MX2007014512A - Gelatin-containing topical composition - Google Patents

Abstract

This invention provides a topical pharmaceutical or cosmetic composition comprising a pharmaceutically or cosmetically active agent and a gelling agent, characterized in that said gelling agent comprises a fish gelatin and a polysaccharide.

Description

TOPICAL COMPOSITION CONTAINING GELATINE FIELD OF THE INVENTION This invention relates to topical compositions containing gelatin, for example, to pharmaceutical or cosmetic compositions for application to the skin, and to their preparation and use. Where a pharmaceutical or cosmetic composition is formulated for external topical application, it will also generally contain, in addition to the "active" component, components that will ensure that the composition has appropriate properties for storage, application and retention on the surface of the skin. . In this regard, many such compositions currently contain mammalian gelatin, for example, as a gelling agent. BACKGROUND OF THE INVENTION i Gelatin is a derivative of collagen, which is the most abundant protein in animals. Collagen is the main constituent of connective tissue, where it is present as collagen fibers insoluble in water. The general amino acid sequence is Gly-X-Y, where X is often prjoline and Y is often hydroxyproline. The content of the proline and hydroxyproline hydroxyproline will differ from species to species, and the collagen coming from homoi-thermal animals (such as mammals) has a higher content "2 ___? O §188105 high" of these iminoaciodes compared to collagen from poikilothermic animals (such as fish.) Gelatin is most commonly produced from collagen from the bone and skin of cattle or pig by procedures of acid extraction - or alkaline.

These give, respectively, type A and type B gelatin that have different isoelectric points. The collagen molecule is a triple helix to the right hand composed of triple alpha chains. The triple helices, the ordered conformation of collagen, are established by the proline and hydroxyproline units in the alpha chains. The term colágjeno refers to unmodified molecules (ordered confladmación) interconnected by segments of disordered aminojácidos - (random curl). These gels are thermoreversible and the gelling and melting temperatures are influenced by the content of prolix and hydroxyproline. Mammalian gelatins, which contain approximately 24% of these imino acids, have gelation and melting temperatures around 20-25SC and 35-4C, respectively. Cold-water fish species contain only 16-lß%, and fish gelatin is gelif-Lca typically below 8gC and melts at 12-142C. Therefore, gels based on modified fish gelatin are only mechanically stable to those found in Gelatins have been used for decades in pharmacology, food and cosmetics as well as in photography, in glues and in composite materials. An increased search for alternatives to mammalian gelatin has been observed in recent decades, especially due to the outbreak of Bovine Spongiform Encephalopathy (BSE), a fatal neurological disorder of adult cattle, which can also! infecting humans in the form of the new variant of Creutzfeldt-Jacob disease (nvCJD). In addition, the use of mammalian gelatin is limited by religious interests; neither the Muslims (Halal / Haram), Jews (Kosher) nor Hi | ndúes accept the gelatine from mammalian sources. It has now been found that the gelling properties of fish gelatins, which will not suffer from religious problems with respect to their use and that are free from the risk of ncCJB, can be modified to produce compositions suitable for external topical application, for example. example in the skin, by co-formulation with polysaccharide gelling agents. Thus, for example, such co-formulation can produce compositions having formulation characteristics equivalent or superior to those of the compositions in which mammalian gelatin is used. In this way, viewed from one aspect, the invention provides a pharmaceutical or cosmetic composition comprising a pharmaceutical or cosmetically active agent and a gelling agent, characterized in that the gelling agent comprises a fish gelatin and a polysaccharide. SUMMARY OF THE INVENTION The compositions of the invention may typically be in the form of gels, emulsions, creams, lotions, emulsions, dispersions or the like, and will typically contain additional conventional ingredients such as solvents, dyes, flavors, stabilizers, pH modifiers. , viscosity modifiers, penetration enhancers in the skin (eg, DMS0), antioxidants, fillers, etc. These may contain additional components such as encapsulation members, supports and the like, for example, where these are to be applied as patches, for example, for transdermal administration, for example, by iontophoresis. ! The compositions preferably contain a continuous aqueous phase having a gel temperature in the range of 10 to 30 ° C, more preferably 15 to 28 ° C and a melting temperature in the range of 20 to 42 ° C, more preferably 24 to 40 ° C, particularly of 28 a 37 aC.

