DE2747279B1 - Resorbable ointment base - Google Patents

Description

The gel-forming associate used according to the invention is according to the following three technical processes produced: 1) Homogeneous acidification The solution of deoxycholate is mixed with a non-acidic substance, which is more suitable

Rate hydrolyzed to acid, e.g. B. acetic anhydride (exactly 1/4 equivalent) at t = O "C. This results in homogeneous spreadable gels; they contain but l / 2 equivalent of sodium acetate, which does not buffer in the critical range (7.3) and therefore does not have a stabilizing effect. With temperature fluctuations it becomes reversible Turbidity until irreversible crystallization was observed by adding phosphate buffer (pH = 7.3) can be eliminated.

2) Solvent exchange equimolar amounts of deoxycholate and Deoxycholic acid are used in a mixed solvent of suitable dielectric constant dissolved (e.g.

Ethanol - water 1 1 (v / v, l followed by the less polar solvent component is distilled off. (Note: If the ethanol content is 20% or more, it also forms No more gel after cooling.) Gels prepared in this way do not contain excess salt, however, like the above, require a small stabilizing buffer addition.

3) Association of DCA with deoxycholate in the water As the binding energy of the gel only appears stronger than the lattice energy in DCS crystals, this method is practically useful with the addition of a suitable one Buffer, the pH of which is 7.3 in the equilibrium state (e.g. Na2HPO4: NaH2PO4 = 3 : 1), but is higher at the beginning. So 1 mol of DCA can easily be added by adding 2 mol Na2HPO4 are dissolved.

In order to reduce the content of phosphate, it is necessary to use part of Dissolve DCA in lye, with the optimal addition of phosphate Na2HPO4 = 4 (DCS - Na () ll) amounts to. The total amount of phosphate = 0.1 to 0.25 DCS is sufficient to stabilize the gel. However, the dissolution of DCS is so slow that it can be combined with solvent exchange is more advantageous. In this way, stable, reversible gels with low Buffer additives are made; an exemplary embodiment is also given.

The gels with a DCS content of up to 0.05 M (= 2%) are thixotropic, the more concentrated maintain spreadability at 40 "C, melt at 43-48" C. The pharmacologically Active substances can be added in aqueous or alcoholic solution at t = 50 ° C the alcohol content must be kept below 10%, if necessary Driving off the excess alcohol. Because of the possibility of such ointments too Applying open wounds should not be isotonic with body fluids be crossed, be exceeded, be passed.

The highest possible osmotic pressure would result from the disintegration of the gel in (almost insoluble) deoxycholic acid and (totally ionized) deoxycholate. That is in vivo unthinkable because deoxycholate is strongly bound to proteins. Practical Injury irritability tests found that with about one half of this Maximum value is to be calculated. For ointments with little influence on the osmotic pressure Additions, stabilized with phosphate, follow as the maximum DCS concentration: DCA = 0.60-5.5 Na2HPO4, at Na2HPO4 = 0.25 DCS results in DCSm, x = 0.25 M (= 10box on the skin these gels have a cooling effect for a short time.

If the DCS content is up to 4%, the rate of absorption and drying is lower comparable; the skin soon appears untouched. Wash off with alcohol and determination from DCS (fluorescence in sulfuric acid) showed that after 15 minutes only <20% of the applied DCS can be eluted. If the DCS content is high, some of the will dry out Gels in the form of a well-adhering film with a half-life of about I. Hour is absorbed. In this way, a depot effect can be achieved can optionally be interrupted by washing off. No erythema appears or pruritus neither in the lobular test, nor when the application is repeated several times a day on the same area of skin, carried out for 3 weeks. The gel also becomes inflamed Skin tolerate excellently and seems to have some healing processes (e.g. with herpes simplex) to accelerate.

The lack of irritation undoubtedly depends on the rate of absorption together. At the most anticipated use of 1 ml of 10% own gel In this way, no more than 0.1 g of DCS entered the body per day. That corresponds to the accepted daily intake of DCS in food and only marginally increases the physiological total DCS level (mean Ig).

The following embodiment describes an economical manufacturing method the ointment base according to the invention stabilized with 1 O / b phosphate.

Solution A: deoxycholic acid 50 g ethanol (96%) 250 ml solution B: deoxycholic acid 50 g NaOH 1.00 M (titer!) 112 ml Na2HP04 2 H20 11.1 g water to 250 ml after warming Both (clear) solutions are mixed at approx. 70 ° C (B in A); the mixture remains clear when all substances are pure. Then 750 ml of water (70 ° C) is added, where effective additives can already be dissolved, possibly about 1% of a sugar-like substance (Sorbitol, etc.) to increase the elasticity of the film. Afterwards becomes alcohol distilled off. When it cools down, the Tyndall effect indicates the start of polymerization at; on further standing at room temperature, the gel forms in 30 minutes.

