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 applied to the skin in the presence of the absorption (25) Odorizing, deodorizing, or odor preventing agents, promoters of this invention. "Drug" is used herein in Such as perfumes, aromatic oils, metal salts and com its broadest sense as including any composition or sub plexes, and the like; stance that will produce a pharmacologic or physiologic 40 (26) Antipruritic such as benzocaine, lidocaine, phenol, response. methol, etc.; Suitable drugs for use in therapy with the absorption (27) Antieczemic drugs such as metallic oxides, salts promoters of the invention include without limitation: Such as zinc oxide, sulfur and sulfur containing com (1) Protein drugs such as insulin; pounds such as sodium thiosulfate and thioglycollic acid, (2) Desensitizing agents such as ragweed pollen phenol and other phenolics, inorganic and organic mer antigens, hay fever pollen antigens, dust antigen and milk curials, coal tars, etc.; antigen; 45 (28) Agents that improve or effect the peeling, (3) Vaccines such as smallpox, yellow fever, distem sloughing, keratinization or follicular character of the per, hog cholera, fowl pox, antivenom, scarlet fever, skin such as Salicylic acid, resorcinol, phenol, sulfur, dyptheria toxoid, tetanus toxoid, pigeon pox, whooping retinoic acid, benzoyl peroxide, thioglycollic acid, their cough, influenza, rabies, mumps, measles, poliomyelitis, derivatives and the like; Newcastle disease, etc.; 50 (29) Other drugs having the same or different physio (4) Anti-infectives, such as antibiotics, including peni logical activity as those recited above can be employed cillin, tetracycline, chlortetracycline, bacitracin, nystatin, together with the absorption promoters within the slope streptomycin, neomycin, polymyxin, gramicidin, oxy of the present invention. Suitable mixtures of drugs can, tetracycline, chloramphenicol, and erythromycin; sulfon of course, be dispensed with equal facility as with single amides, including sulfacetamide, sulfamethizole, sulfa 55 component systems. methazine, sulfadiazine, sulfamerazine, and sulfisoxazole; anti-virals including idoxuridine; and other anti-infectives Drugs can be in various forms, such as uncharged including nitrofurazone and sodium propionate; hexa molecules, components of molecular complexes, or non chlorophene, cetyl pyridinium chloride, pyrithione and irritating, pharmacologically acceptable salts such as hy its salts, undecylenic acid, and others; drochloride, hydrobromide, sulphate, phosphate, nitrate, (5) Anti-allergenics such as antazoline, methapyrilene, 60 borate, acetate, maleate, tartrate, salicylate, etc. For chlorpheniramine, pyrilamine and prophenpyridamine; acidic drugs, salts of metals, amines, or organic cations (6) Anti-inflammatories such as hydrocortisone, cor (e.g., quaternary ammonium) can be employed. Further tisone, hydrocortisone acetate, dexamethasone, dexa more, simple derivatives of the drugs such as ethers, methasone 21 - phosphate, fuocinolone, triamcinolone, esters, amides, etc. which have desirable percutaneous medrysone, prednisolone, prednisolone 21-phosphate, and 65 absorption or retention producing characteristics but prednisolone acetate; which are easily hydrolyzed by body pH, enzymes, etc., (7) Decongestants such as phenylephrine, naphazo can be employed. Other beneficial chemical compounds line, oxymetazoline and tetrahydrazoline; may likewise be administered in the presence of the (8) Miotics and anticholinesterases such as pilocar 70 instant, non-toxic absorption promotors for the purpose pine, eserine salicylate, carbachol, di-isopropyl fluoro of enhancing their absorption into or through the skin. phosphate, phospholine iodide, and demecarium bromide; Thus, for example, cosmetic agents, moisturizers, skin (9) Mydriatics such as atropine sulfate, cyclopen enrichment and toning agents, coloring and pigmenting tolate, homatropine, scopolamine, tropicamide, eucatro agents, bleaching agents, sun screens, pigments and like pine, and hydroxyamphetamine; 5 compounds which are desirably applied topically to the 3,787,571. 5 6 skin may advantageously be combined with the pro active ingredient. Thus, the preparations according to this motors of this invention. invention usually contain from about 50% of the absorp Another application of the present invention resides in tion promoter, and about 0.01 to 30% of the drug. While patch testing which is becoming one of the most widely the presence of even minute amounts of trichloroethanol used methods for testing the skin to determine and iden and trifluoroethanol will enhance the absorption, it is tify sensitization and/or irritation potential to various sub readily apparent that their desired effect will be substan stances such as drugs, cosmetics, and the like. The patch tially diluted, and that the preferred ratio between phar test consists of the application to uninjured skin, contigul maceutically active ingredient and absorption promoter ous to the involved area, of substances suspected to be will be dictated by the recomended dosage