| Title of Invention | A TOPICAL PHARMACEUTICAL COMPOSITION. |
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| Abstract | The invention relates to topical pharmaceutical formulations containing ketoprofen or its S(+) isomer dexketoprofen or mixtures of the two isomers, together with two UV filters, preferably octyl methoxy cinnamate and phenyl benzimidazol sulphonic acid, and an antioxidant, preferably butyl hydroxy toluene (BHT). The formulations enable a photostability of the active principle, have no, or very low, irritant effect on the skin, are well tolerated, and present an adequate penetration through the skin. |
| Full Text | A TOPICAL PHARMACEUTICAL COMPOSITION Field of the invention Forming the subject of the present Invention are formulations containing ketoprofen or its S(+) isomer or mixtures of the two isomers, a combination of two UV filters, and an antioxidant The formulations have very low allergenic and photo-irrfant characteristics in regard to the skin, even folowing upon exposure to sunlight are well tolerated, and present an excellent penetration of the active principle through the skin. State of the art Topical pharmaceutical formulations containing non-steroida) anti-inflammatory agents (NSAlDs), In particular ketoprofen and dexketoprofen, are described in the majority of the relevant scientific literature as Irritant, alergenic, phototoxic, and photo-allergenic (Coz, hnstophe J. et al. Contact Dermatitis, 38(5), 245ff (1989), Bosca, F., J. Photochem. Photoblol., 43(3), 1ff (1998)). Numerous studies have been conducted in the past on the photochemical stabilization of formulations containing NSAIDs. An attempt has In fact been made to Include NSAIDs, in particular ketoprofen or dexketoprofen in ointments, creams, or gets in such a way as to obtain both physically and chemically stable formulations. The works of Coz, J. Christophe and F. Bosca were able to demonstrate that some parts of the structure of NSAIDs are inert, whilst others are photosensitive. In the case of ketoprofen, it is the part of the benzophenone that was found to be Implicated to photodegradation, whilst the residue of proplonic acid was found to be practically insensitive to Interaction with fight The specific photo-sensitivity of the dphenyl ketone group is due to Its properly of initiating the process of oxidation, thanks to the particular stablization of the activated triplet states. in Photochem. Photobiol, 50(3), 359 (1989), it was seen that four Impurities are originated from ketoprofen in aerobic conditions, namely (3-benzoylphenyl)ethane, (3- benzoylphenyl)ethyl hydroperoxide, (3-bsnzoylphenyl)ethanoi and (3- benzeylpheny1)ethanone, whilst in anaerobic coditions only 3-benzoylphenylethane is formed. The document WO9520387 highlighted the tmportance of choosing the appropriate moment for application of active substances; in the case of photosensitive substances, those should be applied only at night. The document JP60155111 describes pharmaceutical formulations for external use, which contain ketoprofen together with a UV filtar, chosen in the group of derivatives of para-aminobenzaic acid (PABA), anthranilic acid, benzophenone, cinnamic acid, coumarin, salicylic acid, or amino adds and, if necessary, an antioxidant Upon more careful analysis, the derivatives of benzophenone appear to be the preferred UV filers, and In particular benzophenone-3, at a concentration of 1 % by weight, with the possible addition of tocopherol as antioxidant, seems to be the only satisfactory one in preserving ketoprofen from photodegradation. Consequently, as may be noted, In no case is a combination of two UV filters suggested for the formulations described. In the document FR2804024, the inventors describe topical pharmaceutical forms containing NSAIDs, In particular ketoprofen, protected against photodegradaBon by means of solar filters chosen in the group: derivatives of cinnamic acid, of dibenzoylmethane, of benzophenone, of para-aminobenzoic acid, with the possible presence of an antioxidant chosen from among: butyl hydroxy anisole. tert-butyl-para- cresol, palmityl ascorbate, or