Abstract:
Topical compositions comprising an active ingredient selected from at least two of the following three classes of compounds: 
     (a) N-methyl-substituted xanthines containing at least two methyl substituents; 
     (b) α-estradiol and certain derivatives thereof; and 
     (c) the mucopolysaccharides 
     have surprisingly beneficial effects on the skin and the scalp. These compositions may be prepared in the form of lotions, emulsions, ointments, gels and like forms for topical administration, and may be used to treat such conditions as acne, wrinkles, and androgen baldness.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application is a continuation of our copending application Ser. No. 750,086, filed on Dec. 13, 1976, now abandoned, which application is in turn a continuation-in-part of our application Ser. No. 509,369, filed Sept. 26, 1974, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to compositions for topical application, and more particularly to such compositions useful in the treatment of androgen baldness as well as skin wrinkles and acne. 
     Because the topical treatment of baldness has in the past acquired a reputation of quackery, the area of utility of the present invention in respect to baldness is carefully circumscribed. Common baldness in men, also known as &#34;male pattern baldness&#34; may be considered a physiological reaction in persons having a tendency towards this type of baldness. The main factor which causes this type of baldness in such persons is the presence of the male sex hormone, testosterone, from which arises the designation &#34;androgen&#34; meaning dependent upon male factors. Androgen baldness also occurs in women. 
     It is not claimed that this type of baldness can always be reversed or that hair can be caused to grow again on a bald scalp. Where the hair folicles have already degenerated and are no longer producing pigmented hairs, no method or treatment is presently known which will reverse this process. In contrast, however, where the process of degeneration has only just begun, if an adequate treatment can be found to arrest or retard the degeneration process, baldness can be prevented or at least mitigated. 
     It has long been known that the androgen baldness process in men can be favorably influenced through the application of female hormones, especially estrogens. See for example, German patent application 23 50 315.3 and British Pat. No. 720,561. However, the risk of irreversible side effects such as changes in the voice, swelling of the breasts, and reduced sexual potency associated with the application of female hormones has been a severe disadvantage associated with this therapy. 
     Even where these risks have been accepted and estrogens have been applied, there does not appear to have been any decrease, much less a cessation, in the loss in hair. See, for example, H. Wustner and C. E. Orfanos-&#34;Alopecia Androgenetica and its Local Treatment Using Preparations for External Treatment Containing Estrogens and Corticosteroids,&#34; Z Hautkr. 49 (20) 879-888 (1974). Even where estrogens have been found effective in the treatment of androgen baldness, only those estrogens having very low estrogenic activity have been suggested. See, for example, U.S. Pat. No. 3,729,560. 
     It is an object of the present invention to provide a composition for topical treatment of androgen baldness which has greater efficacy than those previously suggested. 
     It is a further object to provide such a composition which has no sexual effect. 
     It is also an object to provide topical compositions for treatment of acne and skin wrinkles. 
     SUMMARY OF THE INVENTION 
     The present invention relates to new topical preparations comprising effective combined amounts of active ingredients selected from at least two of the following three classes of compounds: 
     (a) compounds of the general formula I ##STR1## wherein R 1  and R 2  each represent hydrogen or the methyl group and at least one of the substituents R 1  and R 2  is a methyl group, 
     (b) α-estradiol derivatives of the general formula II ##STR2## wherein each of R 3  and R 4 , which may be identical or different from each other, represents hydrogen, a fatty acyl group having from 1 to 18 carbon atoms, the phenyl group or the group --SO 3  Me, Me being the cation of an alkali metal, and 