In the case of the pharmaceutical compositions of the invention, the pharmaceutically active agent can be any medicinal substance capable of exerting a desired therapeutic or prophylactic effect at the site of application or after absorption through the skin, for example, an antibiotic, anti-inflammatory or anti-pruritic effect.

Many, if not most, of the pharmacological substances applied topically in conventional topical compositions (eg, steroids, NSAIDs (eg, ibuprofen), antifungals (eg, keto-onazole), lithium compounds (e.g. , to treat ceborrheic dermatitis or molluscum contagiosum), anti-lacne compounds (eg, azelaic acid), anti-dandruff agents (such as zinc pyrithione), can be used in the composition of the invention. In the case of the cosmetic compositions of the invention, the cosmetically active agent can be any substance capable of exerting a desired cosmetic effect at the site of application or after absorption on the skin, for example, vitamins, vegetable oils, absorbers of UV light, skin moisturizing agents, cleaning agents, dyes, aro aa, etc. Again, many if not most of the cosmetic agents applied topically in conventional topical compositions can be used in the compositions of the invention. Such active agents can be used in similar or compatible concentrations at the concentrations currently used. I The term polysaccharide as it is used in the with a chain to suffer a The polysaccharide gelling agents in the compositions according to the invention may come from a variety of sources, for example terrestrial or marine animals, plants, algae, etc., and may be synthetic polysaccharides or naturally occurring polysaccharides or derivatives thereof. polysaccharides of natural origin. Examples of suitable marine polysaccharides include carrageenans, alginates, agars and chitosans. Examples of polysaccharides derived from alginates, or especially carrageenans. The invention is illustrated below with particular reference to carrageenans. The carrageenan family, which includes iota- and kappa-carrageenans, is a family of linear sulfated polysaccharides produced from red algae.

The disaccharide unit repeated in kappa-carrageenan is β-D-galactose-4-sulfate and 3,6-anhydro-a-galactose, while an iota-carrageenan is β-D-galactose-4-sulfate and 3, 6-anhydro- -D-galactose-2-sulfate. Kappa- and iota-carrageenans are used in food preparations. Carrageenans are used as stabilizers, emulsifiers, gelling agents and fat replacers. These two carrageenans form reversible gels that are hardenable in salt or cold in an aqueous environment. The winding / helix transition and the aggregation of the I helices form the gel network. Kappa-carrageenan has a binding site for specific monovalent cations, resulting in gel formation with decreasing cutting and elastic moduli in the order Cs + > K + > > Na + > Li +. As a rule, an increased salt concentration increases the elastic modulus and the solidification and melting temperatures. of the kappa-carrageenan gel. The use of potassium, rubidium or cesium compounds soluble in water, particularly potassium compounds and particularly compounds of * Natural origin (eg, salts) is preferred when using kappa-carrageenan according to the invention, for example, at concentrations up to 100 mM, more especially up to! 50 mM. A conformational transition dependent on salt is also found for the iota-carrageenan. It is also known that molecules undergo winding-helix transition with strong stabilization of the helix in the presence of multivalent cations, such as Ca2 +. The use of calcium compounds, water-soluble strontium, barium, iron or aluminum, especially calcium compounds, and particularly compounds of natural origin (eg, salts) is preferred when iota-carrageenan is used according to the intion, according to concentrations up to 100 mM. The polysaccharides used according to the invention will typically have average molecular weights in weight from 5 kDa to 2 MDa, preferably 10 kDa to 1 MDa, and more preferably 100 kDa to 900 kDa, particularly 400 to | 800 1J.DA. The polysaccharides will typically be used at concentrations of 0.01 to 5% by weight, preferably 0.1 to 1.5%! in weight, particularly 0.2 to 1% by weight. Where mono or multivalent cations, typically metal ions of group 1 or group 2 are included in the compositions, this will typically be at concentrations in the range of 2.5 to 100 mM, particularly 5 to 50 mM. The fish gelatins used in the composition of the invention can be produced from the collagen of any aquatic species, however, the use of gelatin from saltwater fish and in particular cold water fish is preferred. Fish gelatins having an imino acid content of 5 to 25% by weight are preferred, more especially those having an imino acid content of 10 to 20% by weight. Fish gelatins will typically have a molecular weight by weight in the range of 10 to 250 kDa, preferably 75 to 175 kDa, especially 80 to 150 kDa. Fish gelatin will typically be present in the compositions at a concentration of 1 to 50% by weight, preferably 2 to 15 by weight, particularly 3 to 7% by weight, i Where an anti-aging effect is desired, fish gelatin used may optionally include a low molecular weight compound, for example, having a weight average molecular weight below 10 kDa. The weight ratio of the fish gelatin to the polysaccharide in the compositions of the invention will typically be from 50: 1 to 5: 1, preferably 40: 1 to 9: 1, especially 20: 1 to 10: 1.; The pH of the compositions of the invention is preferably in the range of 3 to 9, more preferably 5 to 7.5! The combination of fish gelatin and polysaccharides is synergistic, resulting in compositions that form stable gels at ambient temperatures (at concentrations in which these individually used components do not) that have properties relevant to topical application.

