CS208088B1 - Dry stabilized composition/2-amino-6-hydroxy-5-/carboxy-butyl/-3,4-dihydro-4-oxo/pyrimidine - Google Patents

Description

The present invention relates to a dry stabilized (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine composition for the preparation of injection solutions.

(2-Amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) -pyrimidine (hereinafter 9777 for brevity) is used in therapy primarily as a potentiator of the effect of cytostatics. Its properties and efficiency are described in detail in MS. Certificate No. 176.667.

9777 has weak acid properties and is insoluble in water. Although its soluble salts have been prepared, the solubility of the monosodium salt is too low; the disodium salt has a strongly basic pH in the solution and decomposes soon. Therefore, for the verification of therapeutic efficacy, 9777 was administered to test animals predominantly intraperitoneally, subcutaneously or orally, in the form of an aqueous suspension, it could not be injected directly into the bloodstream and rapidly reached effective levels.

It has now been found possible to realize a sterile, soluble injectable form of 9777, particularly suitable for intravenous, but also intramuscular, subcutaneous or other administration, if necessary.

The present invention provides a dry stabilized (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine composition for pri;

Solution for Injection, which comprises (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine, a physiologically acceptable amino acid and a sodium ion, for example as part of the hydroxide or carbonate or acid carbonate or salt of the amino acid used, in a molar ratio of 1: 2.5 to 10.0: 1.5 to 2.5.

Said dry stabilized composition preferably comprises glycine as a physiologically acceptable amino acid. A particularly preferred composition of the dry stabilized composition is when it contains (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine, glycine and sodium ion in a molar ratio of 1: 4 : 2.

The dry stabilized composition of the invention contains the components in a ratio such that the solution obtained after adding water for injection has a pH of 8-9. The mixture of amino acid and sodium salt thereof is a buffer that ensures that when the 9777 solution is mixed with a lower solution The pH did not precipitate 9777 from the acidic solution.

From the dry mixture of ingredients, prepare a solution at the time of need by adding water for injections. The concentration of the substance in such a solution may be up to 10% by weight.

It has been shown experimentally that

208 088 aqueous solutions of sodium salts of 9777 (at a ratio approximately equivalent to disodium salt) have a pH that is no longer suitable for injection, its glycine-containing solutions are less basic, thus not only reducing injection irritation (e.g. risk of phlebitis) but prolonging solution stability. The results of the determination of 9777 (bromometric titration) in the solution obtained by dissolving a mixture of 9777 and sodium glycinate (in% by weight) are given in the following table:

content immediately after dissolution 100.00 after 1 h at 22.5 ° C 99.50 after 3 h at 22.5 ° C 98.77 after 5 h at 22.5 ° C 96.87

after another J8 hrs in cooler_______ (total 23 hrs) 95,45__

This is sufficient for practical use in clinical practice, since even with most antibiotics and many other drugs, the solution for injection, prepared from the dry composition at the time of need, must be administered within 24 hours.

The invention is not limited to glycine as the only useful amino acid substance; the advantage of glycine, however, is its excellent solubility, physiological compatibility and ease of availability. However, similarly to glycine, other amino acids can be used in admixture with their salts. Of particular note is the possibility of using basic amino acids which do not require the use of sodium salts, since the amino acid itself adjusts the pH of the solution to the required limits. This is especially true for lysine (basic form); however, to obtain the composition, about 4.5 mol of lysine base is required per mole of 9777 to obtain a clear aqueous solution at a suitable pH.

The preparation of dry sterile injectable compositions of 9777 with an amino acid buffer is most conveniently accomplished by lyophilizing a solution in which the individual components (e.g., glycine, sodium hydroxide, and 9777) are mixed and dissolved in the desired ratio. Prior to lyophilization, the solution is sterilized by filtration through a membrane filter having a pore size of about 0.2-0.3 gm, at the same time freeing any mechanical impurities. After lyophilization in an apparatus allowing freeze-drying of larger volumes of solution (lyophilization "in bulk"), the lyophilisate obtained after sieving is filled into sterile vials, which are then aseptically sealed with rubber stoppers and secured with metal caps. Alternatively, the membrane filtration solution can be filled into sterile vials in appropriate volumes; the contents of the vials are then frozen and dehydrated by sublimation under high vacuum (vial-lyophilization); after lyophilization, the vials are closed with stoppers and caps. In the form of a dry composition, mixtures of 9777 with sodium glycinate are almost unlimited in stability.

