US5145686.Pdf

||||||||||| B US00545686A United States Patent (19) 11) Patent Number: 5,145,686 Horrobin et al. (45) Date of Patent: Sep. 8, 1992 (54) TOPICAL PHARMACEUTICAL 4,386,072 5/1983 Horrobin et al. ................... 424/127 COMPOSITIONS OTHER PUBLICATIONS (75 Inventors: David F. Horrobin, Montreal, Remington's Pharm. Sciences, pp. 353 & 733 (1980). Canada; Julian Lieb, Bethany, Conn. Ando et al., Chem. Abst, 88:65874z (11/8/77). 73) Assignee: Efamol Limited, London, United Queuauviller et al., Chem. Abst. 88:146313t (1977). Kingdom Dianzani et al., Chen. Abst. 91:68529p. 21 Appl. No.: 818,501 Mucsi et al. Chem. Abst. 90:67141y (1978) and 89:71525y (1977). (22 Filed: Jan. 8, 1992 FDA Consumer, "Vitamin E-Miracles on Myth', (Aug. 1973). Related U.S. Application Data The Merck Index, 9th ed., pp. 31 & 649 (1976). (63) Continuation of Ser. No. 312,730, Feb. 17, 1989, aban- Horrobin et al., Chem, Abst. 99:146126m (1983). doned, which is a continuation of Ser. No. 89,035, Aug. Passarella et al., Chem. Abst. 92:28475g (1980). 24, 1987, abandoned, which is a continuation of Ser. Punnoneu et al., Chen. Abst. 107:3394v. (1987). No. 786,517, Oct. 11, 1985, abandoned, which is a continuation of Ser. No. 458,466, Jan. 17, 1983, aban- Primary Examiner-Frederick E. Waddell doned, which is a continuation-in-part of Ser. No. Assistant Examiner-Raymond J. Henley, III 345,204, Feb. 3, 1982, abandoned. Attorney, Agent, or Firm-Foley & Lardner 51) Int. Cl. ..................... A61K 33/14; A61K 33/04; 57 ABSTRACT 52 U.S. C. ....................................A61K 33/00; 2/6, A61K 424/709. 31/61 Topical pharmaceutical compositions- - for the treatment (58) Field of search.424/715; 514/163; 424/677,722,709,715; 514/552; 514/574 aof physiologically lesions of the skin acceptable or mucous lithium membranes salt together containing with 514/574, 163,552 at least one substance selected from substances capable of selectively increasing the in vivo level of E-series (56) References Cited prostaglandins, substances capable of inhibiting cy U.S. PATENT DOCUMENTS clooxygenase enzyme, substances capable of inhibiting 3,527,864 9/1970 MacMillan et al. .................. 424/59 the formation of lipoxygenase products, and lysine. 3,639,625 2/1972 Sherwin ............ 424/153 4,302,447 1/1981 Horrobin ... ... 424/145 4. Claims, No Drawings 5,145,686 1 2 and, in turn, inflammation is believed to be due in part to TOPICAL PHARMACEUTICAL COMPOSITIONS excessive and/or defective production of certain prosta glandins and related substances. Prostaglandins and This application is a continuation of application Ser. related substances are biosynthesised in the body from No. 07/312,730, filed Feb. 17, 1989 now abandoned, 5 two main substances, dihomo-y-linolenic acid and ar which is a continuation of U.S. application Ser. No. achidonic acid. In general, prostaglandins of the E-ser 07/089,035 (filed Aug. 24, 1987), now abandoned, ies exhibit a beneficial anti-inflammatory activity, and which is a continuation of U.S. application Ser. No. while minor amounts of such prostaglandins are formed 06/786,517 (filed Oct. 11, 1985), now abandoned, which from arachidonic acid, most of the prostaglandin prod was a continuation of U.S. application Ser. No. 10 ucts derived from arachidonic acid show an inflamma 06/458,466 (filed Jan. 17, 1983), now abandoned, which tory action. The principal prostaglandin product de was a continuation-in-part of U.S. application Ser. No. rived from dihomo-y-linolenic acid is prostaglandin El 06/345,204 (filed Feb. 3, 1982), now abandoned. which exhibits the anti-inflammatory activity. Concom BACKGROUND OF THE INVENTION itant with the production of prostaglandins and related 5 substances from dihomo-y-linolenic acid and arachi This invention relates to topical pharmaceutical com donic acid by the cyclooxygenase enzyme, other bio positions and their use in the treatment of lesions of the products are formed from these acids as a result of the skin and mucous membranes. action of the enzyme, lipoxygenase. These lipoxygenase The oral and parenteral administration of lithium and products also exhibit an inflammatory action. in particular lithium salts such as lithium carbonate, has 20 Dihomo-y-linolenic acid and arachidonic acid for found widespread application in the treatment of manic metabolism in the body to prostaglandins and lipoxyge depressive psychosis. Lithium treatment has been re nase products are usually available either from endoge ported as being particularly effective in the treatment of nous stores of these acids or from food sources. For the manic phase of this illness and also in the prophy example, dihomo-y-linolenic acid may be biosynthe laxis of both manic and depressive relapses. 