CS276067B6 - Hydrogel of e-series prostaglandins - Google Patents

Abstract

.Hydrogel proetaglandl series E especially for local using and containing hydroxyalkans and esters of polycarboxylic compounds contains from 1.10 to '2 1.10% by weight of the proetaglandlins of the E-series formula I, where A is a CH 2 CH or CH 3 CH 6 group, R knows n-pentyl-.beta.-chlorophenoxy / methyl- or (3-trifluoromethylphenoxy) methyl group, R 1 is hydrogen or alkyl containing 1 to 4 carbon atoms optionally interrupted by one oxygen atom, 0.3 to 3 wt. baaically reactive components 0.05 to 5% by weight of a gel-forming component based on polymeric materials allylsaccharide and acrylic acid compounds, 0.2 to 5 wt. stabilizing additives bases of acid esters or polycarboxylic esters acids or mixtures thereof, 10 to 60% wt. hydroxy- and polyhydroxyalkane optionally in part in the form of their esters, these substances being % to 100 wt. They are supplemented with ethereal water for injection. Hydro l usually hangs on 0.05 to 0.5 wt. cleaning agents. Hydrogel is useful in the treatment of all types of ulcers, deep exhorations, burns, hematons and other cases when it is necessary to increase the local blood supply to the skin, subcutis and mucous membranes.

Description

The invention relates to a pharmaceutically active stabilized prostaglandin hydrogel of the E series of formula I, wherein A represents a CH ₂ CH _{or CH 2 CH 2} group

R mark! n-pentyl or (3-chlorophenoxy) methyl or (3-trifluoromethylphenoxy) methyl group

R 2 denotes hydrogen or alkyl containing 1 to 4 carbon atoms for topical treatment.

The known biological activity of prostaglandins of the E series includes hypotensive, vasodilatory, bronchodilator, inhibition of gastric juice secretion, inhibition of platelet aggregation, cytoprotective and uterotonic effects, where they have found the greatest clinical use in induction of labor and as abortives (DSBindra, R.Bindra Proetaglandin Synthesis, Academie Press, Inc.New York, 1977 »Advances in Prostaglandin, Thromboxane and Leukotriene Reeearch, Vol. 14: Chemistry of the Proetaglandins and Leukotrienea (Ed. OEPike, DR Morton) Raven Prese, New York 1965; Clinical Practice (Ed. WDWatkins, MB Peterson, 3.R. Fletcher), Raven Press, New York 1989). Their use in sunscreens and emulsions / Eur is also protected in patent documents. Pat. Appl. O 302 147 A1 / and gels for the local treatment of ulcers and various theematomas (DOS DE 37 04 825 A1).

The basic active substance prostaglandin series E of general formula X increases blood circulation to the skin and subcutaneous tissue, and thus tissue nutrition by the following mechanism ·: artificial induction of early phase of acute inflammation results in dilatation of arterioles and procapillary sphincters, long-term vasodilation of arterioles and venules leukocytes and a concomitant increase in blood flow to the bone muscle at the application site / see Karim, S.S.M., and spal. Cardiovasc. Res. 5, 525 (1971), Ouatig, G.3., Et al. Progr. cardiovasc. Dig. 21, 405 (1979); Nielson, P.E., et al .: Scand. 3.din.Lab.Invest. 36, 633 (1976); Ferreira, 5.H., et al .: Prostaglandins 15, 706 (1978). Increased blood flow, which causes increased oxygen supply to the tissue, increased nutrition in the given area, faster flushing of catabolic products has the longer effect of increasing the body's abundance in application.

The disadvantage of the preparations is the instability of the active ingredient and the necessity of preparation always before use. The widespread clinical use of E-series prostaglandins is severely limited by their small standard. At room temperature, ββ changes relatively quickly and thus loses its original activity. The presence of acids or bases significantly accelerates this decomposition. In addition, pharmaceutical preparations containing water or hydrolytic compounds in most cases lose a substantial part of their activity within 24 hours. The good stability of this type of prostaglandins at -20 ° C for both the substance and some solutions is unacceptable from a practical point of view for normal operation. Also, solutions of E-series prostaglandins in anhydrous alcohol can be stored at low temperature in U.S. Pat. No. 3,749,800 /, which also represents a significant obstacle to their widespread use in clinical practice. . .

Several substances that substantially stabilize E-series prostaglandins, such as triethyl citrate / U.S. Pat. No. 4,211,793, hydroxylated fatty acid derivatives (U.S. Pat. No. 4,431,833 /, polyhydroxysilanes (Eur. Pat.Appl. No. 0 249 194 A 2 /, glycerol triacetate /Eur.Pat.Appl. No. 0 183 237 A 2 /, tert-butanol / freons 115 or 114 /Ce.pat. No. 191 244 /, or acetals of aldehydes (Eur. Pat. Appl. No. 0 063 367 Al /. These substances have been shown to improve the stability of E-series prostaglandins in some formulations.