tocopherol. The solutions proposed in the examples described in FR2804024 have not, however, proven completely satisfactory, in particular in the case of ketoprofen. In fact • Examples 1 to 8 describe formulations containing ethoxylated esters of para- aminobenzote acid (UV filter) and tart-butyl hydroxyanisole (antioxidant), but it has been possible to note that the decomposition of ketoprofen was still present after irradiation (up to 60% by weighy of the initial amount, see Table 1); moreover, the there were in any case present problems of phototoxicity of the formulations and the permeability through human skin was considerably reduced if compared to known formulations containing ketoprfen without UN filters (such as, Katum); • in Example 10, the use of octyl methoxy dynamate, together with butyl hydroxy anisole, does not prevent photodegradaBon of tenoxicam, and problems can be expected regarding the permeabiility through the skin caused by the large amount of surfactant used; - a formulation similar to that of Example 11 with suLisobenzone and butyl hydroxy anisote, but using ketoprofen instead of dIclofenac has proved to bo phototoxic and has shown a reduced permeability through the skin. Consequently, pharmaceutical formulations containing ketoprofen prepared on the basis of whatjs described In JP60155111 and FR280424 are not completely satisfactory. In general, they have proven phototoxic, and moreover It has been noted that the pharmacological properties are sensibly modified when compared with similar weft-known formulations containing ketoprofen, but without UV filter, such as, for example, Ketum. On the one hand, the. UV fillers described cause a change in the chemico-pnysical characteristics of the formulation (colouring, reduction in viscosity, modification of odour, etc.) and, on the other hand, affect some important pharmacological properties, such as permeabilty through the skin and the presence of photo-allergic reactions. Normally surfactants are used for stabilizing the formulation and for Dissolving the UV filter, but by so doing, permeabilty through the skin is reduced to a fractional value of what is obtained without said UV filter. Furthermore, the potential of photo-alergenicity Increases with the presence of the UV filter. In the case where is the UV filter that has characteristics of surfactant (for example, the ethoxylated derivatives of para-aminobenzoic acid), a considerable reduction in the permeability through the skin has been observed: In conclusion, what has been described in the foregoing Iterature would teach the person skilled in the branch how to increase the photostability of pharmaceutical formulations containing ketoprofen, but not, at least up to now, how to prevent the problems of phototoxlcity, photo-allergenicity, and reduced permeability through the skin, al of which are problems that still await a proper solution. Description of the Invention Surprisingly, t has been found that only formulations containing ketoprofen or Its Isomer S(+) ketoprofen, together with a mixture of two UV filters, in particular a derivative of cinnamic add plus phenyl benzimidazol sulphonic acid, and an antioxidant, present, along with an elimination of photodegradation of the active principle, an excetent prevention of the phototoxic and photo-alergenic characteristics, together with an excelent tolerability and an adequate permeation of human skin. Surprisingly, it has also been noted that, although fitters of the UV-B type have been used, the formulations described also absorb radafion of the UV-A type (absorption extends to values higher than 360 nm); in this way, R becomes possible to protect both the skin and the ketoprofen also from UV-A radiation, thus reducing the risk of secondary photo-allergenic effects. In the case of use, as UV fitters, of derivatives of benzophenone, of anthranilc add, of sallylic acid, of para-eminobenzoic acid, or of amino-acid-based compounds, as described in JP66155111 or In FR2804024, a photoprotection, even though in general only partial, of the active principle (ketoprofen) was observed, but the