# US 5,705,185 A · Transdermal delivery of estradiol and process for manufacturing said device > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,705,185 A - Document ID: US5705185A - Status: Granted - Kind: A - Application number: 08/584,006 - Filed: 1996-01-11 - Granted: 1998-01-06 - Earliest claimed: 1991-09-25 - Assignees: Beta Pharmaceuticals Co. - Inventors: Francisco Jose Evaristo Stefano; Jose Adrian Nowogrodski; Dario Norberto Ramon Carrara - Web page: https://patentgrep.com/patent/US5705185A ## CPC - A61K 9/7053: {obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene} - A61K 9/7061: {Polyacrylates} - A61K 9/7076: {the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins} - A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/12: Carboxylic acids; Salts or anhydrides thereof - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The present invention relates to a transdermal delivery device for estradiol where the metabolic degradation of estradiol to estrone during permeation is inhibited by another substance in the transdermal delivery device. The transdermal device also includes a compound for enhancing the rate of estradiol permeation. The transdermal delivery device containing the inhibitor and enhancer can also be used to simultaneously deliver both estradiol and a progestin at therapeutic rates. ## Claims ### Claim 1 A transdermal delivery device for estradiol including a flexible substrate and a releasable protective film, the protected surface of said flexible substrate being at least partly covered with a coating layer containing: (a) a dermatologically or pharmacologically acceptable pressure sensitive adhesive material; (b) estradiol homogeneously distributed in said coating layer as a pharmacologically active ingredient; (c) one compound as an inhibitor of metabolic oxidation of estradiol to estrone, said compound selected from the group consisting of glycerin and (C.sub.3 -C.sub.6) alkylene 1,2-diols; (d) a second compound which enhances the rate of estradiol permeation, said second compound selected from the group consisting of unsaturated (C.sub.12 -C.sub.18) fatty acids; and (e) a pharmacologically active progestin. ### Claim 2 A transdermal delivery device for estradiol comprising a flexible substrate and a releasable protective film, the protective surface of said flexible substrate being at least partly covered with a coating layer containing: a) a dermatologically or pharmacologically acceptable pressure sensitive adhesive material for securing the device to the skin; b) estradiol homogeneously distributed in said coating layer as a pharmacologically active ingredient, said estradiol comprising from 1 to 5 wt. %; c) one compound as an inhibitor of metabolic oxidation of estradiol to estrone, said compound selected from the group consisting of glycerin and (C.sub.3 -C.sub.6) alkylene 1,2 diols in a concentration from 0.25 to 30 wt %; d) a second compound which enhances the rate of estradiol permeation, said second compound selected from unsaturated (C.sub.12 -C.sub.18) fatty acids in a concentration from 1 to 20 wt %; and (e) a pharmacologically active progestin in a concentration from 2 to 10 wt %, said weight percentages being based on total weight of said coating layer. ### Claim 3 (depends on 1) A device according to claim 1, wherein the amount of estradiol in the coating layer exceeds the saturation concentration thereof. ### Claim 4 (depends on 1) A device according to claim 1, wherein a pharmaceutically active progestin is includes in a concentration from 2 to 10 wt %. ### Claim 5 (depends on 1) A device according to claim 1, wherein said coating layer comprises in an homogeneous mixture; i) an adhesive material selected from silicones, acrylic or methacrylic polymers, natural and synthetic rubber and mixtures thereof; and ii) a reinforcing component selected from polyterpenes, modified colophony resins and mixtures thereof. ### Claim 6 (depends on 1) A device according to claim 1, wherein said rate enhancing component comprises as enhancer oleic acid and propylene glycol as inhibitor of oxidation in ratio of 1:0,5 to 1:5. ### Claim 7 (depends on 6) A device according to claim 6, wherein the ratio is 1:1,5. ### Claim 8 (depends on 1) A device according to claim 1, wherein said flexible substrate is selected from the group consisting of cellulose xanthate, aluminum, a polymer or a laminate. ### Claim 9 (depends on 8) A device according to claim 8, wherein the polymer is selected from the group consisting of polyvinyl chloride, polyvinylidene, polyester or polyethylene. ### Claim 10 (depends on 1) A device according to claim 1, wherein the amount of estradiol in the coating layer is sufficient to maintain its concentration at least at saturation level during predetermined periods of time. ### Claim 