Therapeutic/cosmetic compositions comprising CGRP antagonists for treating the eyes or eyelids

Ocular and/or palpebral pruritus and/or ocular and/or palpebral pain and/or ocular and/or palpebral dysaesthesia afflicting a mammalian, notably human patient, are therapeutically treated by administering to such patient a therapeutically/cosmetically effective amount of at least one CGRP antagonist, advantageously in combinatory immixture with at least one antagonist of a neuropeptide other than CGRP, e.g., a substance P antagonist, and/or at least one inflammation mediator antagonist; the subject compositions are also well suited for making up and/or caring for human eyes, eyelashes and/or eyelids, especially sensitive eyes and eyelids.

BACKGROUND OF THE INVENTION 
 1. Technical Field of the Invention 
 The present invention relates to the formulation of an antagonist of CGRP 
 (peptide derived from the calcitonin gene: Calcitonin Gene Related 
 Peptide, or "CGRP") into pharmaceutical compositions, in particular for 
 topical application, for the treatment of ocular and/or palpebral pruritus
 and/or pain and/or dysaesthesias. 
 This invention also relates to the formulation of a CGRP antagonist into 
 cosmetic compositions intended for making up or caring for the eyes or 
 eyelids, as well as to a regimen for making up and/or caring for sensitive
 eyes. 
 2. Description of the Prior Art 
 It is known to this art that certain patients suffer from ocular and/or 
 palpebral pain following operations or blows received to the eye. 
 Moreover, and although the precise cause is not known, certain individuals
 very often experience sensations of itching or pruritus and dysaesthesic 
 sensations around the eyes and eyelids. These may also be pruritus or 
 dysaesthesic sensations of allergic origin. 
 By the term "dysaesthesic sensations" are intended sensations of burning or
 heating, stinging, tingling, discomfort and tightness. These sensations 
 may be combined with redness. 
 All of these ophthalmic indications may, moreover, be combined with rosacea
 and possibly with conjunctivitis. 
 Among the factors triggering ophthalmic or palpebral pruriginous or 
 dysaesthesic afflictions, exemplary thereof are rapid temperature 
 variations, heat and in particular exposure to ultraviolet or infrared 
 radiation, low relative humidity, exposure to violent winds or to currents
 of air (blowing machine, conditioned air), the application of surfactants,
 exposure to toxic or irritant vapors (solvents) or to dusts, irritant 
 ophthalmological drops or topical products, irritant dermatological or 
 cosmetic palpebral topical products (alpha-hydroxy acids, retinoids) or 
 the use of certain cosmetics, even when these are not known to be 
 particularly irritating. 
 Other factors triggering ocular or palpebral pruriginous or dysaesthesic 
 afflictions which should also be included are allergens such as, in 
 particular, pollen, animal hairs, acarians and molds. 
 Hitherto, the pathological mechanism of these signs was very poorly 
 understood and ocular and/or palpebral dysaesthesias were treated with 
 corticoids and also local antiseptics as an ophthalmic ointment or as 
 drops. 
 Although corticoids are relatively effective at alleviating the above 
 symptoms, they unfortunately have side effects which are often very 
 severe, such as atrophies. Furthermore, they sensitize towards mycotic or 
 bacterial infections and their kinetics are often slow (several minutes to
 a few hours). Moreover, their chronic use may lead to a 
 pharmacodependency. 
 Thus, serious need continues to exist in this art for a treatment of the 
 aforesaid ocular and palpebral dysaesthesias, pains and pruritus which 
 does not have the above drawbacks/disadvantages. 
 SUMMARY OF THE INVENTION 
 A major object of the present invention is the administration of one or 
 more CGRP antagonists to a mammalian, notably human patient, for treating 
 the disease states indicated above. 
 CGRP is a polypeptide chemical species produced and released by a nerve 
 ending. CGRP is involved, in particular, in respiratory and inflammatory 
 diseases, in allergic diseases and in certain dermatological diseases such
 as eczema and prurigo. 