     (c) mucopolysaccharides. 
     The term &#34;effective combined amounts&#34; as used herein means amounts of the active ingredients which, when combined in the claimed compositions, are effective to produce the desired result, e.g. alleviation of reversible androgen baldness. Since the claimed compositions require at least two active ingredients, it should be understood that an &#34;effective amount&#34; of one ingredient will not produce the desired result unless combined with an &#34;effective amount&#34; of at least one other active ingredient. 
     Preferably the combination preparations according to the present invention contain the compound of formula I in an amount ranging from 0.01 to 1.2% by weight, contain the compound of formula II in an amount ranging from 0.005 to 0.1% by weight and contain the mucopolysaccharide in an amount ranging from 0.01 to 5.0% by weight. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The active substances of the combination preparations for external application according to the present invention are mostly known. The compounds of the general formula I represent the xanthines caffeine, theobromine and theophylline. The compound of formula II wherein R 1  and R 2  both represent hydrogen is the known product α-estradiol. This compound is the sexually nonspecific form of the estrogen estradiol, as opposed to the sexually-specific β form. The compounds of formula II wherein R 1  or R 2  is other than hydrogen are derivatives of α-estradiol. The mucopolysaccharides are preferably represented by the heparins and heparinoides, such as hyaluronic acid and chondroitin sulfuric acid, including chondroitine sulphate A and B. 
     The new combination preparations according to the present invention are characterized by surprisingly beneficial effects on the skin and in particular on the scalp. Compositions comprising a compound of formula I and a compound of formula II have been found to be surprisingly useful in the treatment of androgen baldness. Compositions comprising a compound of formula II and a mucopolysaccharide have been found to be surprisingly useful in the treatment of skin wrinkles. 
     Those topical preparations according to the present invention are preferred wherein the xanthine is 1,3,7-trimethyl xanthine (caffeine), the α-estradiol derivative is a compound of formula II wherein R 3  and R 4  represent hydrogen or an alkanoyl group having from 2 to 7 carbon atoms, in particular the acetyl group, or the group --SO 3  Na, and the mucopolysaccharide is heparin. 
     Besides the above active ingredients, the combination preparations according to the present invention further comprise the usual vehicles, diluents and/or solvents used in the preparation of pharmaceutical and cosmetic preparations for external use. The preparations according to the present invention may be in the form of aqueous-alcoholic lotions, water-in-oil emulsions (w/o emulsions), oil-in-water-emulsions (o/w emulsions), ointments, or gels. For treating androgen baldness, aqueous-alcoholic lotions containing compounds of both formula I and II are preferably used; for the treatment of skin wrinkles, the above emulsions, ointments and gels are preferably used which contain compounds of formula II in combination with mucopolysaccharides alone or together with a xanthine of formula I. For the treatment of acne, alcoholic gels are used which contain compounds of formula I and II. 
     The combination preparations according to the present invention may further contain perfumes and/or dyestuffs. They may also contain other active substances producing additional effects, in particular cholesterol, lecithin, nucleic acids, pyrimidines, purines and/or vitamins. 
     The preparations according to the present invention are prepared by the usual processes. Their pH is buffered to a value optimal for the intended use by means of appropriate buffering systems such as disodiumphosphate/monopotassiumphosphate (phosphate buffer) or sodium lactate/lactic acid (lactate buffer). The optimal pH range for preparations to be applied on the scalp is 6.0 to 7.0 and for those to be applied on the skin is 5.4 to 5.8. 
    