I are inaccessible using the compounds individually or using conventional mammalian gelatins. As mentioned above, fish gelatin from cold water species has significantly lower solidification (<8aC) and melting (below 14-15SC) temperatures than mammalian gelatins. At room temperature (20-22aC), the fish gelatin molecules are in a random coiling conformation (in a manner contrary to the mammalian gelatin molecules that are in the ordered conformation). Thus, by itself, fish gelatin is unfit to produce a gel composition that has mechanical stability at ambient temperatures. Nonetheless, the presence of the fish gelatin molecules in the conformation of random curl High molecular weight, random-coiled fish gelatin will also be more efficient in retarding and absorbing water when it is present on the surface of the skin as a biopolymer film. The mixing of fish gelatin with polysaccharides is possible to design gelling systems in which fish gelatin is still present as random coiling molecules, but where the system as a whole contributes to the mechanical properties of the product for skin while still trapping water inside a hydrogel. The fusion of such a system can be tailored to specific temperatures, by controlling the mixing ratio of fish gelatin to polysaccharide. This allows a controlled melting of the combined gelatin / polysaccharide gel and the ability to form skin products with high water contents without further addition of artificial surfactants or fats / lipids. | The combination of fish gelatin polysaccharides thus forms an excellent moisture preservation film on the surface of the skin that supports the hydration of the skin. Some of the molecules I random gelatin curl can also penetrate the skin and replace some of the type I collagen degraded in the dermis. When it enters, the penetration of I The molecules are of great importance so that the molecules are present as flexible random coils rather than as rigid and expanded and ordered molecules with collagen and gelatin in the ordered conformation. Mammalian gelatins or collagens will never melt on the surface of the skin (28-32aC) to give the optimum conformation of random coiling, since these temperatures are significantly below the internal body temperature and therefore also below the melting temperature of such gelatins and collagens. ! A further advantage of the compositions of the invention] is that fish gelatin which, in a manner contrary to mammalian gelatin, is in randomly coiled conformation at skin temperatures, can penetrate into the skin to improve the flexibility of the skin either by strengthening the collagen content of the ! skin or by providing an alternative substrate for the skin's own collagen, for the endogenous matrix metalloproteinases that cause the aging of the skin. Viewed from a further aspect, the present invention provides a method of cosmetic treatment of a human subject, comprising applying to the skin thereof a cosmetic composition, characterized in that the composition is a composition according to the invention.

Viewed from a further aspect, the invention provides the use of fish gelatins and a gelling agent of a polysaccharide in the manufacture of a medicament containing a topically administrable drug substance for use in a method of treatment comprising the application of a medicine on the skin of a human subject. Seen from yet another aspect, the invention provides a method of treating a human subject, which comprises applying to the skin of the subject an effective amount of a pharmaceutical composition according to the invention. Seen from another additional aspect, the invention provides a process for the manufacture of a composition according to the invention, which process comprises mixing a fish gelatin, a polysaccharide gelling agent, a pharmaceutically or cosmetically active substance, and optionally and preferably water, the process optionally comprises the emulsification of the mixture. | The uses, methods and processes of the invention can be effected using conventional methods in the production and application of topical cosmetics and products. in particular topical compositions containing mammalian gelatin. The present invention makes possible the manufacture of skin and optimized preparations with a high water content, containing high molecular weight fish gelatin or mixtures of high and low molecular weight fish gelatins, in randomly wound conformation, in admixture with one or several polysaccharides. This is achieved by tailoring the melting temperature of a combined fish gelatin / polysaccharide system to the surface temperature of the skin. By using the invention, for the first time it is possible to control the melting behavior of the skin preparations emulsified by the aqueous phase instead of the lipid phase. The products give excellent layers of moisture-preserving film on the surface of the skin, and in this way support the hydration of the skin. Penetration of the randomly wound gelatin to the lower layers of the skin will improve the skin's flexibility. These emulsified products will be stable as creams at room temperature due to their polysaccharide content. These optimized physical properties are valid in the state of pure aqueous gel as well as systems emulsified in the presence of lipids, fats and oils.