system proved In any case to be phototoxic and the chemico-physical. properties were significantly modified. Also the addition of an- antioxidant, according to what Is explicity envisaged In JP60155111 and FR2804024, was unable to provide a complete solution to the aforesaid problems. In the case of octyl methoxy dnnamate as UV fitter. the active principle (ketoprofen) proved to be photo-protected, albeit at concentrations of the UV fitter higher than the ones used in the mixture of filiters: however, notwthstanding this, phototoxicity was observed In many cases. Also formulations containing only phenyl benzimidazol sutohornic acid showed a simitar behaviour. Consequently, mixtures of UV liters have been studed. Different UV filters were added to the derivative of cinnamic acid (for example, derivative of PABA, of benzophenone, or of camphor), but the problems of phototoxcity were not eliminated. in practice, on the basis of our findngs, only mixtures of derivatives of dnnamte acid with phenyl benzmidazol sulphonic acid proved satisfactory. Different compositioins containing ketoprofen and a mixture of two UV filters were studted versus the corresponding placebo. In the case of the mixture of octyl methoxy cinnamate and phenyl benzimidazol sulphonic acid as UV filters, the actine principle proved pnotostabte and. In the test for determining the phototoxicity in vitro (neutral- red-uptake test), there was observed a lower phototoxicity potential. The concentrafions of the UV liters in mixture could moreover surprisingly be reduced with respect to the ones necessary when only one of the UV Store was used. It was noted,lntect,that a concentration of 1 % by weight for each of the UV filters -oclyl methoxy cinnamate and phenyl benzimidazol sulphonic acid - was sufficient to guarantee the stability of ketoprofen and the maximum reduction of phototoxicity From the toxicological studies conducted In vivo, it was found, for the formulations forming the subject of the present invention, that: - no skin reactions were attributable to a photo-irrftant effect: - no skin reactions were attributable to photo-ellergenic effects; - cytotoxic or phototoxic effects were observed; and - unike other formulation containing ketoprofen, no photoclastogenic effects were observed (Induction of chromosomal aberrations in Chinese-harnster-ovary cell cultures in the presence of UV light). Furthermore, the problems conceriting the permeabillity of human skin to the active principle In the formulations containing ketoprofen, have been solved. The present invention thus describes pharmaceutical formulations that contain ketoprofen or its isomers in high percentages but have negligible phototoxic or photo- alltergenic effects, high permeabillity through human skin, and excellent preservation of their pharmacological qualities, if compared to other known ketoprofen-based formulations without UV filters. The topical formulations based upon the present Invention are hence characterized as follows: - 2-5 % by weight of ketoprofen as a mixture of the two isomers, or 1-25 % by weight as single S(+) isomer; - 0.5-5% by weight of a derivative cinnamic acid, preferably octyl-para-methoxy cinnamate; - 0.5-5% by weight of phenyl benzimidazol sulphonic acid; - 0.01-0.2% by weight of a antioxidant;and - the residual content, up to 100% by weight, pharmaceutically acceptable excipients. such as adjuvants, vehicles, aromas, stimulants for absorption, etc. The active principle contained In the aforesaid pharmaceutical formulations is chosen from among ketoprofen, as racemic mixture, the isomer S(+) ketoprofen, or mixtures of the two Isomers of ketoprofen. The latter are to be considered both In the form of a free acid and in the form of a pharmaceutically acceptable sal chosen In the group of the sate of sodium, potassium, calcium, magnesium, tromethamine, hydroxyethylamlne, dl(hydroxyethyl)amlne, tri(hydroxyethyl)amine, lysins, arginine, or else in the form of mixtures consisting of a free acid and its salt choeen in the group referred to above. The percentage of active prindpie, calculated as free acid in the form