Satisfactory stability of the pharmacologically active substance is ensured by the hydrogel of proetaglandins of the E series according to the invention, which contains 1.10 ⁴ to 1.10 ^-2 % by weight of prostaglandins of the E series of the general formula I.

wherein A represents a CH-CH or CH ₂ CH ₂ group,

R denotes an n-pentyl or (3-chlorophenoxy) methyl or (3-trifluoromethylphenoxy) methyl group,

R 1 denotes hydrogen or alkyl containing 1 to 4 carbon atoms, 0.3 to 3% by weight, basic components, 0.5 to 5% by weight, gel-forming components based on polymeric compounds of allyl sucrose and acrylic acid, for example carbooxymethylene derivative, Carbamer, Carbopol, 0.2 to 5% by weight, stabilizing additives based on ortho acid esters or polycarboxylic acid esters or mixtures thereof, 10 to 80% by weight of hydroxy- and polyhydroxyalkanes for partly in the form of their esters and the remainder up to 100% by weight. It consists of water for injections. The resulting pH of the hydrogel according to the invention has a value of 6.5 to 7.5, preferably 6.9 to 7.1. From the point of view of microbial stability, the gel can be stabilized by adding 0.05 to 0.5% by weight of disinfectants.

In the preparation of the gel, amino alcohols such as triethanolamine, tris / hydroxymethyl) methylamine, bis-1,4- (2-hydroxyethyl) -1,4-piperazine or 1- (2-hydroxyethyl) -1 are preferably used as basic reactants. , 4-piperazine. Orthoesters of acids, in particular o-triethyl acetate, o-tetraethyl carbonate, and also esters of polycarboxylic acids, such as ethyl citrate, ethyl malate, ethyl tartrate and others, have proved to be suitable stabilizing additives. Of the hydroxyalkanes, ethanol, propanol, isopropyl alcohol are important representatives, and of the polyhydroxy compounds, glycerol and its esters with acetic acid (triacetin), butyric acid (tributirine) or propylene glycol have proved particularly useful. For the possible use of substances with disinfectant effects, p-hydroxybenzoic acid esters, namely methyl ester or propyl ester or mixtures thereof, were tested with very good results.

In the production of the hydrogels according to the invention, the gel-forming components are gradually added to a portion of the hydroxyalkanes, polyhydroxyalkanes and water in a homogenizer at room temperature. A solution of the desired amount of the active compound of the formula X, the stabilizing additive or the disinfectant in the hydroxyalkanes is then slowly added to the hydrogel formed. A solution of the residue of the polyhydroxyalkane, the basic reactant and water is then slowly added to this mixture in such an amount that the final pH of the pharmaceutically active hydrogel is 6.5 to 7.5.

Topical application of the hydrogel according to the invention allows the direct entry of the active substance prostaglandin series E into the vascular bed in the area where its action is needed, in concentrations which cannot be achieved by intravenous (i.v.) administration or continuous infusion. The local route of administration circumvents the possibility of inactivating prostaglandin series E in lung tissue, where approximately 90% of the prostaglandin is inactivated after a single pass after intravenous administration, so that only about 10% of the original dose is available after a single pass through the lungs. in total blood volume. In addition, disproportionately high single doses cannot be dosed without a number of side effects such as diarrhea, headache, gastrointestinal problems, vomiting, loss of appetite, hypotension and phlebitis at the application site.

The pharmaceutically active hydrogel according to the invention is applied 1 to 4 times a day in a thin layer. The hydrogel is particularly advantageous in the treatment of all types of ulcers, deep excoriations, po

CS 276067 86 burns, hematomas and other cases where it is necessary to increase the local blood supply to the skin, subcutaneous tissue, mucous membranes and adjacent tissues, for example in the healing of skin grafts.

The advantages of the hydrogel according to the invention in application are: easy handling and application, prevents contamination of the affected area with bacterial flora, prevents purulence and, by being perfectly transparent, allows monitoring the healing process, does not irritate the treated areas locally. The pharmaceutically active hydrogel retains its biological activity under storage conditions for 1 to 3 years. Another advantage is its easy preparation from readily available substances and additives.

Examples of the formulation of a pharmaceutically active stabilized hydrogel of E-series prostaglandins are given in the following examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1

50 parts by weight of glycerol, 7 parts by weight of ethanol, 7 parts by weight of water for injection were introduced into the homogenizer and under sterile conditions at a temperature of 18 to 22 DEG C. given 0.5 parts by weight of a gelling component (Carbepol 940). After complete homogenization of the mixture (approx. 2 to 6 hours), 1.10 parts by weight, part by weight of prostaglandin E ₂ , 0.8 part by weight and part by weight of o-tristhyl acetate were added in a solution of 1 part by weight of ethanol. Finally, a mixture of 25 parts by weight of glycerol, 0.7 wt. parts of tristhanolamine, 0.1 part by weight, part of methylparaben and the remainder to 100 parts by weight of water for injection. After complete homogenization of the mixture, a pharmaceutical

