Abstract:
The present invention provides a pharmaceutical composition for the therapy of acne vulgaris which comprises a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof ##STR1## wherein R 1  and R 2  may be the same or different and each represents hydrogen or methyl.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a therapeutic drug for acne vulgaris. More particularly, the invention relates to a pharmaceutical composition for the therapy of acne vulgaris which comprises a phosphoric acid ascorbyl tocopheryl diester compound or a pharmacologically acceptable salt thereof. 
     2. Description of the Prior Art 
     Acne vulgaris is a chronic lesion of the pilosebaceous gland, which occurs in adolescence. The focus of lesion lies in the sebaceous follicle and is characterized by well-developed sebaceous glands and delicate vellus. Sebaceous follicles are distributed in the skin areas prone to acne vulgaris, such as the forehead, cheeks, back, and central region of the chest. It is known that, in acne vulgaris, the sebaceous gland function has been stimulated by elevation of the concentration of androgens which are sex hormones. Moreover, while the pores of the skin are inhabited by Propionibacterium acnes (P. acnes) which constitutes a normal flora feeding on sebum, this organism multiplies as the sebaceous glands are enlarged. Moreover, P. acnes has high lipolytic activity. Therefore, it is presumed that neutral fats such as glycerides in the sebum which increases as one approaches adolescence are decomposed by P. acnes to release free fatty acids, and that certain kinds of the free fatty acids stimulate the pore epithelium to cause abnormal keratinization, i.e. acne vulgaris. 
     There are systemic and topical therapies for the treatment of acne vulgaris. The systemic drugs which are most frequently used clinically are antibiotics in the tetracycline (TC) series. In cases not responding to TC antibiotics, erythromycin, which is a macrolide antibiotic, and clindamycin, among others, are used as systemic drugs. For topical therapy, clindamycin and other antibiotics, sulfur, ethyl lactate, salicylic acid, etc. are used. 
     The present inventors investigated the pharmacological profile of a certain phosphoric diester compound and found that the compound is of use as a therapeutic drug for acne vulgaris. The present invention has been developed on the basis of the above finding. 
     The present invention provides a novel, effective therapeutic drug for acne vulgaris. 
     SUMMARY OF THE INVENTION 
     The present invention, therefore, is directed to a pharmaceutical composition for the therapy of acne vulgaris which comprises a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof (hereinafter referred to as compound of the invention) ##STR2## wherein R 1  and R 2  may be the same or different and each represents hydrogen or methyl. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The phosphoric diester compound for use as the therapeutic drug for acne vulgaris according to the present invention is already known to be useful for a variety of applications, such as anticataract drug, a prophylactic and therapeutic drug for climacteric disturbance, a cosmetic ingredient having skin conditioning activity (JP Koho H2-44478), an antioxidant (JP Kokai S63-139972), an antiulcer drug (JP Kokai S63-270626), an antiinflammatory agent (JP Koho H1-27044, JP Koho H5-23274), a prophylactic and therapeutic drug for ischemic organ disorders (JP Kokai H2-111722), a Maillard reaction inhibitor (JP Kokai H3-161444), a lipid metabolism improving agent (JP Kokai H6-336435), and a therapeutic drug for epidermal proliferative diseases (JP Kokai H8-3049). 
     While this compound is known to produce various pharmacological effects such as those mentioned above, it is not known to be therapeutically effective for acne vulgaris. 
     The compound for use as the therapeutic drug for acne vulgaris according to the present invention can be synthesized by or in accordance with the process described in JP Koho H2-44478 or the process in JP Koho H5-23274. 
     The compound for use as the therapeutic drug for acne vulgaris according to the present invention may be a free compound or a pharmacologically acceptable salt. The pharmacologically acceptable salt typically includes salts with alkali metals such as sodium, potassium, etc. and salts with alkaline earth metals such as calcium, magnesium, etc., although any other pharmacologically acceptable salt can also be employed. 
     According to the objective and necessity, the therapeutic drug for acne vulgaris according to the present invention may contain two or more species of the present compound in a suitable combination. 
     The present compound for use as the active ingredient in the pharmaceutical composition for acne vulgaris according to the present invention is a safe compound with a very low toxicological potential and can therefore be used with advantage for the purposes of the invention  e.g. LD 50  of L-ascorbyl DL-α-tocopheryl phosphate potassium (hereinafter referred to briefly as EPC-K): oral, 5 g/kg (rat); intravenous, ≧100 mg/kg (rat)!. 
     The therapeutic drug for acne vulgaris according to the present invention can be administered orally or otherwise. The dosage form that can be used includes solid dosage forms such as tablets, granules, powders, capsules, ointments, etc. and various liquid dosage forms. Those dosage forms can be prepared by using the conventional pharmaceutical auxiliaries a such as the excipient, binder, disintegrator, dispersant, reabsorption promoter, buffer, surfactant, solubilizer, preservative, emulsifier, isotonizing agent, stabilizer, and pH control agent in suitable proportions. 
     The dosage of the present compound as a therapeutic drug for acne vulgaris depends on the species of compound, the patient&#39;s age and body weight, the clinical condition to be controlled, and the specific dosage form used. In the case of an oral dosage form, an adult patient is given about 10-1000 mg/dose a few times daily. An ointment preferably contains about 0.01-10 (w/w) % of the compound. 
     Unless contrary to the object of the invention, the pharmaceutical composition for the therapy of acne vulgaris according to the present invention may further contain other therapeutic drug substances for acne vulgaris and/or ingredients having different kinds of pharmacological efficacy, e.g. antibacterial agents. 
    
