CS246051B2 - Cis-platinum-diaminodichloride's stable concentrated solution production method - Google Patents

Abstract

There are provided stable concentrated solutions of cisplatin in a solvent comprising polyethylene glycol or methoxy polyethylene glycol, or a mixture thereof, plus water and a nontoxic pharmaceutically acceptable source of chloride ion.

Description

The present invention relates to a process for the preparation of a stable, concentrated solution of cis-platinadiaminedichloride. These are solutions in aqueous polyethylene glycol, methoxypolyethylene glycol, or mixtures thereof containing a chloride ion source.

Platinum compounds are an important class of anticancer agents. They were first shown to have an antibiotic effect in Rosenberg B. et al., Nature (London), 205, 698-699 (1965), and then demonstrated high anti-tumor efficacy [Rosenberg et al., Nature. (London), 222, 385-386 (1969)].

Structurally, it is a complex consisting of a central platinum atom with a different arrangement of chlorine atoms and ammonium groups in the cis or trans position in the plane. Two of the better studied compounds of this type are further represented by the structural formula:

cis-platinum (II) diamine dichloride cis-platinum (IV) diamintetrachloride

As can be seen, cis-platinadiaminedichloride has all chloride ions and amino groups in a single plane. This compound, commonly called cisplatin, was synthesized as follows:

NH? Cl

Kz [P 'Jk] + 2NH 3 --- cis- [Pt (NH 3) Cl 2] + 2 KCl [Kauffman, GB et al., Inorganic Synthesis, J. Kleinberg (Ed.), Pp. 239-245, Megraw- Hill Book Co., Inc., New York 1963].

Breusova-Baidala, Y.G. et al., Akademia Nauk USSR, No. 6, pp. 1,239 to 1,242 (June 1974) describes the slow isomerization of platinum cis diamine dichloride in aqueous solution to trans.

Reishus JW and Martin DS, Journal of the American Chemical Society, 83, 2,457-2,462 (1961) describe the hydrolysis of a cis-platinum compound in an acidic medium at 25-35 ° C. These experiments were carried out in an aqueous solution at a concentration of 1.5 x 1 5-5 M, 2.5 x 10 ^-3 M and 5.0 x _ x 10 -3 · corresponding to 0.45, 0.75 and 1.6 mg / ml. The authors report that it was not possible to accurately determine the onset of hydrolysis because the samples dissolved for 10 to 30 minutes even at this low concentration.

Rozencweig M. et al., Annals of Internal Medicine, 86, 803-812 (1977) summarizes the results of various preclinical and clinical investigations using this compound in both experimental and animal tumors. It is emphasized that the substance is supplied through the Investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute, as a white lyophilized powder in vials containing 10 mg cis-platinum compound, 90 mg sodium chloride, 100 mg mannitol and hydrochloric acid. for pH adjustment. After reconstitution with 10 ml of sterile water for injection, each ml of the resulting solution contained 1 mg of active substance, 10 milligrams of mannitol and 9 mg of sodium chloride.

Talley R. W. et al., Cancer Chemotherapy Reports, 57, 465-471 (1973), describes the results of a first phase clinical trial using the cis-platin compound in 65 patients with different tumors. The active substance was again supplied in vials containing 10 mg of active substance, 90 mg of sodium chloride and 100 mg of mannitol for reconstitution in 10 ml of sterile water.

Rossof A. H. et al., Cancer, 30, 1451-1456 (1972), describes the treatment results of 31 patients with different tumors. The active ingredient was supplied by Ben Venue Laboratories, Inc. and contained 10 mg of active ingredient, 10 mg of mannitol and 9 mg of sodium chloride in a vial, this yellow-white powder was easily dissolved in 8 to 10 ml of sterile water.

Information on the chemistry and pharmaceutical processing of this substance can be found on pages 1 to 5 and 31 to 32 of "Clinical Brochure, cis-platinum (II) diamminedichloride (NSC-119 875): H. Heldelsman et al., Investigational Drug Branch, Cancer Chemotherapy Evaluation Program, Divisions of Cancer Treatment, National Cancer Institute (reissued in August 1974). On pages 31 to 32 are listed: · free of charge to doctors · for chemical · evaluation in the treatment of tumors, instructions will be given literally below:

cis-diamindichlorplatin (II):

Dose 10 mg / vial

The contents of each 20 ml vial are an off-white lyophilized substance. Each vial contains 10 mg of the active substance, 90 mg of sodium chloride, 100 mg of mannitol and hydrochloric acid to adjust the pH.

