DD157762A5 - PROCESS FOR THE PRODUCTION OF STABLE, CONCENTRATED SOLUTIONS OF CISPLATIN - Google Patents

Abstract

The invention relates to a process for the preparation of stable, concentrated solutions of cisplatin in a solvent containing polyethylene glycol or methoxy polyethyleneglycol, or mixtures thereof, plus water and a non-toxic pharmaceutically-acceptable chloride ion source. These solutions can contain up to 25 mg / ml cisplatin and are stable for several months.

Description

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Process for the preparation of stable, concentrated solutions of cisplatin.

Field of application of the invention

The invention relates to a process for the preparation of stable, concentrated solutions of cisplatin in aqueous polyethylene glycol, methoxypolyethylene glycol, or mixtures thereof containing a chloride ion source.

Characteristic of the known technical solutions

The platinum compounds are a special compound in the antineoplastic agent group. Rosenberg and his colleagues first described in 1965 that they have an antibiotic effect [Rosenberg, B. et al., Nature (London), 205, 698-699 (1965)] and later Rosenberg and his colleagues found that they were powerful anti-tumor agents Animals are [Rosenberg, G. et al., Nature (London), 222, 385-386 (1969)].

Structurally, they form a complex with a central platinum atom surrounded by various arrangements of chlorine atoms or ammonium groups, either in the cis or transplanar relationship. Two of the more commonly studied platinum compounds are shown below:

Cl

MD

Cl NH ₃ Cl NH

пв ш

Cl NH ₀ CLNH,

Cl

Cis-Platin (II) Cis-Platin (IV)

Diamine dichloride Diaminedetrachloride

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As shown, the compound cis-platinum (II) diamine dichloride has all the chlorine and amino groups in a single plane. This compound, now known under the United States Adopted Name cisplatin, was synthesized by the following reaction:

NH ₄ Cl K ₃ [PtCl ₄ ] + 2NH ₃ > eis [Pt (NH ₃ J ₂ Cl ₂ ] + 2KCl

(See Kauffman, GB et al., Inorganic Synthesis , J. Kleinberg (Ed.) pp. 239-245, McGraw-Hill Book Co., Inc., New York, 1963].

Breusova-Baidala, YG et al., In Akademia Nauk SSSR , no. 6, pages 1239-1242 (June 1974) describe the slow isomerization of cis-platinum (II) diamine dichloride in aqueous solution into the trans form.

Reishus, JW and Martin, DS, described in Journal of the American Chemical Society, 83, 2457-2462 (1961), the acid hydrolysis of cisplatin at 25 ⁰ C and 35 ⁰ C. These studies were conducted in aqueous solutions at concentrations of 1, 5 × 10 ^-3 M, 2.5 × 10 ^-3 M, and 5 × 10 ^-3 M equivalent to 0.45, 0.75, and 1.5 mg / ml, respectively. The authors write that it was somewhat unclear to determine the beginning of the hydrolysis curves (ie, the "zero point"), since the samples required 10 to 30 minutes even at these low concentrations until they were completely dissolved.

Rozenczweig, M. et al., Annals of Internal Medicine , 86 , 803-812 (1977) is a summary of the results of various preclinical and clinical studies of cisplatin in artificially induced tumors in animals as well as in various types of human tumors ,

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They state that the experimental compound, available to qualified researchers through the Investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute, was delivered as a white, lyophilised powder in ampoules containing 10 mg cisplatin, 90 mg sodium chloride, 100 mg Mannitol (USP) and hydrochloric acid to adjust the pH. After reconstitution with 10 ml sterile water suitable for injections (USP), each ml of the solution obtained contains 1 mg cisplatin, 10 mg mannitol and 9 mg NaCl.

Talley, RW et al., In Cancer Chemotherapy Reports , 57 , 465-471 (1973), report the results of their Phase I clinical studies on the use of cisplatin in the treatment of 65 subjects with a wide variety of neoplasms Alternatively, they received the drug from the National Cancer Institute in ampoules containing 10 mg of cisplatin, 90 mg of sodium chloride and 100 mg of mannitol, to be treated with 10 ml of sterile water.