    
     EXAMPLES 
     The following examples and formulation examples are intended to describe the present invention in further detail. 
     EXAMPLE 1 
     Inhibitory Effect of the Present Compound on the Increase in Hamster Sebaceous Gland Area 
     It is known that, in acne vulgaris, the sebaceous gland function of the skin is enhanced by elevation of the androgen level. Therefore, the auricular sebaceous glands were expanded by subcutaneous administration of an androgen to hamsters and the inhibitory effect of the present compound on this enlargement was tested. 
     Experimental Animals 
     Female Syrian hamsters purchased from SLC Japan were used at the age of 7 weeks. 
     Test Materials 
     (1) Methanol (control) 
     (2) 0.2% L-ascorbyl DL-α-tocopheryl phosphate potassium (abbreviation: EPC-K) 
     (3) Normal group 
     Method 
     In 1 ml of sesame oil was dissolved 80 μg of testosterone propionate and the solution was administered subcutaneously to hamsters every other day for 2 weeks to enlarge auricular sebaceous glands. The test material was applied in a volume of 20 μl to the right auricle twice daily for 2 weeks from the beginning of the test. The normal group was subjected to neither treatment. After 2 weeks, the hamsters were sacrificed. The right auricle was bored with a 9 mm-diameter punch and the sebaceous gland area was measured by the whole mount technique. The data were statistically analyzed by Dunnett&#39;s test. The level of significance was p&lt;0.05. 
     References 
     1) Seki, Taiho. et al., Construction of a hamster model of sebaceous gland hyperfunction (disease model) and the effect of Coptis japonica and berberine chloride on sebaceous glands in the disease model, Journal of Wakan Iyakugaku, 12, 436-437, 1995. 
     2) Motoyoshi, K. et al., Whole Mount Technique, Jpn. J. Dermatol., 15, 252-256, 1988. 
     Results 
     The results are shown in Table 1. 
     
                       TABLE 1______________________________________Inhibitory effect of the compound on the increase in auricularsebaceous gland areaGroup          Area (μm.sup.2)                     % Inhibition______________________________________Methanol       10282 ± 1425                     --0.2% EPC-K      3327 ± 225*                     72.5Normal group   686 ± 91                     --______________________________________ Each value represents mean ± standard deviation (n = 7-8). Significantly different vs. control group*; p &lt; 0.01. 
    