The dry stabilized composition of the invention may also be prepared otherwise, for example, by crystallizing 9777 under aseptic conditions and aseptically mixing it with sterile sodium glycinate or a mixture of glycine and anhydrous sodium carbonate. Another alternative is to replace the freeze drying by spray drying, allowing aseptic operation under very gentle drying conditions. In any case, the goal is to obtain a dry, stabilized sterile composition which, upon addition of water, provides a solution with the appropriate ratio of ingredients.

It is irrelevant whether the preparation is based on the anhydrous form of 9777 or its dihydrate; ¹ '

Injectable solutions prepared from the composition of the invention were well tolerated when administered to test animals. The median lethal dose pjro rat (LD _S0) when intravenous administration is approximately li, 3 g / kg, relative to compound 9777, present in the composition.

More detailed information on the preparation of the compositions of the invention is given in the following Examples.

Examples

He did

Dissolve 330 g of glycine in 1500 ml of water for injections, add 880 ml of a 10% aqueous solution of sodium hydroxide and add 290 g of (2-amino-6-hydroxy-5- (4-carboxybutyl- After complete dissolution and water make up to a volume of 2500 ml, the solution is filtered first with a small amount of activated carbon through a thick paper filter and then through a sterile 0.2 pore membrane filter. The sterile solution obtained is aseptically filled into pre-sterilized vials of 2.5 ml, each vial containing 250 mg of the active substance, relative to the anhydrous form. .

Example 2

Dissolve 90 g of glycine in 300 ml of water, add 79 g of (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine dihydrate and add, while stirring, 456 ml 5% aqueous sodium hydroxide solution. After reconstitution, the solution is clarified by filtration with 2 g of activated carbon, filtered through a sterile membrane filter into a sterile stirrer, made up to a volume of about 1500 ml with sterile water for injection and lyophilized in a layer not greater than 1 cm. A volumetric mass is obtained, containing 38 wt. % of active ingredient, 57 wt. glydnate buffer (of which 31 wt.% glycine sodium and 26 wt.% free glycine) and 5 wt. humidity. By passing through a sterile sieve, a free-flowing powder is obtained which is weighed into sterile vials so that each contains 660 mg of lyophilisate, corresponding to 250 mg of active ingredient.

Instead of 90 g glycine 109 g of L-alanine or 157 g of L-leucine can be used.

Example 3

A dry sterile mixture of 115.9 g of (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine dihydrate, 132 g of glycine and 46.7 g of anhydrous sodium carbonate is prepared. . The mixture is weighed

208 088 in sterile vials of 737 mg equivalent to 250 mg of anhydrous active substance. An injection solution is prepared, as in the previous examples, at the time of need by adding the necessary volume of water for injections.

Claims (3)

OBJECT OF THE INVENTION A dry, stabilized composition of (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine for the preparation of injectable solutions, characterized in that it comprises (2-amino- 6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine, a physiologically acceptable amino acid, and a sodium ion, for example, as part of the hydroxide or carbonate or acid carbonate or salt of the amino acid used, in a molar ratio of 1: 2 5 to 10.0: 1.5 to 2.5. 2. A dry stabilized composition according to claim 1, wherein the physiologically acceptable amino acid is glycine. 3. Dry stabilized composition according to points 1 and 2, characterized in that it comprises (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine, glycine and sodium ion in a molar ratio of 1: 4: 2. The dry, stabilized (2-amino-6-hydroxy-5- (4-carboxybutyl) -3,4-dihydro-4-oxo) pyrimidine composition for injection solutions contains this compound in admixture with a physiologically harmless amino acid, in particular glycine and Na ⁺ , for example as part of the hydroxide, carbonate, acid carbonate or salts of the amino acid used.