A COMPOSITION FOR THE EXTEMPORARY PREPARATION OF FORMULATIONS FOR TOPICAL APPLICATIONS FOR PHARMACEUTICAL AND COSMETIC USE

Abstract: A composition for the extemporary preparation of gels and creams for topical application and for pharmaceutical and cosme­ tic use comprises, besides one or more ingredients active under the pharmacological and/or cosmetic point of view, a gum swellable in water and a permeation agent.

Description: The present invention relates to a composition for the extemporary preparation of formulations for topical application, particularly gels and creams, for pharmaceutical and cosmetic use. The most widespread pharmaceutical and cosmetic forms for topical cutaneous application comprise: - Creams or milks These are emulsions of oil in water or water in oil containing emulsifiers of several types, fats, oils, waxes and water in different proportions. - Ointments and fatty sticks They consist prevailingly of oils, waxes and fats with or without emulsifiers, characterized by a very reduced content or by the total absence of water. - Gels These are usually transparent forms, the consistency of which varies from the gelatinous to a very fluid state, prevailingly consisting of vegetal polysaccharides such as arabic gum, tragacanth gum, carrageenin or alginic acids, or synthetic polymers such as carboxyvinyl polymer (carbopol) variously salified and cellulose derivatives. All these polymers form gels with water, the consistency of which is proportional to the concentration and which are variously spreadable, acceptable for the skin and of pleasant feeling. - Lotions These usually consist of a fluid solvent (water or water-alcohol mixtures and water-glycerin mixtures) which, owing to their fluidity, are generally applied onto the skin by means of a napkin or cotton flock. - Dusting powders and talcs These are based on talc, kaolin, silica, lactose, mannitol, waxes and micronized fats, which upon being applied onto the skin form a thin film of protecting powder. All these very common pharmaceutical and cosmetic forms show some drawbacks, which in some cases render their use difficult or even practically not possible. The emulsions of oil in water and of water in oil (creams and milks) are bases unsuitable as vehicles for substances not stable in the presence of water, such as antibiotics, enzymes or anyhow active principles readily degradable in solution. They are moreover of difficult storage and physically poorly stable. The presence of emulsifiers sometimes makes it not certain the skin compatibility, mainly for continuous and extended uses. It is also worth to note that in the emulsions the development of bacteria and mycetes takes readily place and the preservants which can be used are not always sufficient in order to inhibit any microbial growth. The use of ointments (without water) might partially solve these problems, but these fatty bases are of unpleasant application, and cause the garments to be smeared and soiled; moreover the fatty layer applied to the skin may constitute a barrier, both for the normal skin transpiration and for the absorption of the active principales, the latter being included in a vehicle of difficult permeation. Gels and lotions comprising water are affected by the same problems of stability of the substances degradable into contact with water and although exhibiting, mainly as regards gels, undeniable advantages over the emulsions from the point of view of both the physical stability and of ready and pleasant use, still show problems of degradation induced by microorganisms, even if in a reduced degree. The dusting powders, which do not contain water, are undoubtedly the most adequate vehicle for the active compounds raising problems of chemical stability and also possess the undeniable adavantage of not permitting, during the storage, any microbial growth. However their application is precarious and hardly quantitatively determinable; moreover it is easily foreseable that the active substances, dispersed in solid state in the powder, shall not come into intimate contact with the skin and thus their activity is not exploited in a complete, exhaustive and above all constant manner as it occurs when the presence of a solvent leads not only to a more intimate contact with the skin but also to a better surface dispersion. As it can be noticed, none of the usual preparations for topical use is fully free from drawbacks, whereby it is necessary from time to time to choose that formulation seemingly most convenient for the requirements of stability, storage, functionality and practicalness related to the nature of the substances being used and, obviously, to the end purpose of the formulation. In order to obviate to the above mentioned drawbacks it would be necessary to be able to prepare extemporary