Preparation of a 10 mg vial:

When reconstituted with 10 ml of sterile water for injection, each ml of solution contains mg of active substance, 10 mg of mannitol and 9 mg of sodium chloride at pH 3.5 to 4.5.

Storage:

Dry, unopened vials should be stored in the refrigerator at 4 to 8 ^° C.

Stability:

Intact vials are stable for 1 year when stored at 4 to 8 ° C. The substance can be administered for 2 years after stability check. After reconstitution, a light yellow solution is formed, stable only for 1 hour at 22 ^° C in the light and for a maximum of 8 hours at 22 ° C in the dark. A precipitate may form in the reconstituted solution after standing for one hour at 4 to 8 ^° C.

Freeze-dried preparations contain no preservatives and should therefore not be used for more than 8 hours after reconstitution.

British Patent Application 2,021,946A discloses a stable aqueous solution of a cis-platinum compound at a concentration of 0.1 to 1 mg / ml at a pH of 2 to 3. The solution may also contain a non-toxic, pharmaceutically acceptable inorganic chloride ion source such as sodium chloride and a carrier such as mannitol.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a stable, concentrated solution of cis-platinadiamine dichloride in a solvent, characterized in that it is dissolved to a concentration of 2.5 to 25 mg. up to 9,000 or methoxy polyethylene glycols having an average molecular weight of 300 to 6,000 or a mixture of these and 5 to 70 weight percent water and at least one non-pharmaceutically acceptable pharmaceutically acceptable chloride ion source in an amount at least equivalent to the amount of cis-platinadiamine indichloride present in the solution.

Permanent aqueous solutions of this substance have been described in British Patent No. 2,021,946 A. Although stable solutions of up to 1 mg / ml active ingredient concentration at room temperature can be obtained as described above, crystallization may occur in the cold at concentrations greater than 0, 5 mg / ml. Redissolution of the crystals cannot be ensured by shaking at room temperature, although the solution can be recovered by heating to 37 ° C. Since it is not possible to control the temperature during transport and storage, and crystallization poses an undesirable problem for the physician, the actual maximum practical concentration of the active substance in aqueous solutions of this type is only 0.5 mg / ml.

Solutions of the cisplatin compound of the invention may contain up to 25 mg of this compound per ml, although the preferred maximum concentration is 15 mg / ml. Solutions containing mg / ml can be stored at ° C for 12 months without crystallization. The ¹ solutions were also frozen at -60 ° C and thawed again to room temperature without precipitating. That is, the concentration of the solution according to the invention may be at least 30 times higher than the concentration of the previously known aqueous solutions.

It will be appreciated that the concentrated solutions of the present invention require lower transport, storage and handling costs per unit dose compared to known aqueous solutions. Although the known solid freeze-dried form also has higher transportation and storage costs, these savings are offset by other disadvantages, for example the time consumed during freeze-drying and re-dissolution.

In a preferred embodiment, the solvent comprises 80 to 95, preferably 85 to 90% polyethylene glycol with an average molecular weight of 250 to 1600, preferably 250 to 650, and 5 to 20, preferably 10 to 15% water. In a most preferred embodiment, the solvents comprise 90% polyethylene glycol with an average molecular weight of 350 to 450 and 10% water.