    
     The following examples serve to further illustrate the present invention. The conservation agents, (preservatives) Nipastat® and Phenonip® referred to below are products of Nipa Laboratories, London, England. The conservation agent Bronopol is 2-bromo-2-nitropropan-1,3-diol. 
     EXAMPLE I 
     Preparation of alcoholic-aqueous lotions containing caffeine and α-estradiol 
     
         ______________________________________           Parts by Weight______________________________________(a) ComponentsCaffeine          0.18α-Estradiol 0.008Isopropanol       35.Dexadecyl alcohol 0.1Protein hydrolysate             0.1Conservation agent             0.3Distilled water filled up tototal weight of   100.(b) ComponentsCaffeine          0.22α-Estradiol 0.012Isopropanol       60.Hexadecyl alcohol 0.5Portein hydrolysate             5.0Conservation agent             0.3Distilled water filled up tototal weight of   100.______________________________________ 
    
     The components are completely dissolved in the isopropanol and a substantial amount of distilled water, and distilled water is filled up to 100% by weight. 
     EXAMPLE II 
     Preparation of a w/o-emulsion containing α-estradiol and α-heparin. 
     
         ______________________________________              Parts by Weight______________________________________(a) Componentsα-Estradiol    0.008α-Heparin      0.12Mixture of higher molecular weightesters, consisting to the greatestextent of mixed esters pentaery-thritol fatty acid ester and citricacid alkyl ester     7.0Peanut oil           10.0Oleic acid decyl ester                5.0Beeswax, white       0.8Vaseline, white      19.0n-Octadecanol        3.0α-Tocopherol (antioxidant)                0.05Phenonip (conversion agent)                0.3Dimineralized water filled up to atotal weight of      100.(b) Componentsα-Estradiol    0.012α-Heparin      0.18Mixture of higher molecular weightesters, consisting to the greatestextent of mixed esters pentaery-thritol fatty acid ester and citricacid alkyl ester     8.0Peanut oil           20.0Oleic acid decyl ester                4.0Beeswax, white       2.0Vaseline, white      9.0n-Octadecanol        5.0α-Tocopherol (antioxidant)                0.05Phenonip (conservation agent)                0.3Demineralized water filled up to atotal weight of      100.______________________________________ 
    
     The components are thoroughly mixed with the water-free oily components. Thereafter, the demineralized water is admixed with vigorous mechanical stirring. 
     EXAMPLE III 
     Production of an o/w emulsion containing α-estradiol and α-heparin. 
     
         ______________________________________               Parts by Weight______________________________________(a) Componentsα-Estradiol     0.008α-Heparin       0.12Ethoxylated cetyl stearyl alcohol                 2.having about 12 molecules ofethylene oxide per alcohol moleculeMixture of mono- and diglycerides                 12.of palmitic and stearic acids2-Octyldodecanol      10.Caprylic caprinic acid triglyceride                 15.1,2-Propylene glycol  5.Nipastat (conservation agent)                 0.18Demineralized water filled up to a                 100.total weight of(b) Componentsα-Estradiol     0.012α-Heparin       0.17Ethoxylated cetyl stearyl alcohol                 3.having about 12 molecules ofethylene oxide per alcohol molecule                 3.Mixture of mono- and diglycerides                 15.of palmitic and stearic acids                 15.2-Octyldodecanol      20.Caprylic caprinic acid triglyceride                 8.1,2-Propylene glycol  0.5Nipastat (conservation agent)                 0.18Demineralized water filled up to a                 100.total weight of______________________________________ 
    
     The components are mixed as described in Example II. 
     EXAMPLE IV 
     Preparation of a water-free (non-aqueous) ointment containing α-estradiol diacetate and α-heparin. 
     
         ______________________________________               Parts by Weight______________________________________(a) Componentsα-Heparin       0.12α-Estradiol diacetate                 0.01Glycerine monostearate                 12.0Ethoxylated cetyl stearyl alcohol                 2.5having about 20 molecules ofethylene oxide per alcohol moleculeCholesterol           0.8Lecithin              0.8α-Tocopherol (antioxidant)                 0.05Oleic acid decylester filled up to a                 100.total weight of(b) Componentsα-Heparin       0.17α-Estradiol diacetate                 0.015Glycerine monostearate                 16.0Ethoxylated cetyl stearyl alcohol                 3.5having about 20 molecules ofethylene oxide per alcohol moleculeCholesterol           1.0Lecithin              1.0α-Tocopherol (antioxidant)                 0.18Oleic acid decylester filled up to a                 100.total weight of______________________________________ 
    
     The components are thoroughly admixed in an ointment mill (a mill having three rollers made of hardened porcelain) until a homogeneous ointment is obtained. 
     EXAMPLE V 
     Preparation of a transparent gel containing caffeine, the sodium salt of α-estradiol sulphate, and α-heparin. 
     
         ______________________________________                Parts by Weight______________________________________(a) ComponentsSodium salt of α-estradiol                  0.008sulfateα-Heparin        0.17Caffeine               0.4Ethoxylated cetyl stearyl alcohol                  11.0having about 30 molecules of ethyleneoxide per alcohol moleculePolyol fatty acid ester                  18.0Palmitic acid isopropyl ester                  6.0Lecithin               0.8Nipastat (conservation agent)                  0.2Distilled water filled up to atotal weight of        100.(b) ComponentsSodium salt of α-estradiol                  0.010sulphateα-Heparin        0.25Caffeine               0.6Ethoxylated cetyl stearyl alcohol                  13.0having about 30 molecules ofethylene oxide per alcohol molculePolyol fatty acid ester                  20.0Palmitic acid isopropyl ester                  4.0Lecithin               1.1Nipastat (conservation agent)                  0.2Distilled water filled up to atotal weight of        100.______________________________________ 
    
     Two thirds of the water phase are added to the fatty phase molten at about 90° C. at the same temperature. The resulting gel is cooled with stirring to about 50° C., the active agents are dissolved in, or suspended in the remaining amount of water and added to the gel. In order to avoid the admixture of air, the stirring is finished shortly after a homogeneous mixture is reached. 
     EXAMPLE VI 
     Preparation of a gel for the treatment of acne, containing caffeine and the sodium salt of α-estradiol sulphate. 
     