pre-dosed creams or gels in which the solvent (water) can be added a few instants before the use on the skin or the mucosae. The attempts to date made for the preparation of these extemporary formulations for topical use did not lead to practical results since the time needed for the absorption of the solvent were very great so that the product was practically useless for the intended use. Furthermore the gums usually used form with water unpleasant lumps the dissolution of which is very difficult. In the DE-PS 862.044 a process is described for the manufacturing of powder formulations to be used for the extemporary preparation of a base for ointments or directly of the ointment. The composition of said powder is as follows: carboxymethylcellulose 30-45% clay swellable in water (bentonite of Fuller's earth) 30-45% wetting agnet (aliphatic or aromatic sulfonic acids) 3-6% buffer agent, to adjust pH in the range 6-6.5, from 0.4 to 0.8% bacteriostatic agent 3-7% diluent (preferably lactose or similar carbohydrates) 8% at maximum active compound 1-25%. In the examples of the preparation of the extemporary cream the stirring of the initial water suspension is carried out to promote the dissolution. Said operation may have a duration of 30 minutes (ex. 1) or of 0.5 to 1 minute (ex. 2). In turn French Patent No. 2.311.530 discloses a powder or granule composition for the extemporary preparation of ointments. The composition is characterized in that it contains a carboxyvinyl-polymer, having molecular weight of between 860,000 and 1,000,000, insoluble but swellable in water, in a concentration of 1 to 10% by weight. The other components for the formulation are the following: alkalinizing agents (e.g. ammonium or potassium carbonate) 2-5% emulsifier of the type oil in water (e.g. sodium stearate or sodium dioctylsulfosuccinate, preferably sodium laurylsulfate) 0.5-2% fatty substances (e.g. liquid paraffin, triglycerides, decyl ester of oleic acid, cetyl alcohol, isopropyl myristate) 1-30%. To the said composition other thickening agents can be added such as starch, cellulose and colloidal silica, in an amount of 10 to 90%. The ointment is readily prepared by admixing one part of granules or powder having the above composition with 8 parts of waterr and mixing for a time of 1 to 2 minutes. The French Patent 2,068,447 relates to compositions permitting an aqueous preparation for dermatological or cosmetic use to be obtained as well as to their preparation method. Said compositions are in form of a lyophilizate directly obtained from an emulsion of the oil in water type essentially containing: one or more active principles for dermatological or cosmetic use; a lipidic phase containing fatty acids and their derivatives, fatty alcohols and their derivatives, natural and synthetic fats; a hydrophilic phase consisting of a thickening agent and of an emulsifier in water. As thickeners natural gums, cellulose derivatives, pectines, bentonite and colloidal silica, polysaccharides, synthetic macromolecules ans starches can be used. As emulsifiers use can be made of anionic, cationic, non ionic surface active compounds, or salts of organic acids or fatty alcohols oxyethylene derivatives. In the specification of this patent it is stated that the granules as such most not be put directly into contact with the water, since they tend to soften thus hindering the dissolution process. In order to eliminate this drawback these granules are wrapped up in a bag of wide weft cloth, so as to permit the free passage of the water as well as of the emulsion, once it is reconstituted. Said bags are in turn enclosed in paper or aluminium bags, possibly combined with plastic material. In the French Patent No. 2,101,044 a like composition is disclosed but particularly directed to shampooing, hair lotion and tooth paste formulations. A modification is described of the preparation of the dry residue to be later dissolved in water to reconstitute the emulsion. In this case the solution, before the lyophilization, is absorbed in a polyurethane foam "sponge". In this case the emulsion reconstitution takes place by simple immersion of the sponge in water; however the residue part contained in the innermost part of the sponge shall start to dissolve only when that of the outermost parts of the sponge are already dissolved. USP 2,484, 637 relates to a base for the extemporary preparation of ointments, in form of an anhydrous powder comprising methylcellulose and sorbitol in the proportion of 10 to 40 parts of sorbitol for 100 parts of methylcellulose. The powder dissolution in water takes about one minute. Such a preparation does not swell, since methylcellulose is a water soluble polymer. USP 4,097,606 (Chavkin) discloses analgesic tablets for oral use containing N-acetyl-p-aminophenol (APAP), carboxymethylstarch and a binder. The binders are conventional additives for tablets (see column 3, lines 43 to 49) and may include for example microcrystalline cellulose which is seemingly the preferred binder (see column 3, line 54 - column 4, line 12). Example 10 of Chavkin uses the combination of APAP, carboxymethylstarch as the sodium salt and microcrystalline cellulose. However if attention is paid to the technical problem which Chavkin openly is loocking to solve, it relates to the oral administration of APAP tablets, since the prior art tablets containing this active principle had relatively slow and variable pharmacological action, seemingly caused by the fact that absorption of APAP at the gastrointestinal tract was inhibited as a consequence of the manufacturing process of these tablets. It has been now suprisingly found and is the subject of the present invention that solid compositions comprising i.e. carboxymethylstarch and acellulose in dry and solid form, as well as a pharmaceutically or cosmetically active ingredient, which is not N-acetyl-p-aminophenol, when put into contact with water is capable of absorbing 5 to 10 times the weight of the compositin to form almost instantaneously gels, and creams and lotions of easy and ready applicability to the skin. Thus the compositions according to the present invention can be suitably dosed in form of tablets having a predetermined water absorption and thus an adjustable viscosity or consistency. Of course the compositions according to the present invention contain one or more active compounds having the desired topical effect. As regards the carboxymethylstarch, the content thereof in the composition of the invention may range from 10 to 50% by weight, whereas as regards the celluloses, as permeating substance, their content in the composition of the invention is of between 1 and 50% by weight. The function of the cellulose is that of absorbing the solvent (water) without being dissolved and permit it to reach in every part of the tablet the gum which is thus almost istantaneously swelled. From the field experiments it was found that: (a) the tablet according to the invention is swelled in water in a maximum time of one minute forming a soft, voluminous gel, which can be easily topically applied; (b) the amount of absorbed water varies from 5 to 10 times the weight of the tablet and gives place to an increase, in about the same ratio, of the gel volume with respect to the initial one of the tablet; (c) the addition of a hydropholic but water insoluble polymer, i.e. the cellulose, permits the almost instantaneous absorption of the water, which otherwise, in the presence of only carboxymethylstarch, would take place much more slowly. With the composition according to the invention it is possible to prepare any pharmaceutical formulation for topical use and any cosmetic and more precisely: gels with active compounds not stable in water solution (e.g. some antibiotics); antiacne, hair detergent, after-shave, skin protecting, anti-cellulitis, anti-transpirant, deodorizing, hair-removing, nutrient and hydrating, skin detergent and intimate hygiene preparations. Among the advantages of the present invention, apart from the stability and from the practicalness of use, the elimination of water is to be mentioned, the latter being usually the prevailing part of the product sold to the customers. Some examples of compositions and formulations according to the invention are given hereinafter, clearly of having exemplifying but non limiting purpose. EXAMPLE 1 - Tablets for extemporary gel containing penicillin Carboxymethylstarch 0.100 g microgranular cellulose 0.100 g penicillin 250,000 U.I. EXAMPLE 2 - Tablets for extemporary vaginal gel with trichomonacidal activity carboxymethylstarch 0.350 g cellulose 0.200 g metronidazole 0.500 g

Claims: 1. A solid composition capable of absorbing water for the extemporaneous preparation of formulations in form of cream, gel or lotion, for the topical application of a pharmaceutically or cosmetically active ingredient, which is not N-acetyl-p-aminophenol, characterized by containing, besides the said active ingredient, only carboxymethyl starch and a cellulose in dry and solid form, the water absorbed at the time the said formulation is prepared being of between 5 and 10 times the weight of the composition. 2. A composition according to claim 1, characterized in that said carboxymethylstarch is contained in an amount of between 10 and 50% by weight. 3. A composition according to claim 1, characterized in that said cellulose is contained in an amount of 1 to 50% by weight.

Inventors: GAZZANI, GIOVANNI
Applicants: CRINOS INDUSTRIA FARMACOBIOLOGICA S.P.A.
Application year: 1987
Main classification: A61K47
IPC codes: A61K47, A61K9, A61K8, A61Q5, A61Q19, A61Q90