Transdermal delivery systems for active agents

Abstract

A delivery vehicle for topical pharmaceutical formulations that include a C2 to C4 alkanol, a polyalcohol, and a monoalkyl ether of diethylene glycol present in relative amounts sufficient to provide permeation enhancement of an active agent through mammalian dermal or mucosal surfaces. Preferably, the delivery vehicle as well as the formulations that contain it are substantially free of long-chain fatty alcohols, long-chain fatty acids and long-chain fatty esters in order to avoid potential undesirable odor and irritation effects caused by such compounds during use of the formulation. Without these additives, use of the formulations is facilitated and patient compliance is greater

1 . A delivery vehicle for a composition of an active agent that is to be administered transdermally or transmucosally to a subject, which comprises a C2 to C4 alkanol, a polyalcohol, a monoalkyl ether of diethylene glycol, and water, present in relative amounts sufficient to provide permeation enhancement of the active agent through mammalian dermal or mucosal surfaces; wherein the delivery system is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters in order to avoid undesirable odor and irritation effects caused by such compounds during use of the composition. 
     
     
         2 . The delivery vehicle of  claim 1 , wherein the alkanol is selected from the group consisting of ethanol, isopropanol, n-propanol, and mixtures thereof; wherein the polyalcohol is selected from the group consisting of propylene glycol and dipropylene glycol and mixtures thereof; and wherein the monoalkyl ether of diethylene glycol is selected from the group consisting of monomethyl ether of diethylene glycol, monoethyl ether of diethylene glycol, and mixtures thereof. 
     
     
         3 . The delivery vehicle of  claim 1 , wherein the alkanol is present in an amount between about 5 to 80% by weight, the polyalcohol is present in an amount between about 1% to 30% by weight, and the monoalkyl ether of diethylene glycol is present in an amount between about 0.2 to 30% by weight so that the delivery vehicle facilitates absorption of the active agent by the dermal or mucosal surfaces so that transfer or removal of the formulation from such surfaces is minimized. 
     
     
         4 . The delivery vehicle of  claim 3 , wherein the alkanol is in combination with water to form a hydroalcoholic mixture that is present in an amount of between about 40 to about 98% by weight, with the alkanol present in an amount of between about 5% to 80% by weight of the mixture, and the water present in an amount of between about 20% to 95% by weight of the mixture. 
     
     
         5 . The delivery vehicle of  claim 1 , wherein the alkanol is present in an amount between about 45 and 75% by weight; the polyalcohol is present in an amount between about 1 to 30% by weight; and the monoethyl ether of diethylene glycol is present in an amount between about 1 to 15% by weight. 
     
     
         6 . The delivery vehicle according  claim 1 , wherein the alkanol is ethanol, isopropanol, or a mixture thereof present in an amount between about 45 and 60% by weight; the polyalcohol is propylene glycol present in an amount between about 1 to 20% by weight; and the monoethyl ether of diethylene glycol is present in an amount between about 1 to 10% by weight and further wherein the polyalcohol and permeation enhancer are present in a weight ratio of between 1:1 to 3:1. 
     
     
         7 . The delivery system according to  claim 6  consisting essentially of the recited ingredients and amounts. 
     
     
         8 . A non-occlusive formulation comprising the delivery vehicle according  claim 1  and an active agent or a pharmaceutically acceptable salt thereof present in an amount of between about 1 to 20% by weight of the formulation; wherein the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters in order to avoid undesirable odor and irritation effects caused by such compounds during use. 
     
     
         9 . The formulation of  claim 8 , wherein the active agent is a hormone, 
     
     
         10 . The formulation of  claim 8  wherein the active agent is selected from the group consisting of an androgen, estrogen, progestin, or a combination thereof; wherein the androgen is selected from the group consisting of testosterone, 17-β-hydroxyandrostenone, testosterone esters, methyl testosterone, testolactone, oxymetholone, fluoxymesterone, androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate, androstenedione, sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone, 5 adihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, and stanozolol or any combination thereof; the estrogen is selected from the group consisting of 17 beta-estradiol, estradiol, estradiol benzoate, estradiol 17 beta-cypionate, estriol, estrone, ethynil estradiol, mestranol, moxestrol, mytatrienediol, polyestradiol phosphate, quinestradiol, and quinestrol or any combination thereof; and the progestin is selected from the group consisting of allylestrenol, anagestone, chlormadinone acetate, delmadinone acetate, demegestone, desogestrel, dimethisterone, dydrogesterone, ethynilestrenol, ethisterone, ethynodiol, ethynodiol diacetate, fluorogestone acetate, gestodene, gestonorone caproate, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxygesterone caproate, lynestrenol, medrogestone, medroxyprogesterone, megestrol acetate, melengestrol, 16-methylene-17-alpha-acetoxy-19-nor-pregn-4-ene,3,20-dione, norethindrone, norethindrone acetate, norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, 19-norprogesterone, norvinisterone, pentagestrone, progesterone, natural progesterone, promegestone, quingestrone, and trengestone or any combination thereof; provided that the combination of estrogen and progestin is not present. 
     
     
         10 . The formulation of  claim 8 , wherein the pharmaceutically acceptable salt of the active agent is selected from the group consisting of acetate, bitartrate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactate, malate, maleate, mandelate, mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate, salicylate, stearate, succinate, sulfate, tannate and tartrate. 
     
     
         11 . The formulation of  claim 8 , further comprising at least one excipient selected from the group consisting of gelling agents, solvents, cosolvents, antimicrobials, preservatives, antioxidants, buffers, humectants, sequestering agents, moisturizers, emollients, film-forming agents, or permeation enhancers. 
     
     
         12 . The formulation of  claim 8 , in the form of a topical gel, lotion, foam, cream, spray, aerosol, ointment, emulsion, microemulsion, nanoemulsion, suspension, liposomal system, lacquer, or non-occlusive dressing. 
     
     
         13 . The formulation of  claim 8 , wherein the alkanol is ethanol or isopropanol that is present in an amount between about 20 to 65% of the formulation; the polyalcohol is propylene glycol that is present in an amount between about 1% to 15% of the formulation; the permeation enhancer is diethylene glycol monoethyl ether that is present in an amount between about 1% to 15% of the formulation, and further wherein the formulation comprises a gelling agent present in an amount of between 0.05% to about 4% of the formulation, a neutralizing agent present in an amount between about 0.05% and 1% of the formulation, and water present in an amount between about 20% to 65% of the formulation, and wherein the active agent is either estradiol present in an amount between about 0.01% to about 2% of the formulation or testosterone in an amount of about 0.01 to about 1% by weight. 
     
     
         14 . A method for administering an active agent to a mammal in need thereof which comprises topically or transdermally administering to the skin or the mucosa of the mammal a formulation according to  claim 8 . 
     
     
         15 . The method of  claim 14 , wherein the active agent is present in an amount of about 0.01 to about 5% of the composition and between about 40 and about 250 mg of the composition is administered daily upon the abdomen, shoulder, arm, or thigh of the mammal.