tically effective stabilized hydrogel with a pH of 6.95. Example 2 The procedure was as in Example at 1, the composition of the hydrogel Prostaglandin E ₂ isopropyl alcohol Carbopol 940 triathanolamine glycerol triacetate o-triethyl acetate glycerol propylene glycol methylpareben residue up to 100 wt.%, Water for 1.10 ³ wt., Parts 10.0 wt., Parts 0.5 wt., Parts 0.7 wt., Parts 2.5 wt., Parts 1.0 wt., Parts 60 wt., Parts 5.0 wt., Parts 0.1 wt. injection parts. Example 3 Prostaglandin E-glycerol glycerol triacetate propylene glycol o-triethyl acetate tristhyl citrate triethanolamine ethanol Carbopol 940 the rest up to 100 parts by weight is water for 2.10 ^J mass, parts 45.0 mass, parts 1.5 mass, parts 2.5 mass, parts 2.0 mass, parts 3.5 mass, parts 0.6 mass, parts 15.0 mass, parts 0.7 mass, parts of the injection. Example 4 Prostaglandin of formula I, * where R (3-chlorophenoxy) methyl-. A-CH-CH group and R = OH propylene glycol pentaerythritol glycerol Carbopol 934 isopropyl alcohol tristyl citrate o-tatraethyl carbonate tria- / hydroxymethyl / methylamine 2.5.10 ” ³ masses, parts 1.5 masses, parts 3.5 masses, parts 55.0 masses, parts 1.0 masses, parts 10.0 masses, parts 1.0 masses, parts 0.5 masses, parts 0.6 wt., Parts

CS 276057 B6 propylparaben residue up to 100 wt. parts is water for injections. Example 5 Prostaglandin E ₂ Carbopol 940 triethanolamine propylene glycol ethanol o-tristhyl acetate residue up to 100 parts by weight is water for injection.

0.1 wt., Dild

1.10 ³ masses, parts 0.8 masses, parts 0.8 masses, parts 10.0 masses, works 10.0 masses, works 0.2 masses, works

Claims (12)

PATENT CLAIMS 1. E-series proataglandin hydrogel, in particular for topical use, containing hydroxyalkane and esters of polycarboxylic compounds, characterized in that it contains 1.10 to 1.10% by weight, E-series proataglandin of the general formula I wherein A represents a CH-CH or CH ₂ CH ₂ group, R denotes an n-pentyl, (3-chlorophenoxy) methyl or (3-trifluoromethylphenoxy) methyl group, r | denotes hydrogen and / or alkyl containing 1 to 4 carbon atoms optionally interrupted by one oxygen atom, 0.3 to 3% by weight of basic reactants, 0.5 to 5% by weight, gel-forming components based on polymeric compounds of allyl sucrose and acrylic acid, 2 to 5% by weight, stabilizing additives based on orthoesters of acids or esters of polycarboxylic acids or mixtures thereof, 10 to 80% by weight of hydroxy- and polyhydroxysanes, optionally partly in the form of their esters, these substances up to 100% by weight being supplemented with sterile water for injections. 2 ·. Hydrogel according to claim 1, characterized in that it contains 0.05 to 0.5% by weight of disinfectants. 3. A hydrogel according to claims 1 to 2, characterized in that it contains 1.10 ³ to 5.10 ³ % by weight of prostaglandin E _{2 of} general formula I, wherein A is CH-CH, R 1 is H, and R is n-pentyl. 4. A hydrogel according to items 1 and 2, characterized in that it contains 5.10 ^-4 to 5.10 ^-3 % by weight of a prostaglandin E of the general formula I, wherein A is CH ₂ CH ₂ , R is n-pentyl and R * is H, 5. A hydrogel according to items 1 and 2, characterized in that it contains 1.10 ³ to 5.10 ~ ³ % by weight. _{prostaglandin E 2} methyl ester of formula I, wherein A is CH-CH, R is n-pentyl, R 1 is CH ₃ . 6. The hydrogel according to items 1 to 5, characterized in that it contains, as basic reactants, amino compounds soluble in the hydrogel, such as triethanolamine, tris- (hydroxymethyl) methyleaine, 1,4- (2-hydroxyethyl) -1 ₍ 4-piperazine). 7, The hydrogel according to items 1 to 6, characterized in that the carboxypolymethylan derivative is used as the gelling component in an amount of 0.5 to 0.9% by weight. 8. A hydrogel according to items 1 to 7, characterized in that the hydroxyalkanes used contain 2 to 4 carbon atoms, for example ethanol, 2-propanol. 9. A hydrogel according to claims 1 to 8, characterized in that compounds having 3 to 4 carbon atoms and 2 to 4 hydroxyl groups, for example glycerol or propylene glycol, are used as polyhydroxyalkanes. 10. Hydrogel according to items 1 to 9, characterized in that esters of lower fatty acids having 2 to 4 carbon atoms, such as glycerol triacetate or glycarol tribibutyrate, are used as esters of polyhydroxyalkanes. 11. A hydrogel according to items 1 to 10, characterized in that alkyl ethers having a carbon number of 2 to 4, for example from citric, malic or tartaric acid, are used as ee esters of polycarboxylic acids. ' 12. A hydrogel according to items 1 to 11, characterized in that p-hydroxybenzoic acid esters, for example methyl ester, propyl ester or mixtures thereof, are used as disinfectants.