 It has now unexpectedly been determined that it is possible to treat ocular
 and/or palpebral pruritus and/or ocular and/or palpebral pain and/or 
 ocular and/or palpebral dysaesthesias by preventing the synthesis and/or 
 the release and/or the binding of CGRP. 
 Thus, the present invention features the formulation of at least one CGRP 
 antagonist into a pharmaceutical or dermatological composition for 
 treating ocular and/or palpebral pruritus and/or ocular and/or palpebral 
 pain and/or ocular and/or palpebral dysaesthesias. 
 This invention also features the application of compositions containing one
 or more CGRP antagonists to the eyes or the eyelids to effect a marked 
 reduction or even complete disappearance of the ophthalmic pruritus, 
 dysaesthesic sensations and pain; a preventive and curative, calming and 
 soothing effect on the eyes and eyelids is very rapidly attained, and in 
 any event much more rapidly than with corticoids. In addition, no 
 pharmacodependency results. 
 Too, this invention also features formulating these CGRP antagonists into 
 cosmetic compositions for sensitive eyes and, in particular, lotions for 
 cleansing or removing makeup from the eyes, and into makeup products for 
 sensitive eyes and, especially, eye shadows, mascaras, eye pencils or 
 eyeliners for sensitive eyes. 
 Thus, the present invention features the formulation of at least one CGRP 
 antagonist into a cosmetic composition containing a cosmetically 
 acceptable medium, such composition being intended for sensitive eyes. 
 The present invention accordingly features a regimen for making up or 
 caring for sensitive eyes, comprising topically applying a cosmetic 
 composition containing at least one CGRP antagonist, in a cosmetically 
 acceptable medium, to the eyelids, the eyelashes and/or under the eyes. 
 This invention also features cosmetic, dermatological and/or pharmaceutical
 compositions for sensitive eyes, comprising an effective amount of at 
 least one CGRP antagonist, in a cosmetically, pharmaceutically or 
 dermatologically acceptable medium. 
 DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OF THE
 INVENTION 
 More particularly according to the present invention, the subject 
 compositions comprise a cosmetically, pharmaceutically or dermatologically
 acceptable medium (vehicle, carrier or diluent), namely, a medium which is
 compatible with the skin and the eyes. The compositions containing the 
 CGRP antagonist or antagonists are preferably administered via topical 
 application. They may also be ingested or injected (systemic 
 administration). 
 By "CGRP antagonist" is intended any molecule, whether organic or 
 inorganic, which is capable of effecting inhibition of the receptor 
 binding of CGRP or of effecting an inhibition of the synthesis and/or of 
 the release of CGRP by sensitive nerve fibers. 
 In order for a chemical species to be recognized as a CGRP antagonist, it 
 must in particular satisfy the following characteristic: it must have a 
 CGRP antagonist pharmacological activity, i.e., induce a coherent 
 pharmacological response, in particular in one of the following tests: 
 (a) the antagonist species must reduce the vasodilation induced by 
 capsaicin, and/or 
 (b) the antagonist species must induce an inhibition of the release of CGRP
 by sensitive nerve fibers, and/or 
 (c) the antagonist species must reduce inhibition of the contraction of vas
 deferens smooth muscle induced by CGRP. 
 In addition, the antagonist may have an affinity for the CGRP receptors. 
 Hitherto, a link between CGRP and sensitive eyes had not been established. 
 CGRP 8-37 and anti-CGRP antibodies are suitable CGRP antagonists according 
 to the invention. 
 In the compositions according to the invention, the CGRP antagonist is 
 preferably employed in an amount ranging from 0.000001% to 10% by weight 
 relative to the total weight of the composition, and in particular in an 
 amount ranging from 0.0001% to 5% by weight relative to the total weight 
 of the composition. 