Rossof, AH et al. describe in Cancer , 30 , 1451-1456 (1972) the results of their use of cisplatin in the treatment of 31 individuals with a variety of tumors. They state that the drug provided by the National Cancer Institute was manufactured by Ben Venue Laboratories Inc., containing 10 mg cisplatin, 10 mg mannitol, and 9 mg NaCl per ampoule, and that the yellowish-white powder dissolved Dissolve quickly in 8-10 ml of sterile water.

For some information regarding the chemistry and pharmaceutical formulations of cisplatin, see pages 1-5 and 31-32 of the "CLINICAL BROCHURE, CIS-PLATINUM (II) DIAMONDICHLORIDE (NSC-119875)", by H. Haldelsman et al. , Investigational Drug Branch, Cancer Chemotherapy Evaluation Program,

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Division of Cancer Treatment, National Cancer Institute (revised August 1974). Pages 31 and 32 concern the

Formulation of cisplatin provided to researchers of the N.C.I, free of charge for clinical evaluation in the chemotherapy of cancer, and read as follows:

Pharmaceutical data

NSC-119875 cis-diaminedichloroplatinum (II)

Dose formulation mg / ampoule:

The contents of each 20 ml flint glass ampoule are present as whitish, lyophilized cake. Each vial contains 10 mg NSC-119875; 90 mg of sodium chloride, 100 mg of mannitol and hydrochloric acid for pH adjustment.

Preparation of a solution:

mg / vial

After reconstitution with 10 μl of sterile water suitable for injection (USP), each ml of the resulting solution contains 1 mg NSC-119875, 10 mg mannitol and 9 mg sodium chloride with a pH in the range 3.5 to 4.5.

Storage:

The dry, unopened vials should be stored at refrigerator temperatures (4-8.

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Stability:

Unopened vials are expected to be stable for one year when stored at refrigerator temperature (4 - 8 ° C). Statements about stability may change as a result of a current 2-year inventory review. Prepared as indicated, a pale yellow solution is obtained which is stable for not more than 1 hour at room temperature (22 ^° C.) when exposed to normal room exposure and not more than 8 hours at room temperature when stored light protected. Prepared solutions can precipitate after one hour at refrigerator temperatures (4 ^ 8 C).

Attention:

The lyophilized dosage forms contain no preservative and it is therefore advisable to discard them eight hours after processing.

August 1974

Clinical Drug Distribution Section

Drug Development Branch.

Published GB application 2021946A describes stable aqueous cisplatin solutions having a cisplatin concentration between 0.1 and 1.0 mg / ml and a pH in the range 2.0 to 3.0. The solutions may also contain a non-toxic, pharmaceutically acceptable, inorganic source of chloride ions, such as sodium chloride, and a carrier, such as mannitol.

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Object of the invention

The aim of the invention is the preparation of stable, concentrated cisplatin solutions with a concentration of about 2.5 to about 25 mg / ml.

Explanation of the essence of the invention

It has been found that from cisplatin and a solvent containing from about 30% to about 95% of polyethylene glycol having an average molecular weight of from about 150 to about 9,000, or a methoxypolyethylene glycol having an average molecular weight of from about 300 to about 6,000, or mixtures thereof, and about The solution also contains at least one non-toxic, pharmaceutically acceptable source of chloride ion in an amount at least approximately equivalent to the amount of cisplatin contained in the solution, which is a stable cisplatin solution preparable May contain 2.5 to 25 mg / ml of cisplatin.

Stable, aqueous cisplatin solutions are described in British Patent Application 2021946A. Although stable solutions with cisplatin concentrations up to about 1 mg / ml can be obtained in such an aqueous medium at room temperature, in the cold, however, crystallization at concentrations higher than about 0.5 mg / ml cisplatin. By simply shaking at room temperature, crystallized cisplatin can not easily be redissolved, but by heating to about 37 ° C, a solution can be reconstituted. Since the shipping and storage temperatures can not be controlled after sale and the crystallization of cisplatin in the vials causes unwanted problems for the administering physician, the maximum concentration of cisplatin in such aqueous media is in practice about 0.5 mg / ml.

