2,890,152 United States Patent Office Patented June 9, 1959 1. 2 of its stability. It is indeed surprising that of the large 2,890,152 number of anticholinergic agents of the quaternary amine type which are in common use in medical therapy, TOPICAL ANTI-INFLAMMATORY COMPOSITIONS only one, diphemanil methylsulfate, is stable under hy George Babcock, Jr., North Caldwell, and George Ken 5 drous conditions. This distinct property is not easily neth Hawkins, Glen Ridge, N.J., assignors to Schering explained but may be due to the chemical structure of Stration, Bloomfield, N.J., a corporation of New diphemanil methylsulfate. The substance is a piperi ersey dyiidene derivative while for the most part all other anti No Drawing. Application November 29, 1956 cholinergics are structurally related to atropine and/or Serial No. 624,961 10 contain a dialkaminoalkyl grouping. Laboratory test ing of other anticholinergic agents such as methantheline 7 Claims. (CI. 167-65) bromide, methscopolamine bromide, propantheline bro mide, tricyclamol methylsulfate, and the like, have dem This invention relates to therapeutic compositions and onstrated their incompatibility with hydrous media. more particularly to compositions which are useful in 5 Thus our compositions are inherently unique in their the treatment of various dermatogical conditions. content. We have found that topical preparations comprising a The active ingredients of our novel compositions can combination of diphemanil methylsulfate (4-diphenyl be incorporated into any suitable ointment or cream methylene-1,1-dimethylpiperidinium methyl sulfate) with base to provide the topical preparations of the present hydrocortisone or prednisolone (1,4-pregnadiene-11g,17c, 20 invention. Representative examples of suitable bases 21-triol-3,20-dione) offer a long-awaited adjunct in the are given in the specific examples hereinafter set forth. treatment of a variety of skin diseases. Our new com The nature and composition of such bases are well-known positions are useful in treating conditions Such as and well understood by those skilled in the prepara dyshidrotic eczematous lesions caused by drug allergies. tion and employment of topical medications. While In place of the free sterol there may be used, in some 25 each of the active ingredients present in the composi cases, an ester such as a 21-acetate or soluble stable tions of the present invention is ordinarily employed in ester of phosphoric acid and the like. The composition proportions of from about 0.1 percent to 2.5 percent by is especially applicable in the treatment of the disease weight of the final composition, proportions outside this generally known as intertrigo which is aggravated by range can also be used, such as 0.1 to 4 percent di sweating and friction between opposing skin surfaces. 30 phemanil methylsulfate and 0.1 to 4 percent steroid. Lesions which occur in the armpit due from sensitivity For achievement of optimum results, it has been deter to a deodorant, for example, and the common "diaper mined that the preferred proportions of the active in rash” quickly disappear following local application of gredients present in the composition should be one per our therapeutic combination. Furthermore, many der cent of the cortical hormone and two percent of anti matological conditions such as lichen planus, those aris 35 cholinergic agent. ing from food or drug allergies, athlete's foot, inter The compositions of the present invention can be trigo, and the like, are accompanied by severe pruritis, readily prepared by conventional procedures used in the or itching, with weeping of the lesion. The new com preparation of topical ointments or creams. For exam positions of this invention have demonstrated remark ple, the active ingredients can be incorporated into any able ability in overcoming pruritic and weeping manifes 40 suitable ointment of cream base by simply admixing in tations. By so removing the desire to scratch and further a suitable agitating device, such as a mixer or blender. aggravate the sores, the topical preparations hasten the The novel topical medications of the persent inven cure of the disease. tion are illustrated by the following examples which are The new therapeutic combinations, described in more presented for illustrative purposes only. detail below, are thus highly effective agents in combat 45 ting a host of skin diseases. It is indeed surprising that EXAMPLE the particular combination of diphemanil methylsulfate Water soluble cream with hydrocortisone or prednisolone enables control of Parts conditions which are resistant to the action of either Prednisolone ------5.0 active ingredient when used alone. 50 Diphemanil methylsulfate ------20.0 The mode of action of the composition is unknown al Zinc stearate ------60.0 though absorption of the medicament at the site ap Polyethylene Glycol 1500 ------405.0 parently occurs whereby the development of tissue re Polyethylene Glycol 6000 ------120.0 action is counteracted. No toxic reactions arising from Propylene glycol ------350.0 the composition have been observed. 