3,787,571. United States Patent Office Patented Jan. 22, 1974 2 3,787,571. TRICHLOROETHANOL, AND TRIFLUOROETHA SUMMARY OF THE INVENTION NOL TOPCAL AND PERCUTANEOUS STEROD Accordingly, it is an object of this invention to pro ADSORPTION PROMOTERS vide an improved means and method for promoting topi Takeru Higuchi, Lawrence, Kan., assignor to cal and percutaneous absorption of drugs, cosmetics, and Aza Corporation, Palo Alta, Calif. other beneficial chemical compounds administered to No Drawing. Filed Nov. 11, 1971, Ser. No. 197919 humans and domestic animals in the form of topically Int, C. A61k 17/00 applied compositions. U.S. C. 424-239 3 Claims Another object of this invention is to provide improved topically active therapeutic and bio-affecting prepara ABSTRACT OF THE DISCLOSURE 0. tions which exhibit increased absorption into or through Dermal compositions are disclosed which comprise tri the skin. chloroethanol or trifluoroethanol as one component of In attaining the objects of this invention, one feature a vehicle having solubilized therein a drug or other bene resides in compositions containing compounds for and ficial chemical compound. Also disclosed is a method for to a method for increasing topical or percutaneous ab administering a drug or other beneficial chemical com 5 sorption of drugs, cosmetics and other beneficial chemi pound to the body which comprises contacting the skin cal compounds which comprises contacting the skin with with the drug or compound in the presence of trichloro a drug, cosmetic or chemical compound in the presence ethanol or trifluoroethanol which acts as an absorption of a vehicle having as one component thereof an absorp promoter to enhance the topical or percutaneous absorp tion promoter consisting of either trichloroethanol (TCE) tion of the active drug or compound. 20 or trifluoroethanol (TFE). The absorption promoters of the invention can be used as the sole promoter and solu bilizing agent for the drug, cosmetic or chemical com BACKGROUND OF THE INVENTION pound, or they can be employed together with any addi tional pharmaceutically acceptable solvents, vehicles, This invention relates to a composition and to a 25 bases, surface active agents, emulsifiers, and the like. method for administering a drug or other beneficial Other objects, features, and advantages of this inven chemical compound topically to the body. More espe tion will become more apparent from the following cially, the invention concerns composition and a method description. for enhancing dermatological or percutaneous absorption of such active agents in compositions for the use of 30 DETALED DESCRIPTION OF THE INVENTION humans and domestic animals. Percutaneous absorption refers to the passage of a It is well known that the outer or surface division of substance from the surface of the skin through the horny the epidermis, known as the stratum corneum or horny layer of the epidermis, into the cellular epidermis and layer of the skin, acts as a barrier to penetration of ex from there into the corium or dermis. Penetration of the ternal substances into the immediate area as well as into 35 substance through the horny layer constitutes per the body. Oftentimes, however, it is desired to increase cutaneous absorption for the purposes of this invention. the degree of dermatological or percutaneous absorption The passage of the substance on into the corium and or penetration of a particular therapeutically active into the systemic circulation is considered to be the effect, or continuing result of percutaneous absorption. Once a dermal preparation, as for example in the treatment of 40 chemical substance passes through the horny layer of skin disorders, subcutaneous infections, cosmetic effects, the epidermis, there readily occurs further absorption or or the like. penetration through the stratum granulosum, stratum In this regard, several reagents and methods for in malpighii and stratum germinativum, on into the first creasing the permeability of the skin have been disclosed connective tissue beneath the epidermis, and thence into in the art. For example, occlusion of the skin with metal 45 the remainder of the body, since below the cellular layer guards, plastics, or other wraps has been employed to in referred to as stratum corneum there is very little resist crease the penetration of various agents into the epi ance to penetration or absorption. Absorption into the dermis. Similarly, an increased rate of absorption into horny layer alone, or further into the epidermis, without the skin has been produced by adjusting the temperature significant system absorption is considered to be topical of the skin and/or by regulating the temperature and 50 absorption, and it is also referred to as retention. relative