The solution preferably contains 5 to 20 mg of active ingredient per ml, in particular 10 to 15 mg / ml. The non-toxic, pharmaceutically acceptable source of chloride ions, which is preferably present in an amount of at least two equivalents per 1 equivalent of active ingredient, may be different compounds. Concentrations of chloride ions of up to 50 equivalents per equivalent of active ingredient can be used depending on the concentration of the solution, the amount of water present and the source of chloride ions, so a high concentration of chloride ions is usually neither necessary nor desirable. Obviously, at a high concentration of active ingredient and low water content, it would not be possible to dissolve a sufficient amount of chloride ion up to 50 equivalents per 1 equivalent of active ingredient. Furthermore, a saturated or almost saturated inorganic chloride solution would be desirable because of the possibility of crystallization from the solution at a lower temperature. 50 equivalents of chloride ion per equivalent of active ingredient could be achieved using hydrochloric acid, but in this case the solution would be too acidic. It has been found that too acidic solutions are slightly less stable than slightly acidic solutions. The preferred pH range is 1.5 to 4.5. The preferred range is 2 to 10 equivalents of chloride ions, especially 3 to 7 equivalents of chloride ions per equivalent of active ingredient.

Chloride ions can be provided by the addition of a hydrochloric acid, a non-toxic pharmaceutically acceptable metal halide such as sodium chloride, potassium chloride, calcium or magnesium, or a hydrochloric acid addition with a non-toxic, pharmaceutically acceptable tertiary amine such as triethylamine or mixtures thereof. A preferred source is hydrochloric acid, sodium chloride, or a mixture thereof.

Polyethylene glycols and methoxypolyethylene glycols can be represented by the general formula

H (OOH 2 CH 2) n OH and

CH 3 (OCH 2 CH 2) n O'CH 3.

Typical molecular weight ranges of the products are shown in Tables 1 and 2 below:

Table 1 Polyethylene- Molecular weight glycols 200 190 to 210 300 285 to 315 400 380 to 420 600 570 to 630 1000 950 up to 1050 1 540 1 300 up to 1,600 4 000 3 000 up to 3,700 6 000 7 000 up to 9,000 Table 2 Motoxy- Molecular weight propylene- glycols 350 335 to 365 550 525 to 575 750 715 to 785 2 000 1850 to 2,150

The polyethylene glycols may form complexes with some inorganic salts. For example, it forms a blue complex with cobalt-ammonium thiocyanate, the intensity of which may be the basis of the colorimetric method for determining the concentration of polyethylene glycol in various mixtures. The stability of the solution according to the invention may result from the formation of a complex between the active substance and the polyethylene glycol, but this assumption is only theoretical. From the results of thin-layer chromatography, the presence of a complex could be inferred. In the procedures described below, the active substance stains at Rf 0.65. A solution of the active substance in 90% polyethylene glycol 400 and 10% water or 10 · 0.5% hydrochloric acid forms a spot at Rf 0.3 and this spot extends up to Rf 0.65. Upon dilution with a large amount of water, the complex appears to disintegrate, since upon dilution of the above solution with 5 volumes of water, only a spot appears at Rf 0.65. Thin layer chromatography:

(c) developer - 5.6 g of stannous chloride are dissolved in 10 ml of concentrated hydrochloric acid; 90 ml of distilled water and 0.2 g of potassium iodide are added; mix well and prepare daily;

(d) a laboratory oven set at 100 ° C.

Method

(a) Dilute the sample with 5 volumes of dimethylformamide;

(b) 5 µl of sample is applied to the plate and in addition 5 µl of a standard solution of cis-platinum (and transplatin and platinum B) is applied at a concentration approximately equal to the expected sample concentration. It develops to a height of 10 cm after equilibration of the solvent. The plate is dried and sprayed with a developer and stored for 10 minutes to 100 DEG C. ^q subtracted yellow and purple spots.

(c) Approximate Rf values:

0.65 cis-platinum

0,76 transplatina

0,9 platinum B.

In high pressure liquid chromatography, the solutions of the invention can be analyzed as described in British Patent No. 2,021,946A. The mobile phase is a 25: 16: 5: 5 mixture of ethyl acetate, methanol, dlmethylformamide and distilled water. Preferably, the standard is cis-platinum in solution in dimethylformamide at a concentration of 1 mg / ml. The samples were diluted with dimethylformamide to a concentration of 1 mg / ml.

Although the presence of these substances does not provide any particular advantages, carriers or fillers such as mannitol may be used in the solutions of the invention.

The stability of the solution according to the invention, defined as 10% loss of efficacy, is more than 2 years at room temperature.