of the active causes of the sensitivity and/or the irritation reaction. O ingredient and the desired rate of application thereof. This is done by saturating the patch, a small piece of The rate of absorption for the promoter can be meas gauze, with one of these substances, occlusive, or semi ured by various known techniques. One technique is the occlusive agents, in a concentration that will not cause radioactive technique. The use of radioactive substances irritation in the average person. The patch is then covered has simplified the measurement problems allowing for by a piece of impermeable protective material, such as 15 more accurate determinations. Labeled compounds con cellophane, or like polymer, and applied to the skin by taining radioactive carbon atoms have been utilized to adhesive plaster. Unless there is pronounced irritation, determine the rate and degree of percutaneous absorption the duration of a given test is typically about 36 to 72 as well as retention in the horny layer. Another method hours after which the patch is removed. It can, however, of estimating absorption is to utilize the biological activity be two to four days, or longer, before a positive reaction 20 exhibited by the compound. In this manner, the degree is observed in the tested area. By using the absorption of absorption of applied glucocorticosteroids has been promoters of this invention, a suspected chemical may determined by studying vasoconstriction and blanching be applied to the skin, left untouched for only so short of the skin caused when these substances reach the cori a period of time necessary for absorption, whereupon the um. Another example of the utilization of biological ac test will be complete without the necessity of the patient 25 tivity to determine percutaneous absorption is the meas tolerating gauze pads, etc., over an extended period of urement of sweat secretion after application of anti time. cholinergics, Both trichloroethanol and trifluoroethanol display a In testing, particularly for the degree of the factor very strong proton donating propensity, and as such, relied upon to determine penetration is the chemical these two compounds singly, or mixtures thereof, are 30 substance which is absorbed rather than a factor inherent especially suited to promote the absorption of hydrogen in the vehicle or absorption medium. Thus, both in vitro accepting substances, such as amines, certain ketones, and in vivo tests have been devised for determining etc., as exemplified by the atropine, griseofulvin, diphen percutaneous absorption and retention. The general hydramine and the like. This result apparently is achieved method utilized in the examples which follow for deter by the ability of TCE and TFE to reduce the 35 mining percutaneous absorption by the in vitro method is hydrogen binding tendency of the penetrating drug mole set out in U.S. Pat. No. 3,472,931. cules, and/or the skin and tissues being penetrated. The Skin of normal appearance is removed from surgically two promoters also are well adapted for use in conjunc amputated legs or breasts and immediately or after a tion with hydrogen-donating substances such as phenols, 40 period of refrigeration, cut into sections, wrapped in air prostaglandins, alcohols, salicylic acid, acetaminophen, tight containers, and placed in a freezer at about -17 chloramphenicol and the like. The enhanced degree of C. to about -22 C. for future use. Under the usual test absorption in this instance is believed to result from mask conditions, at least four specimens are used in these ing of the fixed hydrogen-donating sites in the dermal experiments. The skin is handled as gently as possible tissue by the trichloroethanol and trifluoroethanol. to prevent cellular damage, and on removal from the The incorporation of emollients such as lanolin and 45 freezer, thawing is carried out at room temperature for lanolin alcohols and their ethoxylated and/or acetylated about one hour. The subcutaneous tissue or fat is cut products, glycerol, glycols and their derivatives, fatty from the under surface until the net-like pattern of the acids, their esters, their alcohols and their derivatives, dermis is seen, with care taken to avoid cutting into into the compositions of the present invention increase the corium. Then, the skin is draped with the epidermis their percutaneous absorption and retention resulting ef 50 outward, over the mouth of an open glass well which is fects, and also result in improved softening and moisturiz about 4 cm. in diameter, and secured in place by an ing effects. elastic band. A plastic cylinder is then attached to the The absorption promoters can be used as the sole pro epidermis with a standard adhesive. Next, the glass well moter and/or solubilizing agent for the drug, cosmetic is connected to a second glass well by a glass tube. The or compounds destined for dermal application. Alter 55 natively, the absorption promoters can constitute only one second glass well contains a stopper so that the wells component of the preparations. Additional components can be filled