humidity of the adjacent atmosphere. Most effec In nature, when a penetratable substance is applied to tive, however, have been the recent efforts directed to the skin, an extremely small percentage of the substance ward the discovery and application of chemical absorp is absorbed into the horny layer and retained there. An tion promotors which are employed as integral compo even smaller percentage of the substance absorbed into nents of therapeutically active or bio-affecting composi 55 the horny layer passes therethrough into the underlying tions. Workers in this area have experienced varying layers identified above, and thence into the systemic cir degrees of success in their endeavors to locate truly effec culation of the human or animal. Thus, there is some tive topical or percutaneous aborption promoters, since absorption.degree of both natural retention and percutaneous a great number of chemical compounds have been found 60 The present invention provides a process whereby this to promote absorption, at least to a degree, as for exam natural rate of percutaneous absorption and retention, ple in British Pat. No. 1,001,949 and U.S. Pat. No. and the amount of penetratable substance actually ab 3,472,931. Sorbed or retained are markedly increased. These effects 3,787,571 3. 4. are accomplished by contacting the skin with trichloro (10) Sympathomimetics such as epinephrine, oph ethanol or trifluoroethanol and simultaneously or in the edrine, phenylephrine; presence thereof with the preferred drug, cosmetic or (11) Sedatives and hypnotics such as pentobarbital beneficial agent. sodium, phenobarbital, secobarbital sodium, codeine, (o- The substances referred to herein as stable, topically bromoisovaleryl) urea, carbromal; active compounds are drugs or other beneficial chemical 5 (12) Psychic energizers such as 3 - (2 - aminopropyl) compounds which can be applied topically to the skin indole acetate and 3 - (2 - aminobutyl) indole acetate; for the purpose of beautifying surface conditions, medi (13) Tranquilizers such as reserpine, chlorpromazline, cating surface conditions or diseases, sub-surface diseases, and thiopropazate; or systemic disturbances, or creating skin conditions help 10 (14) Androgenic steroids such as methyltestosterone ful in alleviating harmful or annoying external factors. and fluoxymesterone; Thus, topically active compounds include those eliciting (15) Estrogens such as estrone, 17 - estradiol, ethinyl a pharmacological or physiological response either at or estradiol, and diethyl stilbesterol; near the site of application, as well as at a site remote (16) Progestational agents such as progesterone, me therefrom. Drugs, cosmetics and compounds utilized ac gestrol, melengestrol, chlormadinone, ethisterone, nor cording to this invention possess the ability to be solubi ethynodrel, 19 - nor - progesterone, norethindrone, me lized or minutely dispersed in trichloroethanol, or tri droxprogesterone and 17 oz-hydroxy-progesterone; fluoroethanol or in a mixture thereof, thus forming a (17) Humoral agents such as the prostaglandins, for formulation for administering to the skin for percutaneous example PGE1, PGE2, and PGFao; absorption or retention of the administered drug, cosmetic (18) Antipyretics such as aspirin, sodium salicylate, or compound. By the terms solubilize or dispersing is and salicylamide; meant that the drug, cosmetic or chemical compound used (19) Antispasmodics such as atropine, methantheline, herein is dissolved or held in suspension by normal mix papaverine, and methscopolamine bromide; ing or shaking operations in trichloroethanol, or trifluoro (20) Anti-malarials such as the 4-aminoquinolines, 8 ethanol, or a mixture thereof, to the extent of at least aminoquinolines, chloroquine, and pyrimethamine; about 0.01% by weight to about 30% by weight of the (21) Antihistamines such as diphenhydramine, dimen drug, cosmetic or compound in the promoter of choice. hydrinate, tripelennamine, perphenazine, and chloro Generally speaking, many drugs are useful in treating phenazine; surface, sub-surface and systemic conditions by topical (22) Cardioactive agents such as hydroflumethiazide, application, and the same can be made more effective if 30 flumethiazide, chlorothiazide, and trianterene; their percutaneous absorption rate or retention rate is (23) Nutritional agents such as vitamins, minerals and increased such that preferred concentrations thereof will other compounds, essential amino acids and essential penetrate through the horny layer of the skin, or be fats; retained therein, or both. Any of the standard drugs. (24) Anhidrotic agents such as atropine, aluminum, cosmetics or the like used to treat the body or skin can Zinc, Zirconium, and other metal salts and complexes; be