25 sized from dietary sources of its precursor substances It has been reported (Lieb, N.Eng.J.Med. 301 (1979), ty-linolenic acid and linoleic acid. In animals arachi 942) that the oral administration of lithium salts in the donic acid may readily be biosynthesised from dihomo treatment of manic-depressive illness has been accom ty-linolenic acid, but in adult humans such a mechanism panied by the remission of recurrent herpes infection in is not particularly effective so that the major source of a patient additionally suffering from labial herpes and in arachidonic acid for prostaglandin synthesis may be a patient also having genital herpes. from ingestion of the acid per se. U.S. Pat. No. 3,639,625 (issued Feb. 1972 to Sherwin) We now believe that the previously noted activity of describes therapeutic compositions containing lithium lithium succinate for treating dermatitis and for produc succinate for treating dermatitis and for producing an ing an antipuritic effect is due to the ability of lithium to antipruritic effect, the compositions thus being suitable 35 block the release of dihomo-y-linolenic acid and arachi for topical application. donic acid from endogenous stores of these compounds, Our copending Application Ser. No. 251901 filed so that the availability of the compounds for conversion Apr. 7, 1981, now U.S. Pat. No. 4,328,243, describes a to the inflammatory prostaglandins and lipoxygenase method for the treatment of the side-effects of lithium products is reduced. treatment in a subject suffering from manic-depressive 40 However, as indicated above, E-series prostaglandins psychosis and undergoing lithium treatment by orally are believed to be benefical in the treatment of skin and administering to the subject an effective amount of mucous membrane fesions due to their anti-inflamma dihomo-y-linolenic acid and/or y-linolenic acid or lin tory activity, so that in one embodiment, the composi oleic acid. tions according to the invention incorporate one or 45 more substances which are capable of selectively in SUMMARY OF THE INVENTION creasing the in vivo level of E-series prostaglandins. We now propose that the conjoint topical administra For example, the in vivo level of E-series prostaglan tion of lithium with one or more substances selected dins and especially prostaglandin E may be increased from substances capable of selectively increasing the in by incorporating dihomo-y-linolenic acid and/or its vivo level of E-series prostaglandins, substances capa 50 bioprecursors such asy-linolenic acid and linoleic acid ble of inhibiting cyclooxygenase enzyme, substances into the compositions, conveniently in an amount of capable of inhibiting the in vivo formation of lipoxyge from 0.01 to 80, preferably from 1 to 15, percent by nase products, and lysine will be effective in the treat weight. If desired, the level of E-series prostaglandins ment of lesions of the skin and mucous membranes. may be increased by including a substance which acts to Thus, in one aspect, the invention provides a pharma 55 mobilise the endogenous stores of dihomo-y-linolenic ceutical composition for topical administration which acid and examples of such substances include physiolog comprises at least one physiologically acceptable lith ically acceptable zinc salts, conveniently in an amount ium salt together with at least one substance selected. sufficient to provide from 0.01 to 10, preferably 0.1 to 5 from substances capable of selectively increasing the in percent by weight of zinc ions. This object may also be vivo level of E-series prostaglandins, substances capa 60 achieved by including in the composition a substances ble of inhibiting cyclooxygenase enzyme, substances which is capable of activating the bioconversion of capable of inhibiting the formation of lipoxygenase dihomo-y-linolenic acid to E-series prostaglandins such products, and lysine. as, for example, ascorbic acid (e.g. in an amount of from 0.01 to 20, preferably 0.1 to 5 percent by weight), etha DETAILEED DESCRIPTION OF PREFERRED 65 nol (e.g. in an amount of form 0.01 to 80, preferably 0.1 EMBODEMENTS to 10% percent, by weight) and spironolactone, (e.g. in Lesions of the skin and of mucous membranes are an amount of from 0.01 to 20, preferably 0.1 to 5, per generally associated with an inflammatory response, cent by weight). 5,145,686 3 4 In the body, E-series prostaglandins may themselves polysaccharides include dextrans, such as dextran sul act as bioprecursors for other prostaglandins. For exam phate. ple, prostaglandin E may be converted to prostaglan The compositions according to the invention are in a din Fla, which does not show the desired anti-inflam form suitable for topical administration. Examples of matory action. The level of E-series prostaglandins may such forms include creams, ointments, solutions, sus therefore be increased by incorporating a substance pensions, emulsions, lotions, gels and sprays. Such which is capable of blocking their bioconversion to forms may be prepared with pharmaceutical carriers other prostaglandins. Examples of such substances are and excipients conventionally used for such purposes.

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