with physiological saline that bathes the include other pharmaceutically acceptable solvents, ve corium side of the skin. The test solution or suspension hiles, or bases, as well as pharmaceutically acceptable sur containing the chemical compound, labeled with a radio face active agents, emulsifiers, etc. The present absorption 60 active carbon atom is then applied to the epidermis con promoters can comprise one component of other pharma tained within the small plastic cylinder. After given in ceutical preparations such as lotions, creams, solutions tervals, about 4 hours, 8 hours, 16 hours, 24 hours or and the like. Similarly, non-liquid preparation, such as larger, aliquots are removed from the glass well and jellies can be prepared by adding a thickener, e.g., silica, measured for radioactivity. The amount of the radio or an unguent base to prepared liquid preparations. The 65 active substance which has penetrated is then determined, absorption delaying effect of these additives may be uti as measured in a Nuclear-Chicago Co. scintilation lized in preparation of compositions wherein it is desirable counter. Radioactivity is expressed as the number of to control the rate of absorption. counts per minute registered on the apparatus at a con The present preparations can contain small amounts, stant efficiency. The percent of applied counts per minute for example 0.01% by weight or volume/volume or 70 penetration in 24 hours is determined by dividing the total large amounts of trichloroethanol or trifluoroethanol, number of counts per minute recovered in 24 hours by that is up to 99.99% by weight or volume/volume to the counts per minute applied, then multiplying by 100. promote percutaneous absorption or drug retention. How The concentration in the saline and the corium is as ever, it is generally preferred that preparations contain sumed to be the same and the volume added by the a higher percentage of absorption promoters that the 75 corium to be negligible. 3,787,571 7 8 The technique then is briefly to apply radioactive tions to determine the amount of retention are made in the labeled material to the epidermal side, incubate in a tem same manner as discussed concerning the in vitro method. perature and humidity controlled chamber for about 4 The effect of the promoters upon the rate of percutane to about 24 hours and take samples of the saline bathing ous absorption or retention begins to take place almost the corium to determine radioactivity in a scintillation immediately upon application of the promotor to the skin, counter. Thus, the percentage of applied material which and, the following examples are illustrative of various has penetrated to the saline can be measured at any formulations comprising the promoters for applying drugs, given time. The in vitro technique is modified to deter etc. to the skin. mine retention in the horny layer as follows. Similar skin EXAMPLE 1. is placed between two aluminum sheets and clamps are O applied. This apparatus is immersed in water at about A steroid solution containing 0.01 to 1000 mg. of an 60° C. for about two minutes, the metal plates are re estrogen component, 0.01 to 10,000 mg. of a progesta moved from the skin, and the epidermis with stratum corneum is carefully removed from the dermis in a con tional component, 17.0 v./v. of glycerine, 41 v./v. tri tinuous sheet. 5 chloroethanol, CCl3CHOH, lavender odor 0.05 v./v. and After the epidermis with stratum corneum is dried on distilled water, q.s. to 100 ml. The steroid components a metal gauze, squares about 1 x 1 cm. are cut from the are mixed into the trichloroethanol in which previously tissue, and placed on glass slides at about 32° C. and the lavender had been dissolved. Next, the glycerine is about 50% humidity. About 0.005 ml. each of solutions added with stirring and distilled water added to volume. of suspensions containing the chemical compound labeled 20 EXAMPLE 2. with a radioactive carbon atom in TCE, and other ve hicles, such as ethanol and benzene, is placed on the Following the procedure of Example 1, a steroid solu stratum corneum side of the 1 cm. pieces and allowed tion is prepared comprising 10 mg. of ethynyl estradiol to remain for 22 hours at about 22° C. and about 50% 3-methyl ether, 200 mg. of 6-chloro-6-dehydro-17 oz-ace humidity before washing. A group of four squares is 25 toxyprogesterone, 17 v./v. of glycerine, 41 v./v of tri usually treated with each solvent. After 22 hours the chloroethanol, 0.05 v./v. of lavender odor, and distilled squares are individually washed for ten minutes in each water to 100 mi., with the mixing of the ingredients as in of three washing fluids: (1) water with detergent, (2) the example. 