of a mixture of the two isomere, contained In the formulation can range from 2% by weight to 5% by weight, and in particular from 2.5 % by weight to 5 % by weight; particulerly preferred are the rates between 2.5 % by weight and 4% by weight When only the S(+) isomer is considered, the percentage of active principle, calculated as free acid, can range from 1 % by weight to 2.5% by weight, and in particular from 1.25% by weight to 2.5 % by weight; particularly preferred are the ratios of 1.25 % by weight to 2 % by weight The percentage of UV filter is comprised between 0.5 % by weight and 4% by weight, preferably between 1 % by weight and 3 % by weight The derivative of cinnamic acid as UV filter is chosen in the group: dnoxate, diethanolamino-para- methoxy dnnamate, or among the folowing esters of cinnmic acid: methyl ester, ethyl ester, propyt ester, isopropyl ester, butyl ester, isoamyl ester, hexyl ester, heptyl ester, n-octyl ester, 2-ethyt-hexyl ester, possibly substituted on the aromatic ring with one or two groups chosen from among: hydroxy, methyloxy, ethyloxy. ecetylemine; the most preferred one is octy-methoxy cinnamate (2-ethylthexyl-4-methoxy-cinnamate). The percentage of antioxidant is comprised between 0.01 % by weight and 0.2% by weight, preferably between 0.01 % by weight and 0.06 % by weight As preferred antioxidant is a compound chosen In the group: butyl hydroxy toluene (BHT), butyl hydroxy anlsole (BHA), tert-butyl-para-cresol, tocopherol, tocopherol acetate, tocopherol succinate, ascorbic acid, ascorbyl palmitate, and sodium ascorbate; BHT is the most preferred. The formulations according to the present invention may moreover contain, as pharmaceutically acceptable excipients, adjuvants, such as water or monoalcohols of the ethanol type, vitamins, amongst which vitamin A and vitamin E are preferred. colouring agents, pigments with colouring enact, inhibitors of the formation of radicals, and preservatives in general, thickeners, plasticizers, hurrdiffiers, aromas - amongst which lavender oil is preferred -, polyols, electrolytes, gelling agents, polar oils and non-polar oils, polymers, copolymers, emulsifiers, stabilzers for emulsions, agents for Increasing permeabillity through the skin, etc As substances facilitetting absorption through the skin, the following are preferred: urea, pyrrolidone, n-methyi pyrrollione, decyl methyl sulphoxide, and sodium lauryl sulphate. Amongst the substances capable of increasing permeability through the sWn, also iposomes are to be considered as forming part of the present Invention. As excipients, also active substances commonly used in the cosmetics field can be used, chosen from among: vitamins* (amongst which vitamin A and derivatives of vitamin A, vitamin E and derivatives of vitamin E are preferred), vitamin complexes, and coloured or colourless extracts of plants.' Particularly suitable gelling agents are chosen In the group: Carbomers, In particular Carbomer 940 (USP24-NF19; page 2427 (2000)), xanthan gum, carrageenin, acacia gum, guar gum, agar gels, alginates, and methytiydroxy cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, methylhydroxypropyl cellulose, hydroxyethyl cellulose, polyacrylates, polyvinyl alcohol, polyvinylpirrolidone, montmorellonite, etc Amongst the humidiffers urea or panthenol may be considered. As preservatives substances commonly used in pharmacy and cosmetics are preferred, such as esters of hydroxybenzoic avid, or parabens. According to the excipients used, the topical formulations forming the subject of the invention may hence be in the form of creams, lotions, powders, or gels. A topical pharmaceutical formulation obtained according to the present invention, expressed as relative quantities of its various components, may, for example, be indicated as follows: 2.5-4 % by weight ketoprofen as mixture of isomers or 1.25-2 % by weight as only S(+) isomer; 0.5-5% by weight gelling agent; 1-3% by weight 1st UV filter (preferahly a derivative of cinnamic acid) 1-3 % by weight 2nd UV fitter (phenyl benzimidazoyl sulphonic acid); 0-2 % by weight preservative; 0-20 % by weight