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The cisplatin solutions prepared according to the invention may contain up to about 25 mg of cisplatin per ml, although the preferred maximum level is about 15 mg / ml. Inventive solutions with 15 mg cisplatin per ml were stored at a temperature of 4 ⁰ C for 12 months without cisplatin crystallized out. Such solutions were also frozen to -60 ° C and then thawed at room temperature, with no cisplatin precipitation occurring. Thus, the cisplatin solutions prepared according to the invention may in practice have a concentration 30 times higher than the solutions prepared according to the prior art for the practice.

The concentrated cisplating solutions prepared according to the invention also have the advantage that they are per dosage unit

lower shipping, storage and other costs, compared with the known aqueous solutions. While the lyophilized solid form also has lower shipping and storage costs, this saving is more than offset by the time and cost associated with lyophilization.

According to a preferred embodiment, the solvent medium used in the present invention contains from about 80 to about 95% (and more preferably from about 85% to about 90%) polyethylene glycol having an average molecular weight of from about 250 to about 1600 (more preferably from about 250 to about 650) and from about 5% to about 20% (more preferably from about 10% to about 15%) of water. In a most preferred embodiment, the solvent medium comprises about 90% polyethylene glycol having an average molecular weight of about 350 to about 450 and about 10% water.

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Preferably, the solution contains from about 5 to about 20 mg cisplatin per ml, and most preferably from about 10 to about 15 mg / ml. The non-toxic, pharmaceutically acceptable chloride ion source is preferably present in the solution at a level of at least about two equivalents per equivalent of cisplatin. Depending on the cisplatin concentration, the percentage of water and the type of chloride ion source, concentrations up to 50 equivalents or more of chloride ion per equivalent of cisplatin can be used, however, such high concentrations of chloride ions are usually neither necessary nor desirable. It will be apparent to those skilled in the art that at high cisplatin concentration and low water content, it would not be possible to dissolve a sufficient amount of chloride ion source, such as sodium chloride, to obtain 50 equivalents of chloride ion per equivalent of cisplatin. In addition, a saturated or near-saturated solution of an inorganic chloride salt would be undesirable _t because of the possibility that the solution crystallized in the cold. In the case described above, 50 equivalents of chloride ion per equivalent of cisplatin can be obtained by using hydrochloric acid as a source of the chloride ions, but this could give an undesirably acidic solution, ie, a low pH. It has been found that excessively acidic solutions are somewhat less stable than moderately acidic solutions. The pH range of the solutions is preferably between about 1.5 to about 4.5. Preferably, about 2 to about 10 equivalents of chloride ion per equivalent of cisplatin, and most preferably about 3 to about 7 equivalents of chloride ion per equivalent of cisplatin are used.

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The chloride ions can be obtained by adding hydrochloric acid, a non-toxic pharmaceutical metal halide such as sodium chloride, potassium chloride, calcium chloride or magnesium chloride or the hydrochloric acid addition salt of a non-toxic pharmaceutically acceptable tertiary amine such as triethylamine or mixtures thereof. Preferred sources of chloride ions are hydrochloric acid, sodium chloride or a mixture thereof.

Polyethylene glycols and methoxypolyethylene glycols have the general formulas:

or CH ₃ (OCH ₂ CH ₂ ) _n OCH ₃

and are commercially available as CARBOWAX polyethylene glycols and CARBOWAX methoxypolyethylene glycols. According to the invention, the SENTRY grades of CARBOWAX polyethylene glycols are used which are described in U.S.P., N.F. and F.C.C. standards for food and drug applications. Typical molecular weight ranges for a variety of CARBOWAX polyethylene glycols and CARBOWAX methoxypolyethylene glycols are summarized in Tables 1 and 4.

Table 1

CARBOWAX Typical molecular weight ·

Polyethylene glycol ranges

200 190 to 210

300 285 to 315

400 380 to 420

600 570 to 630

1000 950 to 1050

1540 1300 to 1600

4000 3000 to 3700

6000 7000 to 9000

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Table 2

CARBOWAX Typical molecular

Methoxypolyäthylenglycole weight range

350 335 to 365

550 525 to 575

750 715 to 785

2000 1850 to 2150

It is known that polyethylene glycols form complexes with certain inorganic salts. Thus, the reaction of polyethylene glycols with ammonium cobalt thiocyanate to form a blue complex is the basis for a colorimetric method for the determination of the polyethylene glycol concentration in various mixtures. It is believed that the particular stability of cisplatin in the solutions of the invention is due to complex formation between cisplatin and the polyethylene glycol, but this is only theory and not part of the invention. The thin-layer chromatography revealed evidence for complex formation. Using the procedure described below, cisplatin gives a spot at about Rf 0.65. A solution of cisplatin in 90% polyethylene glycol 400-10% H ₂ O (or 10% 0.5 N HCl) gives a spot at about R f 0.3 which pulls to about R f 0.65. If one dilutes with larger amounts of water, the complex appears to break up immediately, since dilution of the above PEG-H_O (or HCl) solution with 5 volumes of water then gives only one cisplatin spot at about Rf 0.65.