Claims (1)

Claim: Resorbable ointment bases on an aqueous basis for pharmaceutical and cosmetic preparations, characterized in that they are a Contains gel-forming associate of deoxycholate and deoxycholic acid. The invention relates to the preparation and use of gelling agents Self-associations of deoxycholate and deoxycholic acid as ointment bases for pharmaceutical and cosmetic purposes. So far are used to manufacture for percutaneous drug absorption synthetic or natural polymers applied to certain gels. The subunits these macromolecules are covalently bound, so that depolymerization (as the first Condition of resorption) is impossible under physiological conditions The film remaining on the skin can reduce the utilization of the active ingredients and appear unaesthetic. The invention is based on the object of these disadvantages by a To eliminate the ointment base that deals with the penetration of the active ingredients is absorbed at a comparable rate, is physiological, and possibly one Resorption-promoting solubilization capacity has met these requirements the gel, which under exactly defined conditions by reversible association of Deoxycholate and deoxycholic acid molecules (to form complexes with new properties) arises. The invention therefore relates to absorbable aqueous ointment bases Basis for pharmaceutical and cosmetic preparations, which are characterized are that they contain a gel-forming associate of deoxycholate and deoxycholic acid. Deoxycholic acid (DCS) is formed by intestinal flora from which cholic acid is subject like other bile acids in the enterohepatic cycle, but happens biologically Compartments with a much higher effectiveness and reaches the skin surface (L J. Schön fell d et al Nature 213 [1967l 93), It forms inclusion compounds in vitro ("Choleic acids"), which are also used pharmacologically for the purpose of facilitating enteral drug absorption It binds strongly to serum proteins in body fluids (D. R u d ma n et al J. clin. Inv. 36 [1957l 538l so that release of included Substances generally to be expected. Oral application of DCA for gastroenterological purposes is known usually 0.3-0.6 g / day, in obesity up to 1.2 g / day. Used as a food additive 1.25 mglkg day (i.e. about 0.1 g / day) accepted (Toxicological Evaluation of Food Additives, p. 217 f, WHO Ed. 1974), which roughly corresponds to the daily production in humans Parenterally administered DCA is rapidly absorbed, conjugated, and in the liver stored in this form in the gallbladder. One upon acidification of deoxycholate solution Establishing gelification was observed (H. Sobo tka et al J. Colloid Sci. 13 [19581, 188; A. Rich and D.M. B I o w, Nature 182 [19581 423 and 1. Amer. chem. Soc. 82 [1960l 3566> It is undoubtedly related to the sudden Increase in the number of agglomerations when the pH value is reduced to 7.3 (Bile Acids, Vol. L, p. 321; Nair and Kritchewsky Eds Plenum Press, New York 1971). As binding forces (undefined) hydrogen bonds and hydrophobic association are suspected, but without so the absence of this phenomenon with other bile acids (which are only normal micelles to be able to explain. The possibility of a technical resp. pharmaceutical Working through and using this unique property of DCA was never considered drawn. The key to explaining this uniqueness is your own determination that DCS at pH = 7.3 forms complexes with the substances that form a proton donor-proton acceptor pair at a distance of 4.4 Å. This can be explained by the H-bonding of DCS to dimers, which have a complementary position of the two 12a-OH groups. In absence from Complexing agents, 2 dimers come together to form a tetramer, which is the elementary unit of the gel is to be understood (Fig. 1: Representation of a molecular model; for clarity all methyl groups perpendicular to the plane of the paper are omitted), the stabilizing Force is a kind of mesomerism of the two hydrogen-bond chains between COOH and COO-, due to the possibility of internal proton shifting to form symmetrical structures. It becomes understandable that every splitting off of H + leads to decay; therefore the ratio of deoxycholate: deoxycholic acid = 1: 1 is critical. To that Compliance helps adding a high capacity buffer and pH equal to the pKa of the tetramer, i. e. 7.3 (more precisely 7.28 + 0.03); of which is in further use made. All hydrophilic OH groups (on A 3, A 12, B3, B 12.) Are within of the tetramers are hidden, so that a hydrophobic "polymerisation" leading to gelification is possible. This makes it understandable that cholic acid (due to the non-concealable hydrophilic 7a-OH group) and chenodeoxycholic acid (like cholic acid, plus absence of 12a-OH group) as well as conjugated bile acids (first and foremost as a result of far lower pKa values) do not form such gels. Since the association to macro complexes only through weak hydrophobic Interaction is conditioned, the gel in contact with the too competitive can be hydrophobic Protein substances in the tissue are able to bind back to tetramers, which disintegrate due to their lipophilic surface the well-known penetration ability and selective can mediate bactericidal effects of DCS. The gelification described in the cited publications was brought about by simple acidification (e.g. with hydrochloric acid). The for the properties required here, d. H. Spreadable consistency, homogeneity and stability, are due to this Way unattainable because they critically depend on equivalence. those in the absence The stabilizing buffer often leads to induced crystallization of DCA to total disintegration. In addition, the gel contained 1/2 equivalent of a salt (e.g. According to), which increase the osmotic pressure and useless when applied to the skin would leave a crystalline coating.