 The CGRP antagonist may advantageously be combined with one or more 
 antagonists of another neuropeptide such as substance P antagonists and/or
 one or more inflammation mediator antagonists such as histamine 
 antagonists, interleukin 1 (IL1) antagonists and Tumor Necrosis Factor 
 alpha (TNF alpha) antagonists. 
 The substance P antagonists are preferably receptor antagonists. 
 The substance P antagonists which are particularly well suited according to
 this invention are those described in published French patent application 
 94/05537, filed May 5, 1994 and assigned to the assignee hereof. Exemplary
 substance P antagonists include sendide and spantide II. 
 By way of example, the substance P antagonists and the inflammation 
 mediator antagonists may be formulated in an amount constituting from 
 0.000001% to 10% of the total weight of the composition and, preferably, 
 from 0.0001% to 5%. 
 Exemplary inflammation mediator antagonists according to the invention 
 include diethylenediamine derivatives such as cinnarizine and cyclizine; 
 aminopropane derivatives (dexchlorpheniramine, triprolidine); 
 phenothiazine derivatives (alimemazine, promethazine); auranofin; 
 lisophyline; A802715; sulfasalazine; cetirizine HCl; loratidine; esbatine;
 setastine HCl. 
 The compositions according to the invention may be formulated into any of 
 the pharmaceutical forms normally employed for topical application; the 
 subject compositions may, in particular, be in the form of aqueous, 
 aqueous/alcoholic or oily solutions, or dispersions of the lotion or serum
 type, emulsions of liquid or semi-liquid consistency of the milk type, 
 obtained by dispersion of a fatty phase in an aqueous phase (O/W) or 
 conversely (W/O), or suspensions or emulsions of runny, semi-solid or 
 solid consistency of the aqueous or anhydrous cream or gel type, 
 microemulsions, microcapsules, microparticles, vesicle dispersions of 
 ionic and/or nonionic type, or compacted or cast powders. These 
 compositions are formulated according to conventional techniques. 
 For a topical application intended for therapeutic use, the subject 
 compositions are advantageously in the form of a gel, a cream or an 
 ointment for treating palpebral dysaesthesias and/or pains and/or pruritus
 and in the form of eye drops or eye washing solutions for treating ocular 
 dysaesthesias and/or pains and/or pruritus. 
 For cosmetic applications, the subject compositions are advantageously 
 formulated as protective or care creams for sensitive eyes, milks or 
 lotions for cleansing or removing makeup from sensitive eyes and as makeup
 products for the eyes, in particular for sensitive eyes, such as eye 
 pencils, mascaras, eyeliners and eye shadows. 
 The injectable compositions may be formulated as an aqueous or oily lotion,
 or in the form of a serum. 
 The compositions for oral administration may be formulated as wafer 
 capsules, gelatin capsules, syrups or tablets. 
 The amounts of the various constituents of the compositions according to 
 the invention are those used conventionally in the fields under 
 consideration. 
 When the compositions of the invention are formulated as an emulsion, the 
 proportion of the fatty phase advantageously ranges from 5% to 80% by 
 weight, and preferably from 5% to 50% by weight, relative to the total 
 weight of the composition. The oils, the emulsifying agents and the 
 coemulsifying agents employed in the compositions in emulsion form are 
 selected from among those used conventionally in the cosmetics and 
 dermatological fields. The emulsifying agent and the coemulsifying agent 
 are advantageously present in the compositions in a proportion ranging 
 from 0.3% to 30% by weight, and preferably from 0.5% to 20% by weight, 
 relative to the total weight of the composition. The emulsion may also 
 contain lipid vesicles. 
 When the composition is an oily gel or solution, the amount of oil may 
 constitute up to more than 90% by weight of the total weight of the 
 composition. 