In a preferred embodiment, the solutions are sterile and pyrogen-free and are packaged in sterile and pyrogen-free containers. They may be diluted with sterile water for injection or sterile saline and administered intramuscularly or intravenously. The best sterilization method is to pass through a 0.22 gm filter in a sterile nitrogen atmosphere. The sterile filtrate is placed in sterile pyrogen-free containers and sealed with sterile pyrogen-free stoppers, preferably coated with Teflon, and the stoppers sealed with sterile aluminum.

For the treatment of tumors, the concentrated solution is usually diluted to a concentration of 1 mg of active ingredient per ml with sterile water for injections, sterile saline or sterile glucose solution, used intramuscularly or intravenously as · in-

(a) silica gel plates;

(b) eluent: acetone and 1 N nitric acid 9: 1 (to be prepared daily);

Jection or infusion. Doses with mild toxicity range from 60 to 100 mg / m ² intravenously in a single dose or over 3 to 5 days, with a repeat of 4 weeks. The dose of 60 m ² / m ² is about 1.5 mg / / kg, which is about 105 mg for a 70 kg patient. Usually this substance is used together with other active substances.

Throughout the application, the term equivalent of ⁴ means a molar equivalent. At a preferred ratio of 3 to 7 equivalents of chloride ions per equivalent of active ingredient, 3 to 7 moles of sodium chloride per mole of cisplatin is used, but 1.5 to 3.5 moles of calcium chloride per mole of active ingredient and the like.

Platinum В is the common name for the acidic reaction product of cis-platinum, which can be approximately represented by the following formula:

_x Cl> 4

H ₃ N Ct

The invention will be illustrated by the following examples.

Example 1

Fixed concentrated solution of cisplatin at 10 mg / ml in 90% polyethylene glycol 400 and 10% 1N hydrochloric acid

500 mg of cisplatin are dissolved in a solution of 5 ml of 1N hydrochloric acid and 45 ml of polyethylene glycol 400. After 2.5 days of stirring at room temperature, protected from light by an aluminum foil, a clear yellow solution is formed. A portion of this solution was placed in a 17 ml dark glass vial with a stopper, the stoppers were covered with aluminum and stored at different temperatures to determine the stability of the solution. After 2 weeks storage at 45 ° C, TLC showed approximately 1% platinum B. After 56 weeks storage at 56 ^{° C,} less than 1% transplatin and approximately% platinum could be detected. B. Samples stored at 56 ^° C for 2 weeks were diluted with 4, 9 and 19 volumes of water to clear solutions containing 2, 1 and 0.5 mg / ml cisplatin. In each of the diluted samples, a slight turbidity occurred after standing for 18 hours at room temperature.

Example 2

A stable, concentrated solution of cisplatin at a concentration of 10 mg / ml in 90% polyethylene glycol 400 and 10% hydrochloric acid of 0.5 N ml purified water and 5 ml of 1N hydrochloric acid is mixed and 90 ml of polyethylene glycol 400 are added. ml of this solution is added 500 mg of cisplatin and the mixture is protected from light by aluminum foil and stirred at room temperature for 24 hours to give a clear solution. Thin layer chromatography showed only cisplatin and slight traces of transplatin in this solution. 2 ml of this solution were each stored in dark 17 ml vials, stoppered with teflon stoppers and sealed with aluminum caps, and stored at various temperatures to determine the stability of the solution. One of the samples was frozen in a dry ice / acetone bath for 1 hour and then left at room temperature. A clear solution was formed without any precipitate. After 3 months storage at 37 and 45 ^Q C could be detected by chromatography on thin-to-layer 1-2% platinum, and small traces В transplatin. After 1 month storage at 56 ° C, the presence of more than 5% but less than 10% platinum V and traces of transplatin could be detected in the same manner. Samples stored at temperatures from 37 to 45 ^C, and C 3 months at 56 ^Q C for one month were diluted with 4 volumes of purified water to a clear solution which contained 2 mg / ml of cisplatin. The diluted solutions remained clear after standing at room temperature for 24 hours.