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Thin Layer Chromatography Apparatus and Reagents

(a) TLC plates - EM Laboratories silica gel 60 plates, catalog no. 5763, or equivalent.

(b) Eluent - acetone: 1N HNO ₃ (9: 1). Must be freshly prepared daily.

(c) Developer - Dissolve 5.6 g of stannous chloride in 10 ml of conc. HCl, add 90 mL of distilled water and 0.2 g KJ and mix thoroughly. Must be freshly prepared daily.

(d) The laboratory furnace is set at 100 ^° C. method

(a) Dilute the sample with 5 volumes of dimethylformamide (DMF) [Burdick and Jackson, distilled in glassware]

(b) Place a TLC plate containing 5 microliters of the sample and 5 microliters of a standard solution containing cisplatin (and transplatin and platinum B, if appropriate) in a concentration approximately equivalent to that of the sample to be analyzed One develops 10 cm high in a TLC container which has been previously equilibrated with the eluent. Then sprinkle the dried plate with freshly prepared developer solution and give it for 10 minutes at 100 ⁰ C in an oven-observe the yellow / purple zones.

(c) approximate Rf values;

0.65 - cisplatin, 0.76 transplatin, 0.9 platinum B.

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The HPLC analyzes of the solutions according to the invention with regard to the cisplatin content can be carried out according to the method described in published UK Patent Application No. 2021946A. The preferred mobile phase is ethyl acetate / methanol / dimethylformamide / distilled water (25/16/5/5). Standard is preferably cisplatin dissolved in dimethylformamide at a concentration of 1 mg / ml. Analytical samples are diluted with dimethylformamide to an approximate cisplatin content of 1 mg / ml.

Although no particular advantage is achieved by its presence, the solutions of the invention may, if desired, contain a conventional, physiologically acceptable carrier, such as mannitol.

From previous studies of stability, the likely stability of the solutions of the invention (defined as a 10% loss of potency) is greater than two years at room temperature.

According to a preferred embodiment of the invention, the solutions are sterile and pyrogen-free and are packed in sterile, pyrogen-free containers. Such solutions may then be diluted, for example, with sterile water for injections (U.S.P.) or sterile normal saline (U.S.P.), and administered intramuscularly or intravenously. Means for sterilizing these solutions are known in the art. It is preferred to pass the solutions through a sterile, pyrogen-free 0.22 micron Millipore filter under aseptic conditions and under sterile nitrogen pressure. Millipore is a registered trademark of Millipore Corporation for membrane filters. The sterile filtrate is collected in sterile, pyrogen-free containers and is finally

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filled in the desired amount into suitable, sterile, pyrogen-free ampoules, sealed with sterile, pyrogen-free stoppers (which are preferably Teflon-coated) and sealed with sterile aluminum seals.

For use in the treatment of cancer, the concentrated solutions are diluted to the desired concentration (usually 1 mg cisplatin per ml) with, for example, sterile water for injections (USP) sterile normal saline (USP) or sterile glucose solution, and intramuscular or intravenous injected or administered as an intravenous infusion, as is known for the cisplatin preparations according to the prior art. commonly used dosages with weak to moderate tolerability

Toxicity is intravenously in the range of 60-100 mg / M

Single dose or divided over 3 to 5 days, and should be repeated at intervals of four weeks. A dosage of

2 60 mg / M is equivalent to approximately 1.5 mg / kg, which in turn corresponds to approximately 105 mg per patient weighing 70 kg. For best results, other chemotherapeutic agents are often used simultaneously.