Such products can not be obtained with mammalian gelatins. The following particular advantages can be obtained using the present invention: gels based on fish gelatin can be produced, and emulsions of such gels in the presence of lipids, which are mechanically stable at room temperature; can be produced emulsified skin cream preparations, which are stable at room temperature and have a high water content; j the melting temperatures of such gels can I be specifically designed towards biological surfaces; the rheological behavior and texture of such being optimized with respect to deposition in preparations for cosmetic and pharmaceutical skin can be made from biocompatible polymers that are derived from sustainable sources; the sympathy with the user of the skin preparations can be improved, for example, with respect to the risk of diseases and / or limitations based on religion; J preparations can be produced for skin, based on mepcias of fish collagen and polyscarids, which are biological surfaces; skin preparations can be produced, based on mixtures of fish collagen and polysaccharides, they are optimized with respect to adsorption on the skin and adhesion; and an improved skin moistening effect can be achieved (due to the application of gelatin in the disordered state (random coiling) .The fish gelatins penetrate into the skin and can thus be used to increase skin penetration. For other pharmaceutical or cosmetically active substances, and viewed from a further aspect, the invention provides a topical pharmaceutical or cosmetic composition comprising a pharmaceutical or cosmetically active agent and a skin penetration enhancing agent, characterized in that the enhancing agent of the skin penetration comprises a fish gelatin I. Viewed from a further aspect, the invention provides the use of a fish gelatin for the manufacture of a topical cosmetic or pharmaceutical composition containing a cosmetic or pharmaceutically active agent for the use of a treatment method that includes the application of l medicament on the skin of a human or non-human mammalian subject. The compositions containing a fish gelatin as a skin penetration enhancer will also preferably contain a polysaccharide such that a gelling effect is achieved. However, gelatin itself. Viewed from a further aspect, the invention provides a method of treating a human subject to improve the flexibility of the skin thereof, which method comprises applying to the skin of the subject an effective amount of a sterile composition containing fish gelatin, for example, in the form of a cream, paste, ointment, wax, gel, emulsion, dispersion, suspension, solution or spray. The compositions are desirably applied on the skin of at least one of the face, neck, upper arms, hands, the upper chest, the lower thigh, in particular the face, neck, and upper chest, especially around the eyes ., The fish gelatin used, and any polysaccharides used, in the form of such compositions may be as I described previously. The compositions used according to the invention are preferably provided with instructions for topical application, for example, in container inserts, on the labels of containers or container packages. The compositions are desirably ! sterile and free of fish tissue, and also these I preferably contain at least one pharmaceutical or cosmetic carrier or excipient. BRIEF DESCRIPTION OF THE FIGURES I The compositions of the invention will now be illustrated further with reference to the following non-limiting examples and the accompanying figures, in which: 1 The figures (melting behavior and solidification of the base cream for skin ); Ib (fusion and solidification behavior of the base and water in the ratio 1: 1); le (fusion and solidification behavior of the base and 10% (w / v) of FG in the ratio 1: 1); Id (fusion and solidification behavior of the base ¡n the mixture with 0.75% (w / v) of CG + 15% (w / v) of FG in the ratio 1: 1); and it (melting and solidification behavior of the base and 0.75% of GC + 15% of FG + 20 M KCl mixed in the ratio 1: 1) are temperature graphs (T), elastic module < G '), viscosity (? *) And phase angle (d) against time for five compositions that are heated from 20 to 40 aC and cooled again to 20 aC; Figures 2a (melting of pure cream for skin); 2b (casting a mixture of base and water in the ratio 1: 1); 2c (melting of a base mixture and 10% FG in the ratio of 1: 1); 2d (melting of a mixture of base | and 0.75 of CG + 15 * of FG in the ratio 1: 1); and 2e casting of a base mixture and 0.75 (w / v)% CG + 15 (w / v)!