Example 3

Dissolve 10 mg / ml and 20 mg / ml of cisplatin in concentrated 90% polyethylene glycol 400 and 10% hydrochloric acid, 0,5 N g of analytically pure anhydrous calcium chloride, in a mixture of 5 ml of purified water and 5 ml 1N hydrochloric acid is added. 89 ml of polyethylene glycol 400 are added in a volume of 100 ml. To 50 ml of this solution was added 550 mg of cisplatin and the mixture was protected from light by aluminum foil and stirred at room temperature for 24 hours to give a clear solution. Thin layer chromatography of the freshly prepared solution shows only cisplatin with slight traces of transplatin. Each 2 ml of this solution was placed in dark 17 ml vials, sealed with a Teflon stopper and sealed with aluminum foil, and then stored at different temperatures to demonstrate solution stability. One sample is placed in a dry ice-acetone bath for 2 hours and frozen on a clear gel-like mass. It is then dissolved at room temperature to a clear solution. · After 3 months storage at 37 ^Q C may TLC show 1-2% platinum and В slight traces of transplatin. After 3 months storage at 45 ° C, the presence of approximately 5% platinum V and small traces of transplatin can be detected in the same way. After 1 month storage at 56 ° C, thin layer chromatography shows the presence of 8-10% platinum and traces of transplatin. Samples that were stored for 3 months at 37-46 ° C and 56 ° C for 1 month were diluted with 4 volumes of purified water to clear solutions containing 2 mg / ml cisplatin. These diluted solutions remained clear after standing at room temperature for 24 hours.

Example 4

Concentrated 22 mg / ml cisplatin solution with 25 mg / ml calcium chloride in 90% polyethylene glycol and 10% hydrochloric acid, 0,5 N

To 3 ml of a solution of 90% polyethylene glycol 400 and 10% 0.5 N hydrochloric acid was added 45 mg of cisplatin, and the mixture was stirred at room temperature for one hour to a clear solution. An additional 30 mg of this material to a concentration of 25 mg / ml and the mixture was stirred for one hour at 45 ^Q C. and then 18 hours at room temperature, whereby all the material almost completely dissolves. A small insoluble matter was collected by filtration. Thin layer chromatography of the filtrate showed only cisplatin with slight traces of transplatin. The remainder of the filtrate is stored in dark 17 ml vials fitted with a Teflon stopper, covered with aluminum foil and stored at 45 ° C for 3 months. After 3 months at this temperature, 1 to 2% platinum (V) and no transplatin were detected by thin layer chromatography. The solutions were diluted with purified water to a concentration of 2 mg / ml cisplatin to give clear solutions that did not become cloudy after standing for 24 hours at room temperature.

Example 5

Permanent concentrated solution of cisplatin at 12 mg / ml and 10 mg / ml sodium chloride in 90% polyethylene glycol 400 and 10% hydrochloric acid 0,5 N

Dissolve 100 mg of sodium chloride in a solution of 5 ml of purified water and 5 ml of 1N hydrochloric acid. To this solution are added 90 ml of polyethylene glycol 400 and the mixture is stirred for 15 minutes. To 50 ml of the solution was added 500 mg of cisplatin and the mixture was stirred for 3 days in the dark at room temperature to give a clear solution. Only cisplatin can be detected by thin layer chromatography of a freshly prepared solution. High pressure liquid chromatography of this solution showed a concentration of 12 mg / ml. The solution was dispensed into 17 ml vials as in Example 3 and stored at different temperatures. After storage for 3 months at 37 ° C, less than 1% platinum and no transplatin were detected by thin layer chromatography. After 1 month storage at 56 ° C, 1 to 2% platinum and no transplatin can be detected in the same way. These samples were diluted with purified water to a concentration of 2 mg / ml to give clear solutions which did not become cloudy after standing at room temperature for 24 hours.

High pressure liquid chromatography of samples stored for 3 months at 45 ° C, 6 months at 37 ° C and 8 months at room temperature showed efficacy losses of 6.6%, 6.1% and 2.3%, respectively.

Example 6

Permanent concentrated solution of cisplatin at a concentration of 11.4 mg / ml with 10 mg / ml sodium chloride in 90% polyethylene glycol 400 and 10% water

To a solution of 50 mg of sodium chloride in 5 ml of purified water and 45 ml of polyethylene glycol 400 was added 500 mg of cisplatin and the mixture was stirred at room temperature in the dark for 6 hours to give a clear solution. Thin layer chromatography of this solution showed only a cisplatin spot. HPLC analysis showed a concentration of 11.4 mg per ml. The solution was divided into dark 17 ml vials as in Example 3 and stored at different temperatures.