11 A process for manufacturing a transdermal delivery device for estradiol, comprising the steps of providing a coating layer on at least part of one surface of a flexible substrate, said coating layer including: (a) a dermatologically or pharmacologically acceptable pressure sensitive adhesive material for securing the device to the epidermis; (b) estradiol homogeneously distributed in said coating layer as a pharmacologically active ingredient; (c) one compound as an inhibitor of inhibitor of enzymatic oxidation of estradiol to estrone, said compound being selected from the group consisting of glycerin and (C.sub.3 -C.sub.6) alkylene 1,2 diols in a concentration from 0.25 to 30 wt %; (d) a second compound which enhances the rate of estradiol permeation, said second compound selected from unsaturated (C.sub.12 -C.sub.18) fatty acids in a concentration from 1 to 20 wt %; and (e) a pharmacologically active progestin in a concentration from 2-10 wt %, said weight percentages being based on total weight of said coating layer; and providing a releasable protective layer which, in the finished device, lies on the opposite side of the coating layer to the flexible substrate. ### Claim 12 (depends on 11) A process according to claim 11, wherein the amount of estradiol in said coating layer is in excess of the saturation concentration therein. ### Claim 13 (depends on 11) A process according to claim 11, wherein the coating layer is provided by coating it on the releasable protective layer, bringing the flexible substrate into contact with the coating layer, then cutting the resultant structure to a required shape and size and packaging in a convenient blister system. ### Claim 14 (depends on 1) A device according to claim 1, wherein the packaging is a blister system, which comprises a thermoformed PVC which is heat sealed with a lacquered aluminum foil. ### Claim 15 (depends on 10) A device of claim 10 wherein said predetermined period of time is up to 4 days. ### Claim 16 (depends on 11) A process according to claim 11, wherein said coating layer includes a progestin in a concentration of 2 to 10 wt %. ### Claim 17 (depends on 2) A device according to claim 2, wherein the amount of estradiol in the coating layer exceeds the saturation concentration thereof. ### Claim 18 (depends on 2) A device according to claim 2, wherein another pharmacologically active agent, a progestin, is includes in a concentration from 2 to 10 wt %. ### Claim 19 (depends on 2) A device according to claim 2, wherein said coating layer comprises in a homogeneous mixture: an adhesive material selected from silicones, acrylic or methacrylic polymers, natural and synthetic rubber and mixtures thereof; a reinforcing component selected from polyterpenes, modified colophony resins and mixture thereof. ### Claim 20 (depends on 2) A device according to claim 2, wherein said rate enhancing component comprises oleic acid as an enhancer and propylene glycol as an inhibitor of oxidation in a ratio (oleic acid: propylene glycol) ranging from about 1:0.5 to about 1:5. ### Claim 21 (depends on 2) A device according to claim 2 wherein the packing is a blister system which comprises a thermoformed PVC which is heat sealed with a lacquered aluminum foil. ### Claim 22 (depends on 2) A device according to claim 2, wherein the amount of estradiol in the coating layer is sufficient to maintain its concentration at least at saturation level during predetermined periods of time. ### Claim 23 (depends on 12) A process according to claim 12, wherein the coating layer is provided by coating it on the releasable protective layer, then cutting the resultant structure to a required shape and size and packaging in a blister pack. ### Claim 24 (depends on 2) A device according to claim 2, wherein said estradiol comprises 2 wt %. ### Claim 25 (depends on 2) A device according to claim 2, wherein said compound used as an inhibitor of metabolic oxidation of estradiol comprises 15 wt %. ### Claim 26 (depends on 2) A device according to claim 2, wherein the amount of said second compound which enhances the rate of estradiol permeation comprises 10 wt %. ### Claim 27 (depends on 4) A device according to claim 4, wherein the progestin is selected from the group consisting of levonorgestrel and norethindrone acetate. ### Claim 28 (depends on 16) A process according to claim 16, wherein the progestin is selected from the group consisting of levonorgestrel and norethindrone acetate. ### Claim 29 (depends on 1) A device according to claim 1, wherein said estradiol comprises from 1 to 5 wt %; said inhibitor compound comprises from 0.25 to 30 wt %, said enhancer compound comprises from 1 to 20 wt % and said progestin comprises from 2 to 10 wt %; said weight percentages being based on total weight of the coating layer.