% FG + 20 mM KCl in the ratio 1: 1) are graphs of temperature (T) and elastic modulus (G ') against time for five compositions, as they are heated from 20 to 40 aC; Figures 3a (mechanical response of the cream of I the pure base skin at a shearing stress (cutting tension) increasing. Several replicas), 3c (1: 1 water-based mechanical response with cut-off tension each greater yeast, several replications), 3e (mechanical response in I a mixed subject base: 10% of FG (1: 1) with tension of i cut (increasing several replications), 3g (mechanical response of in mixed base systems: FG / CG / water (1 : 1) with I cutting tension increasing. Several replicas. 2 = 0.5 of i CG + 10% of FG, 14-16 = 0.75% of CG + 15% of FG) and 3i (mechanical response in mixed base systems: FG / CG / KCl 20 mM / water (1: 1) with increasing cutting tension, several replicas) are graphs of the elastic modulus (G ') against the cutting tension and FIGS. 3b (change in phase angle for the pure base with increasing cutting voltage); i 3d (c | ambio in the phase angle for a mixed system of | base: gua (1: 1) with increasing cutting voltage), 3f (change in phase angle for a mixed base system: 10% FG (1: 1) with increasing cutting voltage); 3h (change i in the | phase angle for base systems: FG / CG / water (1: 1) with increasing cutting voltage). No flow at high shear stresses. 2 = 0.5% CG + 10% FG, 14-16 = 0.75% CG + 15% FG) and 3j (change in phase angle for base systems FG / CG / KC1 20 mM / water (1: 1) with increasing cutting voltage No flow at high cut voltages) are phase angle graphs (d) against the cutting voltage for five compositions, each of which is subjected to several voltage times of cut each time m yores (run numbers appear below the graphs); Figure 4a (changes in the phase angle with temperature for a mixed system of 0.5% (w / v) of? -CG and 10% < w / v) of FG, aqueous. Gelation occurs at 27 ° C and melting at 40 ° C), 4b (small tensile oscillatory measurements of 0.5% (w / v) of? -CG). Changes in the phase angle with temperature. Gelification occurs at 13 aC and smelting at 29 aC), 4c (oscillatory measurements of small traction of 10% (w / v) of FG). Changes in the phase angle with temperature. The gelation occurs at 49C and the melting at 13fiC), are graphs of phase angle (d) against temperature for three compositions that are melted and then cooled to form gels; Figure 5a (small tensile oscillatory measurements of 0.5% (w / v) of kappa-CG and 10% (w / v) of FG cooled i to 4aC Extrapolation to G'infinito da G '= 3620 Pa), 5b (results from oscillatory measurements of small traction of 0.5% (w / v) of K-CG cooled to 4BC); 5c (results from oscillatory measurements of small traction of 10% (w / v) of FG cooled to 4SC Extrapolation to G 'infinity of G' = 1100 Pa) are graphs of temperature (T), elastic modulus (G) ') and phase angle (d) for tires that are cooled from 20 to 4 ° C and then heated to 40 ° C; 1 Figure 6 is a graph showing the module of Young for mixed systems of 0.5% (w / v) of? -CG and 10 to 15% (w / v) of FG at room temperature. { average ± S.D., n > 4); 'Figure 7 is a graph of the concentration of I fish gelatin against absorbance at 280 nm; and 1 Figure 8 is a graph of the concentration of fish gelatin against time. The following materials and methods were used throughout the examples. DETAILED DESCRIPTION OF THE INVENTION Carrageenans Kappa-carrageenans (FMC Biopolymer A / S, Drammen, Norway) with an average molecular weight in the range of 4000-8.00 kDa. 1 Iota-carrageenan (FMC Biopolymer A / S, Drammen, I Norueg Ia) with an average molecular weight in the range of 4000 -00 kDa. Fish gelatin Fish gelatin samples (FG) were produced from skins of cold-water fish species (Norlalnd Inc., United States) with an average molecular weight in the range of 90-140 kDa. Model emulsion system 'The model base was the "Bio edica" day cream (BlOlink AS, Sandejord, Norway and Fitzone -KMB GambH, Hamburg, Germany). The lipid and aqueous mixtures were prepared by emulsification with an ultra thurrax. The proportions and percentages are by weight unless otherwise indicated. Example 1: General melting and solidification behavior of the skin cream, emulsified with mixtures (1: 1) of fish gelatin and kappa-carrageenan, with water and with a pure solution of fish gelatin. Figure 1 shows the fusion and the restructuring of the pure cream base for skin, as the temperature is raised from 20 to 40aC and reduced again to 209C.

