comprising:

(a) a backing that is substantially impermeable to clonidine, one face of which forms the top of the patch;

(b) a clonidine reservoir adjacent the opposite face of the backing that contains an amount of clonidine sufficient to provide clonidine for said prolonged time period at a central alpha-adrenergic stimulating rate;

(c) means for releasing clonidine from the reservoir at said rate to said predetermined area of skin; and

(d) means for affixing the patch to said predetermined area of skin.

2. The therapeutic system of claim 1 wherein the central alpha-adrenergic stimulating rate is one that provides hypertension therapy.

3. A therapeutic system in the form of a skin patch for administering 2,6-dichloro-N-2-imidazolidinylidene benzeneamine continuously and transdermally through a predetermined area of unbroken skin in a controlled manner for a prolonged time period to effect central alpha-adrenergic stimulation comprising a sandwich-type laminate of:

(a) a backing lamina that is substantially impermeable to the benzeneamine, one face of which forms the top of the patch;

(b) a benzeneamine reservoir lamina adjacent the opposite face of the backing lamina comprising;

(i) an amount of said benzeneamine at least equal to that required to provide said benzeneamine for said prolonged time period at a central alpha-adrenergic stimulating rate, dispersed in

(ii) a carrier that is permeable to said benzeneamine;

(c) a microporous membrane lamina adjacent and below the benzeneamine reservoir lamina through which the benzeneamine is released from the reservoir lamina at said rate after the skin patch is affixed to the skin; and

(d) a contact adhesive lamina adjacent and below the microporous membrane lamina by which the patch is affixed to the skin comprising;

(i) a contact adhesive that is permeable to the benzeneamine; and

(ii) an amount of benzeneamine that constitutes at least a substantial portion of the quantity of the benzeneamine that is immobilized by said predetermined area of skin.

4. The therapeutic system of claim 3 wherein the rate is one that provides hypertension therapy.

5. The therapeutic system of claim 4 wherein said rate is in the range of 0.1 to 100 mcg/hr and said amount of benzeneamine in said contact adhesive lamina is 10 to 300 mcg/cm² of said predetermined area of skin.

6. The therapeutic system of claim 4 wherein said rate is in the range of 0.2 to 70 mcg/hr and said amount of benzeneamine in the contact adhesive lamina is 150 to 250 mcg/cm² of said predetermined area of skin.

7. The therapeutic system of claim 4 including:

(e) a strippable coating lamina adjacent and below the contact adhesive lamina that is substantially impermeable to the components of the contact adhesive lamina and is adapted to be stripped off the patch before the patch is affixed to the skin.

8. The therapeutic system of claim 4 wherein the carrier and the contact adhesive comprise a gelled mixture of mineral oil of about 10 to about 100 cp at 25°

C. and polyisobutene.

9. The therapeutic system of claim 8 wherein the polyisobutene is a blend of a first polyisobutene having a viscosity average molecular weight of 35,000 to 50,000 and a second polyisobutene having a viscosity average molecular weight of 1,000,000 to 1,500,000.

10. The therapeutic system of claim 9 wherein the mineral oil constitutes 35% to 65% by weight of the gelled mixture, the first polyisobutene constitutes 10% to 40% by weight of the gelled mixture and the second polyisobutene constitutes 10% to 40% by weight of the gelled mixture.

11. The therapeutic system of claim 4 wherein the microporous membrane lamina has a porosity of about 0.1 to 0.85, a tortuosity of about 1 to 10 and a thickness of about 10^-3 to 10^-2 cm.

12. The therapeutic system of claim 11 wherein the microporous membrane lamina is made of polypropylene.

13. The therapeutic system of claim 12 wherein the backing layer is made of aluminized polyethylene terephthalate.

14. The therapeutic system of claim 4 including:

(e) a strippable coating lamina adjacent and below the contact adhesive lamina that is substantially impermeable to the components of the contact adhesive lamina and is adapted to be stripped off the patch before the patch is affixed to the skin, and wherein said rate is in the range of 0.2 to 70 mcg/hr, the amount of the benzeneamine in the contact adhesive lamina is 150 to 250 mcg/cm² of skin, the particle size of the undissolved benzeneamine present in the reservoir lamina and contact adhesive lamina being in the range of about 5 to 20 microns, the carrier comprises a gelled mixture of 35% to 65% by weight mineral oil of about 10 to about 100 cp at 25°

C., 10% to 40% by weight polyisobutene having a viscosity average molecular weight of 35,000 to 50,000, and 10% to 40% by weight polyisobutene having a viscosity average molecular weight of 1,000,000 to 1,500,000, the contact adhesive is made of said gelled mixture, the microporous membrane lamina is made of polypropylene, and the backing layer is made of aluminized polyethylene terephthalate.