Patent Publication Number: US-4923875-A

Title: Method for treatment of mast cell-mediated dermatologic disorders

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The invention relates to methods and compositions for the treatment for acute dermatitis. 
     2. Description of the Prior Art 
     There are different forms of dermatitis (inflammation of skin); erythema, edema, papular eruptions and pruritus may be present in both human and animal dermatitides. 
     It is known that the symptoms present in some forms of dermatitis are caused by degranulation of cutaneous mast cells, resulting in, inter alia, histamine release. Oral and topical antihistamines are thus used to treat the manifestations of mast-cell mediated dermatoses. 
     Many dermatitic conditions also respond to topical corticosteroids of low to medium potency, and such agents are often used in treating the inflammatory and pruritic manifestations of acute dermatitis. Topical antipruritic agents (e.g., menthol, phenol and camphor) and anesthetics (most commonly, benzocaine) are also frequently applied to treat moderately extensive dermatitic eruptions. 
     All of the foregoing pharmaceutical agents conventionally used to treat mast cell-mediated dermatologic disorders suffer from significant drawbacks. Topical corticosteroids can cause epidermal and dermal atrophy, resulting in thinning of the skin and striae, particularly in highly absorptive areas. If applied to extensive areas or with prolonged use of occlusive dressings, corticosteroids may be absorbed in sufficient quantities to cause the same adverse systemic effects observed with orally or parenterally administered steroids, including pernicious effects on the endocrine and immune systems. Topical antihistamines and anesthetics are not very effective, may be sensitizing and, in some instances, actually cause allergic contact dermatitis. Oral antihistamines are often associated with sedative side effects. Antipruritic agents such as camphor and menthol usually provide only short-term symptomatic relief for pruritus. 
     SUMMARY OF THE INVENTION 
     It is the object of the present invention to provide compositions and methods for the treatment of mast cell-mediated dermatologic disorders which avoid the aforementioned drawbacks of the prior art treatment agents and methods while providing effective relief. In keeping with this object and others that will become apparent hereinafter, the present invention resides in the treatment of such disorders through the topical application of pharmaceutical compositions containing as their active ingredient from about 0.01 to about 10% by weight of the narcotic antagonist nalmefene. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Nalmefene (6-methylene-6-desoxy-N-cyclopropyl-methyl-14-hydroxydihydronormorphine) is a long-acting, orally available, potent narcotic antagonist with pure antagonist activity. Apart from its utility in antagonizing the sedation, respiratory depression and other actions of opioid agents, nalmefene has also been found useful in treating diverse conditions such as hyperkinesia in children (U.S. Pat. No. 4,454,142), senile dementia (U.S. Pat. No. 4,511,570) and sudden infant death syndrome (U.S. Pat. No. 4,639,455), among others. Nalmefene has not hitherto been disclosed, however, as having any utility in the treatment of acute dermatitis or any related skin conditions, nor have topical formulations of nalmefene been utilized for any purpose. 
     The method of the present invention consists of the topical application to an affected skin area of a human or animal patient suffering from a mast cell-mediated dermatologic disorder of a topical pharmaceutical composition comprising from about 0.01 to about 10% nalmefene by weight in a pharmaceutically acceptable inert carrier. A preferred concentration range is from about 0.1 to about 2.5% nalmefene by weight. Suitable carriers or vehicles for such compositions include, without limitation, conventional ointments, creams, gels, aerosols, lotions and liquid solutions known to those skilled in the medicinal and pharmaceutical arts. Many examples of such suitable topical vehicles are set forth in Remington&#39;s Pharmaceutical Sciences, 17th edition (1985) and variations of these vehicles which include penetration enhancers. 
     The active ingredient used in the methods and compositions of the present invention may be nalmefene base, or pharmaceutically acceptable salts or esters of nalmefene, e.g., nalmefene hydrochloride or nalmefene glucuronide. 
     Preferred inert vehicles or carriers for use in the present invention are those which are chemically compatible with nalmefene or its salts or esters, form stable solutions, emulsions, dispersions or suspensions of the active ingredient and promote rapid release and absorption of the drug upon application to the affected skin areas. 
     In accordance with the novel methods, a quantity of a lotion, cream, gel or ointment containing nalmefene (or one of its salts or esters) sufficient to form a thin film or coating over the affected skin area is applied from 1 to about 6 times daily for as long as the symptoms persist. Examples of conditions which may be effectively treated with the subject methods and compositions include, but are not limited to, urticaria, contact dermatitis, atopic dermatitis, allergic dermatitis, reactions to intradermal allergy testing, mast cell disease, eczematous dermatitis and dermatitis caused by insect bites or stings. Rapid relief of itching and erythema is achieved. 
     In the case of liquid solutions or aerosol sprays containing nalmefene base, salts or esters, a sufficient quantity of the liquid to throughly wet the affected area should be applied. This treatment may be repeated from 1 to about 6 times daily as needed. 
    