permeability-enhancers; 0.01-0.06 % by weight BHT; 0-0.1 % by weight sodium EDTA; 0-1 % by weight aromas; 20-90% by weight ethanol, and water(as required to reach 100% by weight). The pharmaceutical formulations forming the subject of the present invention can be obtained by mixing the components thereof according to the methods wed Known to a person skilled in the branch. The pharmaceutical formulations -described can be used in the topical treatment of Inflammatory pathological conditions or of muscolo-skeletal affections, such as, for Instance, myalgias/myosites, and in particular for the topical treatment of pain and Inflammation associated to lesions to soft tissue, sprains and distortions, bruises, tendinitis, and venous Inflammation. In adiction to the antiheumatic effect, the aforesaid preparations show a photo- allergenic effect that is considerably lower or altogether absent, and this seems extremely important since, as asserted by S. Baudot In Therapie, 53,137ff (1998), the irritant allergenic, phototoxic, and photo-allergenic effects of formulations containing NSAIDs lead to hospitalizatio in 10% of the subjects treated. For. the purposes of the present invention, the following specifications must be borne in mind: - by "benzophenones" are meant compounds containing the structure of benzophenone and known by the INCI names from benzophenone-1 to benzophenone-11 (amongst which, for example, benzophenone-3 (2-hydroxy-4- rnethoxy-benzophenone), or benzophenone-4 (2-hydroxy-4-methoxy-benzophenone- 5-sulphonicacId); - by "derivatives of para-eminobenzoic acid" are meant compounds in the group: ethyl, propyl, butyl, isopropyl, and monogryceryl esters of para-aminobenzoic acid, ethyl and amyl esters of para-dimetnylaminobenzoic add, ethyl and amyl esters of oara-diathylaminobenzole acid, and polyethoxyyethy ester of 4- bls(polyethyoxy)-para- aminibenzoic acid: by 'phenyl benztmidazolsulphonic acid ismeant preferably 2-phenyl- benzlmidazole-5- sulphonic acid leknown as eneutzol In USP. Appearing below are some non-Limiting example of topical phannaoautical formulation obtained according to the present invention. All nthe Engradent are Included according to weight perents, unless otherwlsapeofoed Example The Formution was made by mixing the indivouis ingridents according to the tetoprofen knows In the state of the art. Kestoproton 2.5 g. hydroxypropylmethyl celluloss 2.1 g. ethwnol 62.0 g. levender oil 0.1 g. octyl methyl chure,ate 3.1 g. phenyl benzolmidazzol sulphonic acid 1.0 g,, Tromatemol to reach pH 5.4, sodium EDTA 0.003 g, diathyeneglycol- monostamol to reach pH BHT 0.01 g. water as required to reach 100 g. Preparation. The water waa heated to 300C, and hydroxyprapytmathyl outlose was added repldly and under stirringg. The mixture waa kapt under sttiing for 30 min at 300C In order to Imbibe the hydroxypropytinemethyl osloss after which location , lavender oll, octy methyl clannaumalo, phenyl benzimidazzol sulphonic unit the add Trometamol and BHT were added. the mixtuire was atlnes slowly und the temprature dropped below 30oC and clamethyl monomethyl, etgand anp other missing eexcipirmts were adeded .The product were stire yo obtasined a homogenaous dieperaton and cooled under stimeting, homogenzing for 80 min Example 2 Katoprofen 2.5 g. hydroxypropymethyl celllose 2.5 g. ethal 52.0 g. levendore oil 0.1 g, octy methoxy clamelo 1.0 g. phenyl benlmidezol sulphonic acid 1.0 g. Tromstamol to reach pH 5.58, diethylenglyyoo-monomethylether 15.0 g. sodium EDTA 0.003 g. BHT 0.02 g. water asd required to reach 100 g. Preparetion In a way simiter to Example 1 Example 3 S(+) ketoprofen 1.0 g, hydroxypropyylmethyl celluoues 2.0 g. ether 55.0 g. glyco0nine 3.0 lenovender oil 0.11 g. methyl ainnemate 2.0 g phenyl benzlmideazol suphonic acid 1.0g, tromethamlne to reach pH5.4, sodium EDTA 0.003 g. diethyeneglycol-monomethylether 10.0 g. BHT 0.02 g. water as required to reach 100 g. Preparation: In a way similar to Example 1. Examole 4 Ketoprofen 2.5 g hydroxypropylmethytceluiose 2.0 g, ethanol 64.14 g, lavender oil 0.2 g, octyl methoxy cimenmate 1.0 g, phenyl benzlmidazol