I The elastic modulus (G '), which reflects the solid properties of the cream, shows a slight dependence on temperature with a slightly monotonous decrease as the temperature is increased, followed by an acute increase; additional, as the temperature is lowered. This histérresis is more likely due to the fusion and re-christening of the lipid components. Component Ib shows the behavior when the base cream is mixed 1: 1 with water. This mixture leads to an inhomogeneous product of a lotion type instead of a cream, thereby exhibiting undesirable behavior. This is due to the suboptimal effect of water in the system, which leads to a lack of stability. A granular consistency due to larger water domains was also observed in this product (suggesting complete phase separation over time). The figure shows the behavior when the base cream is mixed 1: 1 with an aqueous solution of 10% fish gelatin. In this example, the hysteresis behavior of pure cream (see Figure 1) is also observed. G ', however, is very low, implying poor mechanical properties. • Figure Id shows the behavior when the base cream is mixed 1: 1 with an aqueous solution containing 0.75% kappa-carrageenan and 15% fish gelatin. This gel is designed to melt on human skin. A very pronounced effect is observed when the temperature is high, and the hysteresis observed in the Figure is again observed when the temperature is lowered. A mild and sedative product was obtained. The Figure shows you the behavior when the cream! base is mixed 1: 1 with a solution of 0.75% kappa4carrageenan and 15% fish gelatin, and with 20 mM KCl. This mixture is designed to maintain its mechanical structure also on the surface of the skin. A picture now emerges that resembles that of the pure cream base (Figure 1) except for the hysteresis after the cooling of the system. This result suggests that the mechanical properties in this non-melting product are considerably governed more by the polysaride content. Example 2: Initial melting behavior of the base cream for emulsified skin with mixtures (1: 1) of fish gelatin and kappa-carrageenan, with water and with a solution of pure fish gelatin. Contact behavior with the skin Figures 2a-2e correspond to the initial phase of Figures la-le. It is clearly seen that the mμestra designed to melt on human skin (Fig. 2d) is the only sample that shows a pronounced break in the development of -G 'around the skin temperature (30 ° C), indicating that the fish gelatine / carrageenan gel fuses and eases from this mode the distribution of the random winding gelatin on the skin. All other samples show a more or less monotonous decrease in G '! with the decrease in temperature, indicating that the weakening of the cream is due to changes in the jip phase. Example 3: Tension tolerance of the base cream for skin emulsified with mixtures (1: 1) of fish gelatin and kappa-carrageenan, with water and with a pure fish gelatin solution. Stability at 20 ° C | Figures 3a and 3b show the mechanical response (G 'development and phase angle d) of the pure skin cream. It is observed that the cream starts to flow <G 'decreases and d increases) to a tension around 20 Pa. There is also a slight reversibility of the system in the sense that no change is observed in the linear region or at the beginning of the flow when the cream is tested varies. s times Figures 3c and 3b show the same response in a 1: 1 mixture of base and water. It is clearly observed that the system begins to flow at a considerably lower voltage, I and that the voltage necessary to induce the flow becomes smaller with the repeated voltage cycles, suggesting a non-equilibrium system and a sub-optimal product. > . 1 Figures 3e and 3f show the tensile behavior of a 1: 1 base mixture and a 10% aqueous solution of fish gelatin. As in the case of the aqueous mixture, this system also shows a flow at considerably lower voltages and a dependence of the inductor voltage of the flow with respect to the number of deformation cycles. This shows that fish gelatin alone is not enough to give a stable cream for skin. I Figures 3g and 3h show the stress-induced mechanical response of the 1: 1 mixture of skin cream and two aqueous mixtures of fish gelatin and kappa-carrageenan (15% / 0.75% and 10% / 0.50%) . These systems prove to be very different from the addition of pure water and 10% fish gelatin due to the fact that they do not flow until the stresses are comparable to those needed for the pure cream base, and these are also completely reversible systems ( for example, the mechanical response does not depend on the number of deformation cycles). In addition, observing the phase angle, it is shown that these gels do not become liquid dominant at all within the tested voltage regime (phase angle, d, is always less than 45 °). This reflects the importance of the gelled polysaccharide in the stabilization of the cream. Therefore, this 1: 1 mixture with increased water content is a more stable product than the