    
     The following Examples provide detailed illustrations of the compositions and methods of the present invention. The Examples are not intended, however, to limit or restrict the scope of the invention in any way, and should not be construed as providing formulations or methods of administration which must be utilized exclusively to practice the present invention. 
     EXAMPLE 1 
     Liquid Solution 
     Nalmefene (1 g) is dissolved in 49 g dimethylisosorbide to yield a 2% nalmefene solution by weight. That solution is then diluted with 50 g ethyl alcohol to yield a 1% solution of nalmefene. 
     EXAMPLE 2 
     Creams 
     (a) Oil in Water 
     Nalmefene (0.5 g) is dissolved in a mixture of diisopropyl adipate (7 g), polyoxyl-50 stearate (1 g) and glyceryl stearate (5 g) at 70° C. with stirring. After dissolution, the mixture is diluted with sufficient purified water to reach a total weight of 100 g and allowed to cool with stirring. 
     (b) Water in Oil 
     Nalmefene (0.5 g) is dissolved in a mixture of stearic acid (10 g), squalene (10 g), isopropyl myristate (10 g) and mineral oil (5 g) at 70°-80° C. with stirring. After dissolution, the following ingredients are added successively to the above: 
     
         ______________________________________                                    
Petrolatum               2.0    g                                         
Cetyl alcohol            1.0    g                                         
Sobitan monostearate     4.0    g                                         
Tween 60 (ICI Americas, Inc.)                                             
                         4.0    g                                         
Propyl paraben           0.2    g                                         
BHT                      0.05   g                                         
Glycerin                 1.0    g                                         
Triethylamine            0.5    g                                         
Methyl paraben           0.1    g                                         
Purified water           51.65  g                                         
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     The formulation is allowed to cool with stirring. 
     Alternatively, up to 25 g isopropyl myristate may be used in the above formulation. 
     EXAMPLE 3 
     Ointment 
     Nalmefene (300 mg) is dissolved in 900 mg cetyl alcohol. An ointment is then compounded with 900 mg white wax (melted) and 27.9 g petrolatum. 
     EXAMPLE 4 
     Gel 
     Nalmefene (0.5 g) is mixed with 3 g dimethylisosorbide. The resultant mixture is added to 88.5 g SDA 40 alcohol with stirring. Propylene glycol (5 g) is added, followed by slow addition of 3 g hydroxypropyl cellulose. Stirring at a slow rate is continued for 2.5 hrs, during which time a gel forms. 
     EXAMPLE 5 
     Lotion 
     Nalmefene (1 g) is admixed with the following ingredients to form a homogeneous lotion: 
     
         ______________________________________                                    
Mineral oil            21.0   g                                           
Isopropyl palmitate    1.5    g                                           
Glyceryl stearate      3.0    g                                           
Cetyl alcohol          1.5    g                                           
Tween 60               2.5    g                                           
Polyoxyl 40-stearate   0.5    g                                           
Propylene glycol       2.0    g                                           
Purified water         67.0   g                                           
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     EXAMPLE 6 
     Aerosol 
     Nalmefene (1 g) is dissolved in 90 g ethyl alcohol. Acetylated lanolin alcohol, povidone, tris (hydroxymethyl)-amino methane, wheat germ glycerides and sufficient purified water are added for a total weight of 100 g. 
     EXAMPLE 7 
     In a double-blind study, 30 subjects were treated with the gel of Example 4 (or a similar gel containing 1% nalmefene) and placebo for pruritus and irritation incident to intradermal skin testing for allergies. All patients reported greater relief with nalmefene gel than with placebo. 
     EXAMPLE 8 
     In an open study, six subjects suffering from common insect bites reported relief from inflammation and pruritus after application of the gel of Example 4 and/or the liquid solution of Example 1. 
     It has thus been shown that there are provided methods and compositions which achieve the various objects of the invention and which are well adapted to meet the conditions of practical use. 
     As various possible embodiments might be made of the above invention, and as various changes might be made in the embodiments set forth above, it is to be understood that all matters herein described are to be interpreted as illustrative and not in a limiting sense.