After 3 months of storage at 37 ^{° C} and 45 ^° C, thin layer chromatography showed the presence of 1% platinum and no transplatin. After 1 month storage at 56 ^and C, 2 to 3% platinum and no transplatin can be detected in the same way. Dilution of these samples with purified water to a concentration of 2 mg / ml gives clear solutions which remain clear after standing at room temperature for 24 hours.

High pressure liquid chromatography of samples stored for 3 months at 45 ° C, 6 months at 37 ° C and 7 months at room temperature showed a loss of potency of 6.1%, 7.0% and 0.9%.

Example 7

Fixed concentrated solution of cisplatin 10 mg / ml in 90% polyethylene glycol 600 and 10% hydrochloric acid 0,5 N

To a solution of 2.5 ml of purified water, 2.5 ml of 1N hydrochloric acid and ml of polyethylene glycol 600 was added 500 mg of cisplatin and the mixture was stirred for 5 hours in the dark at room temperature to form a clear solution. Thin layer chromatography of the freshly prepared solution was determined by g

14 only cisplatin. Dilute samples of freshly prepared ¹ solution with 1, 2, 3, 4, 5 and 9 volumes of purified water. These solutions do not crystallize for 16 hours at room temperature or 4 ^° C. The solution was divided into dark 17 ml vials as in Example 3 and stored at various temperatures. After 3 months storage at 37 and 45 ° C, 1% platinum B and no transplatin were detected by thin layer chromatography. After storage for 1 month at 56 ° C, the presence of 3.4% platinum B and no transplatin can be detected in the same way. The samples are then diluted with purified water to a concentration of 2 mg / ml to give clear solutions which do not become cloudy after 24 hours at room temperature.

Example 8

Fixed concentrated solution of cisplatin 10 mg / ml with 10 mg / ml sodium chloride in 90% polyethylene glycol 400 and 10% hydrochloric acid · 0,2 N

To a solution of 0.5 g of sodium chloride in 4 ml of purified water, 1 ml of 1 N hydrochloric acid, 45 ml of polyethylene glycol 400 was added 250 mg of cisplatin, and the mixture was stirred in the dark at room temperature for 4 hours to give a clear yellow solution. Only cisplatin can be detected by thin layer chromatography of the freshly prepared solution. The solution is diluted with 1, 2, 3, 4, 5 and 9 volumes of purified water to give a clear solution that remains clear for 24 hours at room temperature. Dilutions of 1, 2, 3, 4 and 5 volumes were allowed to stand for 24 hours at 4 ^° C, no crystallization occurred. Samples of the solution were stored as in Example 3 in dark 17 ml vials and stored at different temperatures. After 3 months storage at 37 T, 1% platinum B and a small trace of transplatin can be detected by thin layer chromatography. After 3 months storage at 45 ° C, 5% platinum B and traces of transplatin can be detected in the same way. After 1 month storage at 56 ^Q C may be demonstrated in the same manner 2-3% platinum B and no transplatinum. The samples are diluted with purified water to a concentration of 2 mg / ml to give clear solutions that do not cloud after 24 hours at room temperature.

Example 9

Concentrated 2.5 mg / ml cisplatin solution with 9 mg / ml sodium chloride and 12.5 mg / ml mannitol in acidified 31% aqueous polyethylene glycol 6000

0.9 g of sodium chloride, 1.25 g of mannitol and 31.3 g of polyethylene glycol 6000 are dissolved in purified water to a volume of 100 ml of solution, and the solution is then acidified to pH 2.2 by adding

0.7 ml of 1 N hydrochloric acid is added. 255 mg of cisplatin is added and the mixture is stirred for 3 days in the dark at room temperature to form a clear solution. Thin layer chromatography of the fresh solution shows only cisplatin. The solution was divided as in Example 3 into dark 17 ml vials and stored at 45 and 56 ° C. After 2 months of storage at these temperatures, less than 1% platinum B and no transplatin were detected by thin layer chromatography. Dilution of the solution with an equal volume of purified water gives clear solutions which do not become cloudy after 24 hours at room temperature.