55 Distilled H2O ------40.0 There appears to be a potentiation of each of the active The steroid, prednisolone, is dissolved in the mixture ingredients upon each other. Although large doses of of glycols by stirring and heating on a steam bath at hydrocortisone have been used internally or topically to about 75° C. Diphemanil methylsulfate is dissolved in combat certain skin diseases, the presence of diphemanil the distilled water. The aqueous solution is added to methylsulfate permits the use of a smaller dose of the 60 the stirred steroid solution. When a homogeneous mix corticoid. ture has been obtained, zinc stearate is dispersed through Our new compositions consist essentially of the active out the mixture and the entire batch is homogenized in ingredients suspended or dissolved in a carrier suitable an ointment mill. for topical application such as a hydrocarbon base of the petrolatum type, absorption bases, hydrophilic petro 65 EXAMPLE 2 latum bases, water-soluble bases containing polyethylene Water soluble ointment glycols and lotions. In certain instances a water-soluble Parts base is preferred so as to permit proper healing of weep Diphemanil methylsulfate ------20.0 ing lesions and overcome intertrigo. Diphemanil methyl Hydrocortisone ------10.0 sulfate is particularly adaptable to incorporation into 70 Zinc stearate ------200.0 water-soluble bases and water containing bases by virtue CarboWax 1500 ------549.0 Distilled Water ------221.0 2,890,152 3 4. Hydrocortisone is dissolved in Carbowax 1500 by heat EXAMPLE 6 ing and stirring. The remaining ingredients are added Lotion preparation in the same manner as described in Example 1. Parts EXAMPLE 3 5 Diphemanil methylsulfate ------30 Prednisolone ------5 Water-removable or hydrophilic preparation Methyl Paraben ------0.25 Parts Propyl Paraben ------0.15 Hydrocortisone ------10.00 Stearyl alcohol ------245 Diphemanil methylsulfate ------40.00 O Propylene glycol ------50 Methyl Paraben ------0.25 Polyoxyethylene lauryl alcohol------10 Propyl Paraben ------0.15 Distilled water, q.s. to a total of 1000 parts. Steryl alcohol ------245.00 This formulation is prepared in the same manner as the White petrolatum ------245.00 hydrophilic preparation of Example 3 except that the Propylene glycol ------120.00 5 etrolatum is omitted. Polyoxyethylene lauryl alcohol ------50.00 Having disclosed our invention, what we claim to be Distilled Water ------290.00 new and wish to secure by Letters Patent is: - 1000.00 1. A therapeutic composition of matter comprising a Steryl alcohol and white petrolatum are melted to steroid of the group consisting of hydrocortisone and gether on a steam bath at about 75°. The remaining 20 prednisolone in combination with diphemanil methylsul ingredients, except for the steroid, are dissolved in water. fate and a carrier. The aqueous mixture is stirred into the stearyl-alcohol 2. A therapeutic composition of matter comprising petrolatum melt. The resultant mixture is thoroughly from about 0.1 percent to about 4.0 percent of a steroid stirred at 75° C. When proper mixing has been ob defined in claim 1, from about 0.1 percent to about 4.0 tained, the mixture is allowed to cool to 50° C. Hydro 25 percent diphemanil methylsulfate, the remainder of the cortisone is then added and the preparation is stirred composition comprising a viscous supporting carrier. and allowed to cool until it completely congeals. 3. A therapeutic composition of matter comprising from about 0.1 percent to about 2.5 percent of a steroid EXAMPLE 4 defined in claim 1, from about 0.1 percent to about 2.5 Hydrocarbon ointment 30 percent of diphemanil methylsulfate, the remainder of the Parts composition comprising a viscous supporting carrier. Prednisolone ------10 4. A therapeutic composition of matter according to Diphemanil methylsulfate ------25 claim 2 in which the steroid is hydrocortisone. Petrolatum U.S.P. ------965 5. A therapeutic composition of matter according to 1000 35 claim 2 in which the steroid is prednisolone. 6. A therapeutic composition of matter comprising es A slurry of the prednisolone and diphemanil methyl sentially the following: sulfate in about 100 parts of petrolatum is milled. The Percent by weight remainder of the petrolatum is then added and the batch Prednisolone ------0.1 to 2.5 is mixed in an ointment mixture until uniform. 40 Diphemanil methylsulfate ------0.1 to 2.5 EXAMPLE 5 Absorption formulation in an aqueous glycol vehicle. Parts 7. A therapeutic composition of matter comprising es sentially the following: Cholesterol ------30 45 Percent by weight Stearyl alcohol ------30 White wax ------80 Hydrocortisone ------0.1 to 2.5 White petrolatum ------830 Diphemanil methylsulfate ------0.1 to 2.5 Diphemanil methylsulfate ------20 in an aqueous glycol vehicle. Hydrocortisone ------10 50 Cholesterol is added to a warm melt of the stearyl References Cited in the file of this patent alcohol, Wax, and petrolatum. The mixture is stirred Frank et al.: A.M.A., Arch. Derm, 72:547-549, until the cholesterol completely dissolves. Hydrocorti December 1955. sone is then mixed in by stirring. Diphemanil methyl Physician's Desk Reference, 9th ed; copyright 1954, sulfate is added and the mixture is thoroughly stirred and 55 cooled until it congeals. Med. Econ., pp. 529-530 and 523.