pure cream base at 20 ° C. Figures 3i and 3j show the mechanical response of the 1: 1 mixture of the base and the fish gelatin / kappa-carrageenan mixture with an addition of 20 mM of the K + ion I promoter of the gel. These figures show that it is possible to make the system even more stable by the addition of such ions due to the extra stabilization of the carrageenan network. In this system, the phase angles are still lower than the highest voltage tested, compared to the mixed system that does not flow, without extra potassium ions. Example 4: Gelation and melting temperatures of one I aqueous mixture of fish gelatin and kappa-carrageenan Figure 4a shows the gelation (Tg) and melting (Tm) temperatures of a 0.5% kappa-carrageenan and 10% fish gelatin mixture, while Figures 4b and 4c present the same values for the two simple components (0.5% kappa-carrageenan (Ib) and 10% fish gelatin (le), respectively). These results are presented as a change in the phase angle to small oscillatory measurements (= arctanG "/ G ') reflecting the change from a predominantly solid system to a predominantly liquid one (d = 45 °) and vice versa. The mixture represents a true synergistic system in the sense that neither of the two components alone gives a gel at room temperature, I while the mixed system surprisingly gives gelation (about 27 ° C) and melting (about 40 ° C) temperatures close to those of mammalian gelatin gels. Example 5: Development of gel strength of a mixture of fish gelatin and kappa-carrageenan Figure 5a shows the development in geel strength (given as the dynamic storage module (G ') from oscillatory measurements of small traction ) of a mixture of 0.5% kappa-carrageenan and 10% fish gelatin. The corresponding development of the two components alone (0.5% of kappa-carrageenan and 10% of substantially higher than the G 'values measured for the two components alone. Example 6: Resistance of the mixed gelatin fish / kappa-carrageenan gels at a high concentration of FG I 1 Figure 6 shows the gel strength (given as Young's modulus (E) from the compression analysis) 0.50% kappa-carrageenan mixed with 10 to 15% fish gelatin without any added salt. Example 4 showed that neither of the two components alone gives stable gels at room temperature, but that a mixture of 0.50% kappa-carrageenan and 10% fish gelatin does. Figure 6 shows that this result is also valid for a 15% inclusion of fish gelatin. In fact, there is no significant effect on gel strength in this mixed system ranging from a ratio 1:20 to 1:30 between kappa-carrageenan and fish gelatin, a result that proves the robustness of this mixed system. I Example 7 Fish gelatin with an average molecular weight of 55,000 Da is dissolved in 5% by weight PBS, and 500 μl aggregatized to 8 tissue inserts. The membrane in the tissue inserts is covered with an epidermis model, 17 days old, from SkinEthic, France. 1 ml of PBS is added to the wells in a plate of 24 pofeos. A tissue insert with the peeling gelatin solution is placed inside the 8 wells on the plate I multiple wells. The system is incubated at 30 ° C and an insert is removed every 30 minutes for 3 hours and every hour until 5 hours. The solutions in the wells are collected and the absorbance at 280 nm measured to indicate that the fish gelatin molecules have penetrated the I epidermis models. The absorbance values increased over time indicate that the fish gelatin molecules penetrate the epidermis model after incubation at 30 ° C. Example 8 Fish gelatin with an average molecular weight of 120,000 Da is dissolved in 5% by weight PBS. A low molecular weight fraction of fish gelatin with average molecular weight of 30,000 Daltons is added at a concentration of 2.5% by weight. 500 μl of the fish gelatin solution is added to 8 tissue inserts. The membrane in the tissue inserts is covered with an epidermis model, 17 days old, from SkinEthic, France. 1 1 of PBS is added to the wells on a plate 24 grounds. A tissue insert with the fish gelatin solution is placed within the 8 wells in the multiple well plate. The system is incubated at 30 ° C and a tissue insert is removed every 30 minutes for 3 hours and every hour until 5 hours. The solutions in the wells are collected and the absorbance at 280 nm is measured to indicate that the fish gelatin molecules have penetrated the epidermis models. The absorbance values increased over time indicate that the fish gelatin molecules penetrate the epidermis model after incubation at 30 ° C. Example 9 | Fish gelatin with an average molecular weight of 30,000 Da was dissolved in PBS up to 5% by weight, and 500 μl was added to 16 tissue inserts. The membrane in the tissue inserts was covered with an epidermis model, 20 days old, from SkinEthic, Nice, France (Lot No.: Q6 022A 0304). soft ly and a tissue insert was removed every 20 minutes for 3 hours and every 30 minutes up to 6.5 hours. Solutions in the wells and inserts were collected and the absorbance measured at 280 nm