Example 10

A fixed concentrated solution of cisplatin at a concentration of 15.8 mg / ml with 10 mg / ml sodium chloride in 90% aqueous polyethylene glycol 400 ml polyethylene glycol 400 is dissolved in a solution of 1.0 g sodium chloride in 10 ml purified water. To 60 ml of this solution was added 900 mg of cisplatin and the mixture was stirred in the dark for 5 hours at room temperature to give a clear solution. Thin layer chromatography of the fresh solution showed only cisplatin. High pressure liquid chromatography indicated a concentration of 15.8 mg / ml. The freshly prepared solutions are diluted with 4 volumes of purified water to a clear solution which remains clear after standing at room temperature for 24 hours. The solution was dispensed as in Example 3 into dark 17 ml vials and stored at various temperatures. After 2 months storage at 45 ° C, no transplatin was detected by thin layer chromatography (1.5% platinum B). After 1 month storage at 56 ° C 2% platinum B and no transplatin can be detected in the same way. The sample stored at 56 ° C is diluted to 2 mg / ml with sterile water for injection and the sample stored at 45 ^Q C was diluted to 2.5 and 5.0 mg / ml sterile water for injection · administration. In each case, a clear solution is formed which remains clear after storage at room temperature for 24 hours.

High pressure liquid chromatography of a sample stored for 3 months at 45 ° C, 6 months at 37 ° C and 8 months at room temperature showed a loss of potency of 7.6%, 7.6%, and 0%, respectively.

Example 11

Concentrated cisplatin solution at a concentration of 15 mg / ml with 25 mg / ml calcium chloride in 90% aqueous polyethylene glycol 400 '

To a solution of 2.5 g of calcium chloride in ml of purified water is added 901 ml of polyethylene glycol 400 and the resulting solution is stirred for 10 minutes. To 50 ml of this solution was added 750 mg of cisplatin and the mixture was stirred for 5 hours in the dark at room temperature to give a clear solution. Only cisplatin can be detected by thin layer chromatography of the fresh solution. The solution is diluted with 1, 2, 5 and 10 volumes of purified water to clear solutions. These solutions were dispensed as in Example 3 into dark 17 ml vials and placed at 45 and 56 ° C. After 2 months of storage at 45 ° C, 1.5% platinum and no transplatin were detected by thin layer chromatography. After 1 month storage at 56 ° C, 2.5 to 5% platinum and no transplatin can be detected in the same way. This sample is diluted to a concentration of 2 mg / ml, the sample stored at 45 ° C is diluted to a concentration of 2.5 and 5.0 mg / ml with sterile water for injection. Clear solutions are formed which remain clear even after storage at room temperature for 24 hours.

Example 12

Sterile, stable, concentrated solution of cisplatin in 90% polyethylene glycol 400 and 10% 0.5 N hydrochloric acid (approximately 15 mg / ml) • Cisplatin is a carcinogen. Protective clothing, gloves, mask, glasses and headgear should be worn throughout the procedure. The entire workplace must be thoroughly cleaned to avoid contamination.

Composition in ml in 10 ml

cisplatin 0.015 g ' ¹ ' 0.150 g sodium chloride 0.015 G 0.150 G hydrochloric acid 0,5 N ⁽²⁾ 0.10 ml 1.0 ml polyethylene glycol 400 to 1.0 ml do 10,0 ml

⁽¹⁾ This amount of cisplatin means an efficacy of 1000 µg / ml. The following formula can be used to determine the amount of this substance required:

000 x 0.015 g h. η v.

The required amount of compound in g activity in µg / ml ⁽²⁾ 1 liter of 0.5 N hydrochloric acid is prepared as follows:

1. Place 957.25 ml of sterile water for injections in a clean 1 liter Erlenmeyer flask.

2. With vigorous stirring, 42.75 ml of concentrated hydrochloric acid is added slowly and carefully. The mixture was stirred for 10 minutes and then the flask was stoppered with a clean rubber stopper.

