Enhanced drug delivery in transdermal systems

• US 7,456,159 B2
• Filed: 12/30/2002
• Issued: 11/25/2008
• Est. Priority Date: 06/18/2001
• Status: Expired due to Term

• Current Assignee: Noven Pharmaceuticals Inc (Hisamitsu Pharmaceutical Company Incorporated)
• Original Assignee: Noven Pharmaceuticals Inc (Hisamitsu Pharmaceutical Company Incorporated)
• Inventors: Houze, David, Nguyen, Viet
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US10/330,281
• Publication Number:
  US 20030232073A1
• Time in Patent Office: 2,157 Days
• Field of Search: 514/171
• US Class Current: 514/171
• 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 31/403 condensed with carbocyclic rings, e.g. carbazole
• 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 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 38/556 Angiotensin converting enzyme inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

A composition for transdermal administration resulting from an admixture includes: a therapeutically effective amount of a drug that includes a parent drug and a prodrug; and and a pharmaceutically acceptable carrier, wherein the parent drug and prodrug are individually present in an amount sufficient for a pharmacological effect. In a preferred embodiment, the admixture includes: a therapeutically effective amount of a pharmaceutically active agent that includes a corresponding steroid and a steroid derivative; and a carrier for the pharmaceutically active agent. The steroid and the corresponding steroid derivative are present in a weight ratio of 10:1 to 1:10 steroid: corresponding steroid derivative. In a preferred embodiment ratio is 6:1 to 1:6. In a preferred embodiment, the corresponding steroid derivative is a steroid ester. In another preferred embodiment, the carrier is a polymer that includes a pressure-sensitive adhesive. In another preferred embodiment, the parent drug is an ACE inhibitor such as ramipril and the prodrug is an ACE inhibitor prodrug such as ramipril ethyl and/or methyl ester.

Claims

1. A method of adjusting the blood level profile or permeation of a drug from a transdermal drug delivery composition, comprising:

(a) selecting a parent drug and a corresponding prodrug, wherein the parent drug is a steroid and the prodrug is a corresponding steroid derivative that provides a source of therapeutically active steroid;

(b) combining the parent drug and prodrug in a carrier that includes at least one pressure-sensitive adhesive, wherein the steroid and corresponding steroid derivative are present in a wt/wt ratio of from 10;

1 to 1;

10 steroid;

corresponding steroid derivative;

(c) measuring the permeation and/or blood level profile of the drug;

(d) adjusting at least one of;

(i) the selection of the corresponding prodrug and (ii) the relative concentration of the parent drug and prodrug,

wherein the parent drug is a steroid comprising a steroid ring with a free hydroxy group at position 3, 11 or 17 and the prodrug is a corresponding steroid derivative where the free hydroxy group at the 3, 11 or 17 position has been reacted with an alcohol moiety.

2. A method according to claim 1, wherein the at least one pressure sensitive adhesive includes two pressure sensitive adhesives and the step of adjusting (d) further comprises:

(iv) adjusting the type and/or proportions of the two pressure sensitive adhesives.

3. A method as claimed in claim 1, wherein the parent drug is a steroid comprising a steroid ring with a free hydroxy group at position 17 and the prodrug is a corresponding steroid derivative where the free hydroxy group at the 17 position has been reacted with an alcohol moiety.

4. The method according to claim 1, wherein the corresponding steroid derivative is a steroid ester.

5. The method according to claim 1, wherein the steroid is selected from the group consisting of estradiols, progestins, anabolic steroids, androgenic steroids, estrogens, glucocorticoids, and mineralcorticoids.

6. The method according to claim 5, wherein the steroid is a progestin selected from the group consisting of allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, gestodene, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17-α

-hydroxyprogesterone, lynestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, norvinisterone, pentagestrone, and trimigestone.

7. The method according to claim 5, wherein the steroid comprises one or more anabolic steroids or one or more androgenic steroids.

8. The method according to claim 7, wherein the one or more anabolic steroids are selected from the group consisting of androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone and trenbolone.

9. The method according to claim 7, wherein the one or more androgenic steroids is selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17-α

-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal and tiomesterone.

10. The method according to claim 5, wherein the drug comprises testosterone and the prodrug comprises testosterone acetate.

11. The method accbrding to claim 7, wherein the parent drug is norethindrone and the prodrug is norethindrone acetate.

12. A method as claimed in claim 11, wherein the norethindrone and norethindrone acetate are present in a wt/wt ratio of from 10:

1 to 1;

10, and wherein the norethindrone acetate is present at a greater weight than the norethindrone.

13. A method as claimed in claim 5, wherein the parent drug is estradiol and the prodrug is estradiol 17-enanthate.