sutohonie acid 1.0 g, Trometamol to reach pH 5.4, sodium EDTA 0.003 g, BHT 0.08 g, water as required to reach 100 g. Preparation: The water was heated to 40oC, and hydroxypropylmethyl celulose was added rapidly:and under stirring. The mixture was kept under stirring for 30 min at 40oC In-order to-lmbibe the hydroxypropylmethyl cellulose. In a second container, ketoprofen and at the other components were Dissolved In ethanol. The aqueous gel was brought to 30oC, and the ethanol solution was added under stirring. The product was stirred until a homogeneous dispersion was obtained, and then cooled under stirring, homogenizing for 60 mln. Example 5 Ketoprofen 2.5 g,hydroxypropylcellulose 1.0 g, Carbomer 940 (USP) 1.0 g. ethanol 54.5 g, lavender oil 0.2g. octyl methoxy clnnamate 2.0 g, phenyl benzlmidazol sulphonic acid 1.0 g, Trometamol to reach pH 5.4, diethyleneglycol-monomethyletrher 10.0 g, BHT 0.05 g, sodium EDTA 0.003 g, urea 3.0 g, arninomethyl propanol 0.1 g, water as required to reach 100 g. Preparation: The procedure was as for Example 4, with the difference that the mixture of hydroxypropylceluiose and Carbomer was Imbibed in an aqueous solution containing arrinomethyi propanol and urea, whilst al the other components were dissorved in ethanol/diethylene glycol-methyl ether. Exampte 6 Ketoprofen 2.5 g,hydroxypropylcelulose1.0g, nydroxypropylmethyl cellulose 1.0 g, ethanol 44.0 g, 2-prapanol 20.0 g, lavender oil 0.2 g, octyl methoxy drmamate 1.0 g, phenyl benzimldazol sulphonic acid 3.0 g, Trometamol to reach pH5.4. sodium EDTA 0.003 g, BHT 0.05 g, water as required to reach 100 g. Preparation: In a way similar to what is described in Example 5. Example 7 Ketoprofen2.5g, hydroxypropyl cellulose2.0 g , ethanol 88.0 g, lavender on 0.2 g, octyl methoxy cinnamate 1.0a phenyl benzimidazol sulphonic acid 1.0g, Trometamol to reach pH 5.4, BHT 0.05 g, water as required to reach 100 g. Preparation: In a way similar to what is described In Example 1. Example 8 Ketoprofen 2.5g, hydtoxypropyl celulose 2,0g, ethanol 90.2 g, lavender oil 0.2 g, octyl methoxy cinnamate.1.0 g, phenyl benzimidazol sulphonic acid 1.0 g, Trometamol to reach pH 5.4, BHT 0.05 g, pynolidone 3.0 g, water as required to reach 100 g. Preparation: All the components with the exception of hydroxypropylcelulose were added to the. ethanol and were stirred gently. until a clear solution was obtained (30 min). Hydroxypropylceklluse was then, added, and the product was stirred vigorously for 2 hours. Examples for comparison Example A: "PABA only" Ethanol 40 g,ketoprofen, 2.5 g,Carbomer 9401.8 g, BHA 0.05 g, lavender oil 0.1 g, poryethoxyethyiestar of 4-bis(polyethoxy)-para-arnlnobenzoic acid 4.0 g, triethanolamine to reach pH 6, water as required to reach 100 g. Examole B:-"OMC only Ethanol 40 g, ketoprofen, 2.5 g, Carbomer 940 2.0 g, BHA 0.05 g, lavender oil 0.1 g, octyl methoxy dnnamate 3.0 g, glycolethylene monomethylether 15.0 g, Cremophor RH40 10.0 g, Trometamol to reach pH 5, water as required to reach 100 g Photodagradation: after Irradiation with a Schott WG320/15 mm xenon lamp, with 100 klux/h and 75 Wh/m. Table 1 gives the percentage of ketoprofen degraded after irradation for one hour with approximately 10J/cm2 In two preparations of the present invention, as compared to formulations according to the prior art Table 2 glves tha percentage of katoprofan remaning after Insolation In formulation promoted with PABA or mathoxy cinnemmale (OMC) othre slom or In mixture with pheneyl benzlmidazol sulphonic acid (PBISS). PHOTOTOUYCITY: A commerclally avalable sun lotion with a factor of protrction 8, contaning a UR fitrr of an Inoganic type (TIOg/ZnO) was spplied on the sikh of the back of two group of 10 haalhy human subjects. The formulation descrised In Example 1 was applied to thye firdt yo the group of 10 subjects (group 1), who had alre3ady been treated with 2 mg/cm of sun oream, on their backs (skin type). Applad on the skin of the secound group of 10 subjects (group 11), skin type II) was a formulation woith all the Ingredients of Example 1 expected for octyl methoxy chnnamats. The subject underwent