         ______________________________________               Parts by Weight______________________________________(a) ComponentsSodium salt of α-estradiol                 0.01sulphateCaffeine              0.8Ethoxylated cetyl stearyl alcohol                 11.0having about 30 molecules ofethylene oxide per alcohol moleculePolyol fatty acid ester                 18.0Palmitic acid isopropyl ester                 6.0Ethanol (70%)         0.5Lecithin              0.8Bronopol (conservation agent)                 0.02Distilled water filled up to atotal weight of       100.(b) ComponentsSodium salt of α-estradiol                 0.07sulphateCaffeine              1.1Ethoxylated cetyl stearyl alcohol                 13.0having about 30 molecules ofethylene oxide per alcohol moleculePolyol fatty acid ester                 20.0Palmitic acid isopropyl ester                 4.0Ethanol (70%)         10.0Lecithin              1.2Bronopol (conservation agent)                 0.02Distilled water filled up to atotal weight of       100.______________________________________ 
    
     The gel is prepared as described in Example V. 
     EXAMPLE VII 
     Clinical testing of a composition of the invention to determine its usefulness for the alleviation and retarding of reversible androgen baldness was conducted as set forth below. 
     Compositions comprising about 0.05% α-estradiol and about 0.1% caffeine by weight were administered to out-patients over a period of about three years. While the preparations tested were not of identical composition throughout the entire period, a typical formula is given below: 
     
         ______________________________________Ingredient        Percent W/W______________________________________caffeine          0.10α-estradiol 0.05isopropanol       35.00hexadecyl alcohol 0.10Nipastat® (preservative)             0.30distilled water   q. s.             100.00______________________________________ 
    
     The results of tests on 53 persons with a composition illustrated by the above are presented in the following Table I. The composition was applied in a single application of 3 ml/day over an area of approximately 200 cm 2  for at least six months in each case. 
     
                                           TABLE I__________________________________________________________________________Treatment of loss of hair using a composition comprising0.05% of 17 alpha-estradiol and 0.1% caffeine.                  male   female__________________________________________________________________________Number of test persons:        53        24     29(a)  Trichogramm stage in        telogen stage                  30%    40%  the parietal region        growth stage                  55%    50%  before treatment  (arithmetic mean)        variable  15%    10%  Trichogramm stage in  the parietal region  after a treatment of        telogen stage                  35%    30%  6 to 24 months        growth stage                  60%    65%  (arithmetic mean)        variable   5%     5%(b)  Hair count before treatmt.                  80 hairs                         60 hairs  (number of hairs        (arith. mean)  counted by test per-  sons as removed by        after treatment                  40 hairs                         40 hairs  combing in the morn-        as described above  ing)       (arith. mean)(c)  Number of test       18 test per-                         24 test per-  persons reporting    sons (after                         sons (after  stop of intensive    3 months of                         3 months of  loss of hair or con- treatment at                         treatment at  siderable slow-down  the earliest)                         the earliest)(d)  Type of newly        lanugo hair                  15      5  growing hair        vellus hair                   1     10 +(e)  Undesired side       none   none  effects  Desired                     Decrease of                         a migraine                         observed by                         3 patients__________________________________________________________________________ + of these, 3 after 20 treatments 
    
     The results in Table I demonstrate that this composition of the invention alleviates and retards reversible androgen baldness. There is shown a comparative increase in the number of hairs in a growth stage in men, while indicating in a more marked degree a decrease in the number of hairs in the telogen (resting or dead) stage and, simultaneously, an increase in the number of hairs in a growth stage in women. Moreover, this table demonstrates the pronounced decrease in the loss of hairs removed during combing, particularly in the case of men. The decrease or stop in the intensive loss of hair caused by the treatment with the composition of the invention was observed in 18 out of 24 (75%) of the male patients and in 24 out of 29 (85%) of the female patients. These surprisingly good results are superior to any obtained with prior art compositions. 
     None of the subjects of this test showed any unwanted local or systemic side affects. 
     The above examples have been provided for illustration only and not to restrict the scope of the present invention, which scope is defined by the appended claims.