below and above the epidermis model, to indicate that the fish gelatin molecules have penetrated the barrier. Increasing absorbance values over time in the solution below the barrier indicate that the fish gelatin molecules penetrate the epidermis model after incubation at 30 ° C. Figure 7 shows the standard curve for the consistency between fish gelatin (average molecular weight = 30,000 Da) concentration in PBS and A280 values. Table 4 shows the absorbance values at 280 nm and the calculated concentrations of fish gelatin i in PBi5 (700 μl) below the inserts of the i epidermis model. PBS was used as the blank sample. The standard curve showing the consistency between the concentration of fish gelatin and A280 was used to calculate fish gelatin concentrations as a function of time i The data in Table 1 are graphically plotted in Figure 8 as concentration of FG in PBS below the barrier, as a function of time. I The maximum possible concentration of FG in the equilibrium in the system is calculated as approximately 2.08%. This means that 19% of FG has penetrated the epidermal barrier at 6.5 hours. It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (12)

1. CLAIMS Having described the invention as above, the contents of the following claims are claimed as property: 1. A topical or cosmetic pharmaceutical composition comprising a pharmaceutically or cosmetically active agent, and a gelling agent, characterized in that the gelling agent comprises a fish gelatin and a polysaccharide.
2. 2. A topical or cosmetic pharmaceutical composition comprising a pharmaceutical or cosmetically active agent and a skin penetration enhancing agent, characterized in that the skin penetration enhancing agent comprises a fish gelatin.
3. 3. The composition according to claim 1 or 2, characterized in that it contains an aqueous phase! continuous that has a gelation temperature in i the range of 10 to 30 ° C. < 4. The composition according to claim 3, characterized in that the gelation temperature is in the range of from 15 to 28 ° C. 5. The composition according to any preceding claim, characterized in that it contains a continuous aqueous phase having a melting temperature in the range of 20 to 42 ° C. 6. The composition according to claim 5, characterized in that the melting temperature is in the range of 20 to 40 ° C. The composition according to claim 6, characterized in that the melting temperature is in the range of 28 to 37 ° C. 8. The composition according to any preceding claim, characterized in that the fish gelatin has an imino acid content of 5 to 25% by weight. | 9. The composition according to any preceding claim, characterized in that the pendent gelatin has a weight average molecular weight in the range of 10 to 250 kDa. ! 10. The composition according to any preceding claim, characterized in that the fish gelatin is present in the composition at a with any because the 12. The composition in accordance with the I claim 11, characterized in that the charged polysaccharide is a carrageenan. of claims 11 to 17, characterized in that it contains as a cosmetically active agent, a skin moisturizing agent. 20. A method of treating a human subject, characterized in that it comprises applying to the skin of the subject an effective amount of a pharmaceutical composition according to any of claims 1 to 18. 21. A method of cosmetic treatment of a human subject , comprising the application to the skin of the same Ide a cosmetic composition, characterized in that the composition is a composition according to any of claims 1 to 17 and 19. 22. The method of treatment of a human subject in accordance with the claim 21, to improve the skin's flexibility thereof, characterized in that it comprises applying to the skin of the subject an effective amount of a sterile composition containing fish gelatin. 23. The use of a fish gelatin according to any of the preceding claims, for the manufacture of a cosmetic, topical or pharmaceutical composition containing a cosmetically or pharmaceutically active agent for use in a method comprising the application of the drug in human subject or non-human mammal. 24. The use of fish gelatine in accordance with claim 13, and a polysaccharide gelling agent in the manufacture of a medicament containing a topically administrable pharmacological substance for use in the treatment of the drug. a method of treatment, comprising the application of the medicament on the skin of a human subject. 25. The use of a fish gelatin from I according to claim 23, for the manufacture of a topical composition for application to human skin, to improve the flexibility thereof. 26. A process for the manufacture of a composition according to any of claims 1 to 19, characterized in that the process comprises mixing a fish gelatin, a polysaccharide gelling agent, a pharmaceutically or cosmetically active substance, and optionally and preferably water, the process i optionally comprises the emulsification of the mixture J