Irradition with a Schott WG32OV-5 mm xanon lamp, with 100 khx/h and 75 Wh/m In 5 doesse, and were examined after 24 h No reddening of the skin was observed after 24 h In group E in group II, the skin of 3 subjects was not reddened, whilst 4 subjects showed a sight reddening, and 3 subjects presented medium reddening of the skin. Different formulation containing ketoprofen, a UV fitter, and possibly an agent for enhancing the permeablly through the skin were compared with the respective placebos, and in all cases the phototoxicity was examined In vitro (neutral-red-uptake test). The test was conducted according to the standard procedure COLIPA. In the -tests conducted, the placebos in no case proved phototoxlo. Using the formulaSons containing the active principle, an antioxidant and, as UV filter, octyl methoxy cinnamate, and phenyt benzoimidazol sulphonlc acid, no phototoxic effects were observed. In the case of use of other UV filters (such as benzophenone- . 3, benzophenone-4, derivatives of salicyc acid), the formulafions were in all cases phototoxic even when the active principle was kept quite stable during irradiation. In Table 3, the results obtained with two formulations described In the examples are compared with the results obtained with formulations prepared as described in FR28O4024 and JP80155111. From these results it is possible to deduce that formulations with ketoprofen/cinnemate-phenyl benzlmicladazol sulphonic acid/BHT do not lead to photo- allengenic reactions. Permeability: Table 4 shows the results on the permeabilty through human skin of various formulafiona, alt performed In comparison with simitar formutattons without the UV filter and the antioxidant We Claim : 1) A topical pharmaceutical composition comprising: a) a non-steroidal anti-inflammatory agent chosen from among: ketoprofen, as racemic mixture, the isomer S(+) ketoprofen, or mixtures of the two isomers of ketoprofen; these are to be considered both in the form of free acid and in the form of a pharmaceutically acceptable salt chosen in the group of the salts of sodium, potassium, calcium, magnesium, tromethamine, hydroxyethylamine, di(hydroxyethyl)amine, tri(hydroxyethyl)amine, lysine, arginine or else in the form of mixtures consisting of a free acid and its salt, chosen in the group referred to above; b) a derivative of cinnamic acid, as UV filter, chosen in the group: a) cinoxate, diethanolamino-para-methoxy cinnamate b) ester of cinnamic acid chosen in the group: methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, amyl ester, isoamyl ester, hexyl ester, heptyl ester, n-octyl ester, and 2-ethyl-hexyl ester, optionally substituted on the phenyl moiety of the cinnamic acid with one or two groups chosen from among: hydroxy, methoxy, ethoxy, acetylamine; c) 2-phenyl benzimidazol-5-sulphonic acid as additional UV filter; d) an antioxidant, chosen in the group: butyl hydroxy toluene (BHT), butyl hydroxy anisole (BHA), tert-butyl-para-cresol, tocopherol, tocopheryl acetate, tocopheryl succinate, ascorbic acid, sodium ascorbate, and ascorbyl palmitate; together with pharmaceutically acceptable excipients. 2) The topical pharmaceutical composition as claimed in Claim 1, in which the derivative of cinnamic acid as UV filter is the 2-ethyl-hexyl ester of 4-methoxy cinnamic acid (octyl methoxy cinnamate). 3) The topical pharmaceutical composition as claimed in Claims 1 and 2, in which the concentration of ketoprofen, calculated as free acid, ranges from 2 % by weight to 5 % by weight when it is the racemic form or the mixture of isomers, and from 1 % by weight to 2.5 % by weight when it is the S(+) isomer. 4) The topical pharmaceutical composition as claimed in Claim 3, in which the concentration of ketoprofen, calculated as free acid, ranges from 2.5 % by weight to 5 % by weight when it is the racemic form, or from 1.25 % by weight to 2.5 % by weight when it is the S(+) isomer. 5) The topical pharmaceutical composition as claimed in Claim 4, in which the concentration of ketoprofen, calculated as free acid, ranges from 2.5 % by weight to 4 % by weight when it is the racemic form, or from 1.25 % by weight to 2 % by weight when it is the S(+) isomer. 