Patent Application: US-56455909-A

Abstract:
it has been found that the combination of an antihistamine with a corticosteroid is more effective in the treatment of atopic dermatitis than either one used separately . the synergistic effect in some cases results in the disappearance of the atopic dermatitis lesion within one to five days with little or no relapse . compositions and the methods of utilizing these preparations are disclosed .

Description:
in the preferred embodiments of the present invention there are provided spray composition for topical administration of antihistaminically active compounds and corticosteroids or a glucocorticoid where these active compounds are soluble in a pharmacologically acceptable polar solvent , the spray comprises , in weight % of total composition : polar solvent 90 - 99 . 9 %, active compounds 0 . 002 - 10 %. in some cases a mixture of polar and non - polar solvents can be used as long as a homogenous solution is obtained where the active compounds are soluble in a pharmacologically acceptable non - polar solvent the spray composition comprises in weight % of total composition : a pharmaceutically acceptable propellant , 45 - 93 %, non - polar solvent 5 - 55 %, and active compounds 0 . 002 - 10 %. in some cases a mixture of polar and non - polar solvents can be used as long as the combination is compatible with the propellant such that a homogenous solution is obtained . while the invention is in no way limited thereto , as active antihistamines clemastine , chlorpheniramine , astemizole , triprolidine , hydroxyzine , dextromethorphan , citirizine and loratadine in their nonionized form or as the pharmaceutically acceptable salts thereof , have been found most suitable . while the invention is in no way limited thereto , as active corticosteroid or glucocorticoid betamethasone dipropionate or valerate , triamcinolone acetonide , fluocinonide , alclometasone dipropionate , fluocinolone acetonide , clobetasol propionate , flurandrenolide , monetasone furoate , hydrocortisone butyrate , halobetasol propionate have been found most suitable . additionally , the topical spray compositions may comprise , by weight of total composition : aromatizing agent 1 - 10 %, suitably synthetic or natural oil of peppermint , oil of spearmint , rose oil , citrus oil , fruit aromas , perfumes and aromas commonly used in ointments and lotions and combinations thereof . as preferred polar solvents there may be mentioned low molecular weight polyethylene glycols ( peg ) of 200 - 600 mw , c 2 - 8 mono - and polyalcohols , and alcohols of c 7 - 8 hydrocarbons of a linear or branched configuration . most suitable in this group are polyethylene glycol and ethanol . as non polar solvents , there may be utilized ( c 2 - fatty acid ( c 2 - 6 ) esters , ( c 7 - 18 ) hydrocarbons of a linear or branched configuration , and ( c 2 - 6 ) alkanoyl esters , and triglycerides of said fatty acids . most suitably , miglyol . a combination of polar and non - polar solvents can be used as long as they are compatible with the propellant such that a homogenous solution is obtained at 0 - 40 degrees c . there are also provided lotion compositions , including ointments , creams , emulsions and the like , for topical administration of antihistaminically active compounds in combination with a corticosteroid or glucocorticoid such as the general group and preferred species listed above , wherein the composition comprises in weight % of total composition : solvent 75 - 99 . 99 %, active compounds 0 . 002 - 10 %. if desired , the foregoing aromatizing agents may also be used . as solvents , the polar and non polar solvents listed above are also operative . the occurrence of atopic dermatitis in a mammal may be modified or relieved by administering an antihistaminically pharmacologically active compound in combination with a corticosteroid or glucocorticoid to said mammal having been exposed to a atopic dermatitis causing substance , by spraying the potentially affected skin location thereof with any of the forgoing spray compositions , or applying any of the foregoing lotion compositions . antihistamines which may be used are limited to those that exhibit antihistamine properties and that are soluble enough in the solvent of choice to lead to solutions having a concentration of 0 . 001 - 5 % w / w . suitably , there may be used clemastine , chlorpheniramine , astemazole , triprolidine , dextromethorphan , citirizine and loratadine in their nonionized form or as the pharmaceutically acceptable salts thereof . the antihistamine of choice would be clemastine hydrogen fumarate or clemastine base . a second first choice would be chlorpheniramine hydrochloride or base . corticosteroids and glucocorticoids which may be used are limited to those that exhibit anti inflammatory and antipruritic properties and that are soluble enough in the solvent of choice to lead to solutions having a concentration of 0 . 