The term "equivalents" of chloride ion per "equivalent" of cisplatin used in the specification and claims refers to molar equivalents. For example, using the preferred range of about 3 to about 1 equivalents of chloride ion per equivalent of cisplatin would require from about 3 to about 7 moles of NaCl per mole of cisplatin but from about 1.5 to about 3.5 moles of CaCl ₂ per mole Moles of cisplatin, etc., use.

Platinum B is an arbitrary name used in describing the present invention for an acidic reaction product of cisplatin, which is one-half of the known Magnus Red complex and

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the following structure has been assigned:

Cl

Pt

H ₃ N

Cl

Cl

The invention is further illustrated by the following examples, but not limited.

example 1

Preparation of a Stable Concentrated Solution of Cisplatin (10 mg / ml) in 90% Polyethylene Glycol 400 - 10% In HCl

500 mg of cisplatin are slurried in a solution of 5 ml of 1 N HCl and 45 ml of polyethylene glycol 400. After stirring at room temperature for 2.5 days (protecting the container from light with aluminum foil), a clear yellow solution is obtained. Samples of the solution are placed in 17 ml dark brown vials., Sealed with teflon-covered stoppers, sealed with aluminum caps, and undergo a storage stability test at various temperatures. After two weeks of storage at 45 ° C, thin layer chromatography (TLC) gives the presence of a trace of transplatin and about 1% platinum B. After two weeks storage at 56 ^° C, TLC gives <1% transplatin and about 3% platinum B. Samples, which take two weeks at 56 ⁰ C

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are stored are diluted with 4, 9 and 19 volumes of water to give clear solutions containing 2, 1 and 0.5 mg / ml cisplatin. After standing at room temperature for about 18 hours, all diluted samples turn slightly cloudy.

Example 2

Preparation еіпэг stable, concentrated solution of cisplatin (10 mg / ml) in 90% polyethylene glycol 400 - 10% 0.5 η HCl

5.0 ml of purified water (USP) and 5.0 ml of 1 N HCl are added, and 90.0 ml of polyethylene glycol 400 are added. 500 ml of cisplatin are added to 50 ml of the above solution, the mixture is protected against light with aluminum foil and stirred for 24 hours at room temperature until a clear solution is obtained. Thin layer chromatography of the freshly prepared solution yields only one cisplatin zone with a possible trace of transplatin. Samples of 2 ml each of the solution are placed in brown 17 ml ampoules, sealed with teflon-covered stoppers, sealed with aluminum caps, and subjected to storage stability tests at various temperatures. A sample vial is frozen in a dry ice-acetone bath for one hour and then allowed to warm to room temperature. A clear solution is obtained without precipitation. After three months storage at 37 ^° C. and 45 ^° C., thin layer chromatography gives the presence of 1-2% platinum B and a possible trace of transplatin. After one month of storage at 56 ^° C., TLC shows the presence of more than 5% but less than 10% platinum B and a trace of transplatin. Samples maintained at 37 ^° C. and 45 ^° C. for three months and 56 ^° C. for 1 month were diluted with four volumes of purified water (USP) to give clear solutions containing 2 mg / ml cisplatin. The diluted solutions remain clear after standing at room temperature for 24 hours.

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Example 3

Preparation of a stable, concentrated solution of cisplatin (10 ng / ml) plus CaCl ₃ (20 mg / ml) in 90% polyethylene glycol 10% 0.5 N HCl

Dissolve 2 g of anhydrous CaCl ₃ (reagent grade) in a mixture of 5 ml of purified water (USP) and 5 ml of In HCl. Then add polyethylene glycol 400 (89 ml) to a volume of 100 ml. 550 ml of cisplatin are added to 50 ml of this solution, the mixture is protected against light with aluminum foil and stirred at room temperature for 24 hours, after which a clear solution is obtained. TLC of the freshly prepared solution shows only one cisplatin zone with a possible trace of transplatin. Samples of the 2 ml solution are placed in brown 17 ml vials, sealed with Teflon coated stoppers, sealed with aluminum caps, and run storage stability tests at various temperatures. A sample vial is placed in a dry ice-acetone bath for 0.5 hours and freezes to a clear gel. It is then allowed to warm to room temperature again and receives a clear solution. After storage at 37 ^° C. for 3 months, TLC shows the presence of 1-2% platinum B and a possible trace of transplatin. After storage at 45 ° C for 3 months, TLC shows the presence of about 5% platinum B and a trace of transplatin. After one month storage at 56 ° C, TLC shows the presence of 8-10% platinum B and one lane of transplatin. Samples that had been stored at 37 ^° C. and 45 ^° C. for three months and at 56 ^° C. for one month were diluted with four volumes of purified water (USP) to give clear solutions containing 2 mg / ml cisplatin receives. The diluted solutions remain clear after standing at room temperature for 24 hours.