     It will be apparent from Table 1 that 0.2% EPC-K significantly inhibited the increase in auricular sebaceous gland area by 72.5%. This result indicates that the present compound is of value as a therapeutic drug for acne vulgaris. 
     EXAMPLE 2 
     Determination of the Minimal Growth Inhibitory Concentration of the Compound Against Propionibacterium Acnes (P. acnes) 
     The minimal growth inhibitory concentration (MIC) of the present compound against P. acnes, which is a factor in the onset of acne vulgaris and a member of the normal flora of the skin, was determined. 
     Test Materials 
     (1) EPC-K (dissolved in distilled water) 
     Doubling dilutions from 10 mg/ml to 1.953125×10 -2  mg/ml in final concentration 
     (2) dl-α-tocopherol and L-ascorbic acid (dissolved in a mixed solution which consists of HC-60 (trademark, manufactured by NOF corporation) and propyleneglycol) 
     Dubling dilutions from 5 mg/ml to 7.8125×10 -2  mg/ml in final concentration 
     (3) As control, the mixed solution mentioned above was tested. 
     Method 
     This test was performed by the method published by Committee for the Study of Methods for MIC Determination in Anaerobic Bacteria. 
     A frozen clinically isolated strain of P. acnes was subcultured on GAM agar medium for 3 generations and suspended in saline at about 10 8  cells/ml. This cell suspension and a 100-fold dilution thereof were used as inocula. 
     To molten GAM agar medium was added 1/9 volume of the test solution of a varying concentration and, after thorough mixing, sensitivity assay plates ranging from 10 mg/ml to 1.953125×10 -2  mg/ml in final concentration were prepared (plate pH 6.64-7.10). Using a loopful of the inoculum, each plate was streaked and incubated anaerobically at 37° C. for at least 48 hours. The incubated plate was then observed grossly and the lowest concentration causing a definite inhibition of growth was regarded as the MIC. 
     The inoculum was serially diluted 10-fold down to 10 8  and GAM medium was inoculated with each dilution. After culture, the number of colonies were similarly countered for confirmation of the cell count. 
     References 
     Committee for the Study of Methods for MIC Determination in Anaerobic Bacteria: the method for MIC assays in anaerobic bacteria, Chemotherapy, 27, 559-560, 1979. 
     Results 
     The results are shown in Tables 2 and 3. 
     
                                           TABLE 2__________________________________________________________________________Minimum inhibitory concentration of EPC-K against Propionibacteriumacnes       Concentration (mg/ml)                            7.8125 ×                                 3.90625 ×                                       1.953125 ×Test material Cell count       10.0          5.0            2.5              1.25                 0.625                    0.3125                        0.15625                            10.sup.-2                                 10.sup.-2                                       10.sup.-2__________________________________________________________________________EPC-K 10.sup.8 CFU/ml       -  - - -  -  +   +   +    +     + 10.sup.6 CFU/ml       -  - - -  -  -   +   +    +     +__________________________________________________________________________ The symbol &#34;+&#34; means growth and &#34;-&#34; means growth inhibition. 
    
     
                                           TABLE 3__________________________________________________________________________Minimum inhibitory concentration of vitamins against Propionibacteriumacnes         Concentration (mg/ml)                           7.8125 ×Test material   cell count         5.0           2.5             1.25                0.625                   0.3125                       0.15625                           10.sup.-2__________________________________________________________________________dl-α-Tocopherol   10.sup.8 CFU/ml         + + +  +  +   +   +   10.sup.6 CFU/ml         + + +  +  +   +   +L-Ascorbic acid   10.sup.8 CFU/ml         + + +  +  +   +   +   10.sup.6 CFU/ml         + + +  +  +   +   +Control 10.sup.8 CFU/ml         + + +  +  +   +   +   10.sup.6 CFU/ml         + + +  +  +   +   +__________________________________________________________________________ The symbol &#34;+&#34; means growth. 
    
     It is apparent from Table 2 that the present compound showed a MIC value of 0.625 mg/ml at the cell count of 10 8  /ml and a MIC value of 0.3125 mg/ml at 10 6  /ml. On the other hand, it is apparent from Table 3 that dl-α-tocopherol and L-ascorbic acid showed a MIC value of not less than 5 mg/ml, respectively. These results indicate that the antibacterial activity of the compound of the present invention is superior to those of dl-α-tocopherol and L-ascorbic acid. 
     
         ______________________________________Formulation Example 1Oral Tablets______________________________________EPC-K             100 mgLactose           75 mgStarch            20 mgPolyethylene glycol 6000              5 mg______________________________________ 
    
     The above components per tablet are blended in the routine manner. Where necessary, the tablet may be sugar-coated. 
     
         ______________________________________Formulation Example 2Ointment______________________________________L-ascorbyl DL-α-tocopheryl phosphate                5.0         gsodium (EPC-Na)Glycerin             12.0        gStearyl alcohol      25.0        gWhite petrolatum     25.0        gMethyl p-hydroxybenzoate                0.025       gPropyl p-hydroxybenzoate                0.015       gSterilized pure water                to make 100 g______________________________________ 
    
     The above components are mixed in the routine manner to provide an ointment. 
     
         ______________________________________Formulation Example 3Gel______________________________________EPC-K             0.2          gCarboxyvinyl polymer             1.0          gTriethanolamine   q. s.Propyl p-hydroxybenzoate             0.014        gEthanol           30           mlSterilized pure water             to make 100  ml             pH 7.0______________________________________ 
    
     The above components are mixed in the routine manner to provide a gel.