6) The topical pharmaceutical composition as claimed in Claim 2, in which the concentration of octyl methoxy cinnamate UV filter ranges from 0.5 % by weight to 5 % by weight. 7) The topical pharmaceutical composition as claimed in Claim 6, in which the concentration of the octyl methoxy cinnamate UV filter ranges from 1 % by weight to 3 % by weight. 8) The topical pharmaceutical composition as claimed in Claim 1, in which the concentration of the 2-phenyl-benzimidazol-5-sulphonic acid UV filter ranges from 0.5 % by weight to 5 % by weight. 9) The topical pharmaceutical composition as claimed in Claim 8, in which the concentration of the 2-phenyl-benzimidazol-5-sulphonic acid UV filter ranges from 1 % by weight to 3 % by weight. 10) The topical pharmaceutical composition as claimed in Claim 1, in which the oxidant is butyl hydroxy toluene (BHT), and its concentration ranges from 0.01 % by weight to 0.2 % by weight. 11) The topical pharmaceutical composition as claimed in Claim 10, in which the concentration of the antioxidant BHT ranges from 0.01 % by weight to 0.06 % by weight. 12) The topical pharmaceutical composition as claimed in any one of Claims 1 to 11, in which the agent for enhancing permeability through the skin possibly used is a substance chosen in the group: urea, pyrrolidone, N-methyl pyrrolidine, decylmethyl sulphoxide, sodium lauryl sulphate, and dimethyl sulphoxide. 13) The topical pharmaceutical composition as claimed in any one of Claims 1 to 12, in which lavender oil is used as aroma. 14) The topical pharmaceutical compositions as claimed in any one of Claims 1 to 13, in the form of creams, gels, lotions, sprays or powders, in which the non- steroidal anti-inflammatory agent is protected from photodegradation, and the composition does not have phototoxic and photo-allergenic residual effects following upon application on the skin. 15) The topical pharmaceutical composition as claimed in Claim 1, which contains: 2.5-4 % by weight ketoprofen as mixture of isomers or 1.25-2 % by weight as S(+) isomer alone; 0.5-5 % by weight gelling agent; 1-3 % by weight 1st UV filter (preferably, a derivative of cinnamic acid); 1-3 % by weight 2nd UV filter (phenyl benzimidazoyl sulphonic acid); 0-2 % by weight preservative; 0- 20 % by weight permeability-enhancing agent; 0.01-0.06 % by weight BHT; 0- 0.1 % by weight sodium EDTA; 0-1 % by weight aromas; 20-90 % by weight ethanol; water as required to reach 100 % by weight. 16) The topical pharmaceutical composition as claimed in Claim 1 useful for the topical treatment of pain and of inflammation associated to lesions to soft tissue, sprains and distortions, bruises, tendinitis, and venous inflammation. The invention relates to topical pharmaceutical formulations containing ketoprofen or its S(+) isomer dexketoprofen or mixtures of the two isomers, together with two UV filters, preferably octyl methoxy cinnamate and phenyl benzimidazol sulphonic acid, and an antioxidant, preferably butyl hydroxy toluene (BHT). The formulations enable a photostability of the active principle, have no, or very low, irritant effect on the skin, are well tolerated, and present an adequate penetration through the skin. |
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| Patent Number | 223381 | ||||||||||||||||||
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| Indian Patent Application Number | 02033/KOLNP/2005 | ||||||||||||||||||
| PG Journal Number | 37/2008 | ||||||||||||||||||
| Publication Date | 12-Sep-2008 | ||||||||||||||||||
| Grant Date | 10-Sep-2008 | ||||||||||||||||||
| Date of Filing | 17-Oct-2005 | ||||||||||||||||||
| Name of Patentee | MENARINI RICERCHE S.P.A. | ||||||||||||||||||
| Applicant Address | VIA TITO SPERI, 10, I-00040 POMEZIA | ||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61K 31/192 | ||||||||||||||||||
| PCT International Application Number | PCT/EP2004/050317 | ||||||||||||||||||
| PCT International Filing date | 2004-03-17 | ||||||||||||||||||
PCT Conventions:
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