70% ethanol, and (3) benzene. The fluids are constantly EXAMPLE 3 stirred during the washing process. Following the wash 30 ing, the squares of tissue are individually dissolved in A topical solution comprising 10 mg. of ethynyl estra 0.5 ml. of methylbenzenethonium chloride, scintillation diol-3-methyl ether and 500 mg. of 6a-methyl-17a-ace fluid was added and the radioactivity counted. toxyprogesterone are dissolved in turn in a portion of tri An in vivo technique, described in U.S. Pat. No. chloroethanol and then sufficient trichloroethanol is added 3,472,931, for determining percutaneous absorption uti 35 to produce the desired amount of solution, for example lizing the biological activity of the compounds is as q.S. to 100 ml. follows: Healthy, young, adult male and/or femal sub EXAMPLE 4 jects are selected. The volar surfaces of the forearms are used and solutions or suspensions of corticosteroid com 40 An aerosol liquid spray comprising 10 mg. ethynyl es pounds are prepared with 95% ethanol and TFE in dilutions ranging from about 1:100 to about 1:5,000,000. tradiol-3-methyl ether, 200 mg. of 6-chloro-6-dehydro Then 0.02 ml. of the various dilutions are applied from 17a-acetoxyprogesterone, 10% trichloroethanol, and a dropping pipette on the flexor aspects of both fore 89.8% of the propellants trichlorofluoromethane and di arms, slightly spread over an area of about 1 inch di chlorodifluoromethane 50/50 is prepared by compound ameter and allowed to dry. The areas are left undis of the above ingredients and then placing it in an aerosol turbed for about 16 hours, and any sites of vasoconstric 45 container. tion are then noted. The TFE containing fluid was com EXAMPLE 5 pared with the non-TFE containing fluid by placing each on equivalent areas of the forearms. The presence or Repeating the procedure of Example 4, except that the absence of the physiologic reaction, i.e., vasoconstriction, promoter trifluoroethanol (CFCHOH) is used for the was determined after a designated interval of time, and 50 promoter of Example 4, there is prepared a liquid, aerosol if the reaction was present, it was recorded as a positive spray formulation. response. This test can be utilized with corticosteroids This invention provides a means and improved method as they cause blanching and vasoconstriction upon reach for enhancing the percutaneous absorption of drugs and ing the corium. Anti-cholinergics also are tested with this other beneficial chemical compounds, and it is suitable for procedure by recording the presence or absence of the 55 employment in conjunction with drugs which are either physiologic reaction, for example, the inhibition of sweat hydrogen-accepting or hydrogen-donating. While there Ilg. have been shown and, described and pointed out the fun The in vivo technique used to determine retention in damental novel features of the invention as applied to the horny layer involves a similar method where a solu the preferred embodiments, those skilled in the art will tion containing the compound labeled with a radioactive 60 appreciate that various modifications, changes and omis carbon atom is applied to the body of animals or the fore sions in the method for enhancing the percutaneous ab arms of human volunteers. The compound is solubilized in TCE and ethanol and in a placebo cream base. A 0.01 sorption of drugs illustrated and described can be made cc. aliquot of each is applied to the forearm, about 10 mg. without departing from the spirit of the invention. It is of the placebo cream base, and it is allowed to remain in 65 the intention, therefore, to be limited only by the scope of place for about 60 minutes. The forearms are then washed the following claims. with soap and water and wiped with wet ethanol sponges. What is claimed is: Surface counts were measured before and after washing 1. A pharmaceutical composition of matter comprising procedures with the gas flow, thin Mylar8 window, skin a first ingredient selected from the group of absorption probe made by the Nuclear-Chicago Co. similar to that 70 promoters consisting of trichloroethanol, trifluoroethanol, described in Malkinson, P.D.: Studies on the Percutane and mixtures thereof and at least one steroid as, a second ous Absorption of C-14 Labeled Steroids by Use of the ingredient and where the first ingredient is an absorption Gas Flow Cell, J. Invest. Derm., 31.19 (1958). The skin promoter for increasing the retention and percutaneous probe had a background count close to 30 counts per absorption of an effective amount of the steroid, the sec minute and operating at about 10% efficiency. Calcula 75 ond ingredient. 3,787,571 9 O 2. A pharmaceutical composition of matter according OTHER REFERENCES to claim35; 1 whereinEAEENS:36% the composition contains about 0.01% 40 Asily:523-7 (1943), "The& Present of the steroid, the second ingredient. s Hewer et al.: Lancet, 2.35:1290-1 (1938), "Trichloro 3. A pharmaceutical composition of matter according 5 ethanol as Basal Narcotic.” to claim 1 wherein the composition contains a progesta- Lehman et al.: J. Pharmacol. 63:453-465 (1938) ticallyionisteroiddan acceptable carrier. strogenic steriod and a pharmaceu andtrichloroethanol, Bromal Hydrate.' ribomohol. s Cior a References Cited 10 SHEP K. ROSE, Primary Examiner FOREIGN PATENTS 1,227,617 10/1966 Germany. U.S. C. X.R. 1,001,949 8/1965 Great Britain. 424-2, 9, 45, 88, 89, 91, 92, 65, 66, 67,68, 178,238, 901,674 7/1962 Great Britain. 240, 242, 243, 358