 In a known manner, the compositions of the invention may also contain 
 additives and adjuvants common in such fields, such as hydrophilic or 
 lipophilic gelling agents, hydrophilic or lipophilic active agents, 
 preservatives, antioxidants, solvents, fragrances, fillers, sunscreens, 
 odor absorbers, pigments and dyestuffs and colorants. The amounts of these
 various additives and adjuvants are those used conventionally in the 
 fields under consideration and range, for example, from 0.01% to 10% of 
 the total weight of the composition. Depending on their particular nature,
 these additives and adjuvants may be introduced into the fatty phase, into
 the aqueous phase and/or into lipid spherules. 
 Exemplary oils which are suitable for the compositions of the invention 
 include mineral oils (liquid petrolatum), plant oils (liquid fraction of 
 karite butter and sunflower oil), animal oils (perhydrosqualene), 
 synthetic oils (purcellin oil), silicone oils (cyclomethicone) and fluoro 
 oils (perfluoropolyethers). Fatty alcohols, fatty acids (stearic acid) or 
 alternatively waxes (paraffin wax, carnauba wax or beeswax) may also be 
 used. 
 Exemplary emulsifying agents according to the invention include glyceryl 
 stearate, polysorbate 60 and the mixture of PEG-6/PEG-32/glycol stearate 
 marketed under the trademark Tefose.RTM. 63 by Gattefosse. 
 Exemplary hydrophilic gelling agents which are suitable include 
 carboxyvinyl polymers (carbomer), acrylic copolymers such as 
 acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such 
 as hydroxypropylcellulose, natural gums and clays, and, as lipophilic 
 gelling agents, representative thereof are the modified clays such as 
 bentones, fatty acid metal salts such as aluminum stearates, hydrophobic 
 silica, polyethylenes and ethylcellulose. 
 Exemplary hydrophilic active agents which may be incorporated include 
 proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, 
 sugars and sugar derivatives, vitamins, starch and plant extracts, in 
 particular Aloe vera extracts. 
 And exemplary lipophilic active agents which are suitable include 
 tocopherol (vitamin E) and derivatives thereof, retinol (vitamin A) and 
 derivatives thereof, essential fatty acids, ceramides and essential oils. 
 It is also intended, inter alia, to combine the CGRP antagonists with other
 active agents, in particular cicatrizing agents (for example vitamin 
 B.sub.12), antiseptics (for example boric acid), antiallergic agents (for 
 example sodium cromoglycate), antiviral agents (for example acyclovir), 
 anaesthetics (for example lidocaine hydrochloride and derivatives thereof)
 and nonsteroidal anti-inflammatory agents (for example indomethacin). 
 In order to further illustrate the present invention and the advantages 
 thereof, the following specific examples are given, it being understood 
 that same are intended only as illustrative and in nowise limitative. 
 In said examples to follow, all parts and percentages are given by weight.

EXAMPLE 1 
 Eye Drops 
 
 CGRP 8-37 0.5% 
 Excipient: qs 100% 
 Sodium chloride 
 Sodium borate 
 Polysorbate 80 
 Boric acid 
 Water 
 EXAMPLE 2 
 Ointment 
 
 Anti-CGRP antibody 1% 
 Excipient: qs 100% 
 Benzalkonium chloride 
 Sodium edetate 
 D-mannitol 
 Carbomer 
 Sodium hydroxide 
 Water 
 EXAMPLE 3 
 Solution 
 
 CGRP 8-37 2% 
 Excipient: 
 Boric acid 5% 
 Sodium chloride 0.3% 
 Phenylmercuric borate 0.5% 
 Water qs 100% 
 EXAMPLE 4 
 Ointment 
 The formulation of this example was identical to that of Example 2, except 
 that it also contained 0.1% of sendide. 
 EXAMPLE 5 
 Eye Drops 
 The formulation of this example was identical to that of Example 2, except 
 that it also contained 0.3% of loratidine. 
 While the invention has been described in terms of various preferred 
 embodiments, the skilled artisan will appreciate that various 
 modifications, substitutions, omissions, and changes may be made without 
 departing from the spirit thereof. Accordingly, it is intended that the 
 scope of the present invention be limited solely by the scope of the 
 following claims, including equivalents thereof.