001 to 5 . 0 % w / w . suitably , there may be used betamethasone dipropionate or valerate , triamcinolone acetonide , fluocinonide , alclometasone dipropionate , fluocinolone acetonide , clobetasol propionate , flurandrenolide , monetasone furoate , hydrocortisone butyrate , halobetasol propionate . the preferred polar solvent properties are as follows : for salts and such polar drugs , one can use water , low molecular weight alcohol &# 39 ; s ( preferable ethanol ), polyethylene glycols ( peg ) in the range 200 - 600 , low molecular weight ketones such as acetone and combinations thereof . at least one of the solvents acts as a dermal penetration enhancer . the preferred non - polar solvent properties may be expressed as follows : non - polar , c 7 - 18 hydrocarbons and their alcohols , esters of fatty acids , fatty acid triglycerides such as migylol , must be miscible with the propellant such that one phase is formed at temperatures 0 - 40 . degree . c . one of the solvents acts as a dermal penetration enhancer . in the case of a foam formulation , the composition comprises an oil and water combination emulsified using an emulsifying agent commonly known in the art . hence both a polar and non - polar solvent will be required . optionally , there may be employed aroma agents such as : oil of peppermint , oil of spearmint , oil of wintergreen , citrus oils , both synthetic and natural as well as oil of rose or other perfumes which are normally used in creams and lotions . preferred most preferred amount amount amount polar solvent 75 - 99 . 9 % 85 - 99 . 8 % 90 - 99 . 4 % corticosteroid 0 . 001 - 5 . 0 % 0 . 002 - 4 . 0 % 0 . 01 - 3 . 0 % antihistamine salt 0 . 01 - 5 . 0 % 0 . 02 - 4 . 0 % 0 . 1 - 3 . 0 % aroma 0 . 05 - 10 % 0 . 1 - 8 . 0 % 0 . 5 - 6 . 0 % a metered dose valve is preferred so that a measured amount of the preparation is deposited on the site . foams can be formulated as is common in the art usually as oil / water emulsions and as such use the above solvents as well as emulsifying agents to maintain the mixture as an emulsion . these foams can be delivered to the site of the atopic dermatitis either in a pump or aerosol delivery system . in either case a metered dose valve is preferred so that a measured amount of the preparation is deposited on the site . the preferred solvent properties for the solution formulation are : solvents such as polyethylene glycols ( peg ) of the 200 - 1000 molecular weight , but preferred are those in the 200 - 600 range , fatty acid esters and triglycerides . low molecular weight alcohols and poly - alcohols can also be used . one of the solvents acts as a dermal penetration enhancer . if the ointment or gel is packaged as a soft gelatin capsule , glycerin and water should be used sparingly as they will migrate into the shell and weaken the shell or make it tacky . optionally aroma agents may be employed such as : oil of peppermint , oil of spearmint , oil of wintergreen , citrus oils , both synthetic and natural . oil of rose or other perfumes normally used in creams and lotions may be used . a specific formulation for clemastine hydrogen fumarate and triamcinolone acetonide as a topical spray : a . clemastine hydrogen fumarate 0 . 107 gm b . triamcinolone acetonide 0 . 04 gm c . polypropylene glycol 11 . 7 gm d . glycerin 0 . 58 gm e . ethanol 29 . 8 gm f . water 1 . 6 gm g . oil of peppermint 0 . 78 gm 1 or 2 activations of 50 micro liters each would be used to deliver a therapeutic amount of the combination to lesion of moderate size ( 3 × 6 cm in area ) in accordance with the above formulation , but where , in place of clemastine hydrogen fumarate there is utilized chlorpheniramine maleate , astemizole , triprolidine hydrochloride , dextromethorphan hydrobromide , citirizine hydrochloride or loratadine , and in place of triamcinolone acetonide there is used betamethasone dipropionate or valerate , fluocinonide , alclometasone dipropionate , fluocinolone acetonide , clobetasol propionate , flurandrenolide , monetasone furoate , hydrocortisone butyrate or halobetasol propionate , or fluocinonide , a spray of similar activity is obtained , however actual dosage amounts of the active substance as well as the amounts of solvents will vary . a specific formulation for clemastine hydrogen fumarate and betamethasone dipropionate as a topical ointment : a . clemastine hydrogen fumarate 0 . 362 gm b . betamethasone dipropionate 0 . 270 gm c . polypropylene glycol 46 . 4 gm d . glycerin 2 . 30 gm e . ethanol 10 . 6 gm f . water 0 . 53 gm g . oil of peppermint 3 . 