Instructions for making 1 liter of sterile solution

1. Place 100 ml of 0,5 N hydrochloric acid solution in a clean, 1 liter graduated Erlenmeyer flask equipped with a stirrer, for example a Teflon-coated rod with a 6 cm propeller.

2. Add 15.0 g of sodium chloride with gentle stirring. The solution is stirred until the salt is completely dissolved.

3. Add 750 ml of polyethylene glycol 400 with vigorous stirring and stir the solution for 5 minutes.

4. Remove the stirrer and return the excess liquid to the flask.

5. Carefully add 15.0 g of cisplatin.

6. Add polyethylene glycol 400 up to the 1 liter mark, a total of 880 ml of polyethylene glycol 400 is required.

7. Return the Teflon stirrer to the mixture and stopper the flask with a clean rubber stopper.

8. Wrap the flask with aluminum foil to eliminate light.

9. Stir the mixture rapidly at room temperature for 24 to 48 hours. A clear solution should be formed. If no clear solution is formed within 48 hours, the mixture can be heated at 37-40 ^{° C /} C for 2-6 hours in the absence of air and light to facilitate dissolution of the cisplatin compound. The solution was then cooled to 23-27 ^° C.

10. Under aseptic conditions, pass the dark yellow solution through a sterile, pyrogen-free 0.22 micron filter under nitrogen pressure. Collect the sterile filtrate into a sterile, pyrogen-free Erlenmeyer flask. The flask is stoppered with a sterile, pyrogen-free rubber stopper. The solution can be stored in the dark.

11. The required amount of sterile solution is filled into sterile, pyrogen-free dark vials. The vials are stoppered with a sterile, pyrogen-free Teflon stopper and sealed with aluminum foil.

12. The vials shall bear the following label: 'Not for direct intramuscular or intravenous use'.

The solution may be diluted with 14 sterile portions

216951 water for injection or sterile saline to a concentration of 1 mg / ml of cisplatin compound. If higher concentrations are required, less sterile water or saline should be added. The diluted solutions can be used intravenously and are stable at 22 to 26 ° C for at least 48 hours. It is not recommended to freeze the solutions as crystals may form.

13. The solutions should be stored in the dark.

Example 13

Fixed concentrated solution of cisplatin at a concentration of 2.5 mg / ml with 9 mg / ml sodium chloride, 15 mg / ml calcium chloride and 10 mg / ml mannitol in acidified 31% aqueous polyethylene glycol 400

0.9 sodium chloride, 1.5 g calcium chloride and 1.0 g mannitol are dissolved in a mixture of 31.25 ml polyethylene glycol 400 and 40 ml purified water. The solution is acidified to pH 2.2 with 0.4 ml of 1N hydrochloric acid, 255 mg of cisplatin is added, the volume is made up to 100 ml with purified water and the mixture is stirred in the dark for 5 hours at room temperature to form a solution. Only cisplatin can be detected by thin layer chromatography of the fresh solution.

Example 14

The process of Example 5 was repeated except that sodium chloride was replaced with an equivalent amount of magnesium chloride to obtain a stable, concentrated cisplatin solution.

Example 15

The procedure of Example 5 was repeated except that sodium chloride was replaced with an equivalent amount of triethylamine hydrochloride to obtain a stable, concentrated cisplatin solution.

Example 16

The procedure of Example 5 is repeated, but the polyethylene glycol 400 is replaced with an equal volume of polyethylene glycol 200 and 300 to give a stable, concentrated cisplatin solution.

Example 17

The process of Example 9 is repeated except that the polyethylene glycol 6000 is replaced with an equal amount of 1000-4000 polyethylene glycol to obtain a stable, concentrated cisplatin solution.

Claims (1)

A process for the preparation of a fixed concentrated solution of cis-platinadiamindichloride in a solvent, characterized in that it is dissolved to a concentration of 2.5 to 25 mg / ml of cis-platinadiamindichloride in a solvent containing 30 to 95% polyethylene glycol with an average molecular weight of 150 to 9,000; % of methoxypolyethylene glycol having an average molecular weight of 300 to 6,000 or a mixture thereof and 5 to 70% water, and at least one non-toxic, pharmaceutically acceptable source of chloride ion in an amount at least equivalent to the amount of cis-platinadiaminedichloride present in the solution.