08 gm 1 or 2 drops of approximately 50 micro liters each would be used to deliver a therapeutic amount of the combination to lesion of moderate size ( 3 × 6 cm in area ) in accordance with the above formulation , but where , in place of clemastine hydrogen fumarate there is utilized chlorpheniramine , astemizole , triprolidine , dextromethorphan , citirizine and loratadine , and in place of betamethasone dipropionate there is used betamethasone valerate , fluocinonide , alclometasone dipropionate , fluocinolone acetonide , clobetasol propionate , flurandrenolide , monetasone furoate , hydrocortisone butyrate , halobetasol propionate , triamcinolone acetonide , or fluocinonide , a ointment of similar activity is obtained , however actual dosage amounts of the active substance as well as the amounts of solvents will vary . a specific formulation for clemastine fumarate , triamcinolone acetonide and betamethasone dipropionate as a topical ointment : a specific formulation for citirizine and fluocinolone acetonide as a topical ointment : a specific formulation for astemazole and hydrocortisone butyrate as a topical cream : a specific formulation for chlorpheniramine maleate and clobetasol propionate as a topical ointment : a specific formulation for triprolidine hydrochloride and betamethasone dipropionate as a topical ointment : a specific formulation for fexofenadine hydrochloride and alclometasone dipropionate as a topical ointment : a specific formulation for chlorpheniramine maleate , clemastine fumarate , triamcinolone acetonide and betamethasone dipropionate as a topical ointment : a specific formulation for clemastine , fumarate triamcinolone and betamethasone dipropionate as a topical ointment : treatment of atopic dermatitis with composition of example 2 . on day 1 subject diagnosed by his physician as having atopic dermatitis on his back . the physician prescribed a topical corticoid steroid ( betamethasone propionate ) which the subject applied several times a day to relieve itching . after one week with no improvement in the scope of the lesion or intensity of the itching once the effect of the ointment wore off , the subject applied a topical antihistamine and again the itching was relieved but after a week the lesion was unchanged . on day 15 the subject applied a combination product of example 2 to the site and again the itching was relieved and after 4 days of treatment the lesion regressed and the skin returned to a normal condition . there was no relapse as of 24 months . a subject with an atopic dermatitis lesion between the middle finger and the ring finger of the right hand was treated for 10 days b . i . d with the invention containing flucinolone acetonide and cetirizine hydrochloride resulting in complete clearing of the lesion . there has been no reoccurrence at the site for a minimum of 13 months . the longer duration of the treatment was attributed to the daily if not more often washing of the hands which probably dilute if not removed the preparation from the site . the best time to apply the invention in this case is probably after bathing or at bed time . in the latter case one has at least 8 hours of contact . a subject with a atopic dermatitis lesion on the first knuckle of the index finger of the left hand was treated with the invention containing triamcinolone acetonide and clemastine hydrogen fumarate for 7 days resulting in complete clearing of the lesion which has not return for at least 11 months . as in example 13 above , more time was require to clear the lesion . the product was applied on an irregular basis with the longest exposure time at night . a subject with an atopic dermatitis on the outside surface of the ring finger of the left hand was treated with the invention containing betamethasone dipropionate and clemastine hydrogen fumarate for 5 days resulting in complete clearing of the lesion which has not return for at least 8 months . as in example 13 more time was require to clear the lesion and the product was applied on an irregular basis with the longest exposure time at night . a subject with an atopic dermatitis lesion on the palm of the right hand is presently being treated with the invention containing betamethasone and clemastine hydrogen fumarate . the lesion is about 90 % cleared . the problem in clearing is again the hands are constantly being washed and the palm is in constant contact with other materials which can remove or dilute the preparation . as above the best time is at bed time and during the day to apply a loose band aid to the site . . a . belsito d ., management of atopic dermatitis in the adult patient . medscape dermatology 2005 ; 6 ( 1 ). b . williams ii , robertson c , stewart a , et al . worldwide variations in the prevalence of symptoms of atopic eczema in the international study of 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