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Example 4

Preparation of a stable, concentrated solution of cisplatin (about 22 mg / ml) plus CaCl ₂ (25 rag / ml) in 90% polyethylene glycol - 10% 0.5 η HCl

To 3 ml of a solution of 90% polyethylene glycol 400 and 10% 0.5 η HCl are added 4 5 mg of cisplatin and the mixture is stirred for about one hour at room temperature to give a clear solution. A further 30 mg of cisplatin are added (in total 25 mg / ml) and the mixture is stirred for one hour at about 45 ^° C. and then for 18 hours at room temperature, forming an almost complete solution. The small amount of insoluble material is filtered off. TLC of the filtrate shows only one cisplatin zone with a possible trace of transplatin. The remaining filtrate is placed in a brown 17 ml vial, sealed with a teflon-coated stopper, sealed with an aluminum cap and held at 45 ^° C. for three months. Thereafter, the TLC shows 1 to 2% platinum B and no transplatin. Diluting the aged solution with purified water (USP) to a concentration of 2 mg / ml cisplatin gives clear solutions which remained clear after standing at room temperature for 24 hours.

Example 5

Preparation of a stable, concentrated solution of cisplatin (12 mg / ml) plus NaCl (10 mg / ml) in 30% polyethylene glycol 10% 0.5 N HCl

Dissolve 100 mg of sodium chloride in a solution of 5 ml of purified water (U.S.P.) and 5 ml of 1 N HCl. To this solution add 90 ml of polyethylene glycol 400 and stir the mixture for 15 minutes. To 50 ml of the latter solution are added

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500 mg of cisplatin and the mixture is stirred in the dark for 3 days at room temperature to give a clear solution. TLC of the freshly prepared solution shows only one cisplatin stain. HPLC (High Performance Liquid Chromatography) test of the freshly prepared solution shows that it contains 12 mg / ml cisplatin. Samples are sealed in brown 17 ml vials as described in Example 3 and tested for storage stability at various temperatures. After three months storage at 37 ^° C., TLC shows less than 1% platinum B and no transplatin. After one month of storage at 56 ^° C., TLC shows 1-2% platinum B and no transplatin. Diluting the aged samples with purified water (USP) to a concentration of 2 mg / ml cisplatin gives clear solutions, which remain clear after standing at room temperature for 24 hours.

HPLC analyzes of the three months at 45 ^° C., 6 months at 37 ° C. and 8 months at room temperature yielded efficacy losses of 6.6%, 6.1% and 2.3%, respectively.

example

Preparation of a stable, concentrated solution of cisplatin (11.4 mg / ml) plus NaCl (10 mg / ml, in 90% polyethylene glycol 400 - 10% water

To a solution of 50 mg of NaCl in 5 ml of purified water (U.S.P.) and 45 ml of polyethylene glycol 400 is added 500 mg of cisplatin and the mixture is stirred in the dark for 6 hours at room temperature to give a clear solution. TLC of the freshly prepared solution gives only one cisplatin stain; HPLC analysis shows that it contains 11.4 mg cisplatin per ml. Samples are sealed in brown 17 ml vials as described in Example 3 and tested for storage stability at various temperatures. After you

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For 3 months at 37 ⁰ C and 45 ⁰ C, the TLC showed the presence of. 1% platinum B and no transplatinum. After one month storage at 56 ° C, TLC showed the presence of 2 to 3% platinum B and no transplatin. Diluting the aged samples with purified water (USP) to a concentration of 2 mg / ml cisplatin gives clear solutions, which remain clear after standing at room temperature for 24 hours. HPLC analyzes of the 3 months at 45 ° C, 6 months at 37 ⁰ C and 7 months at room temperature stored solutions show efficacy losses of 6.1%, 7.0% and 0.9%.

example

Preparation of a stable concentrated solution of cisplatin (10 mg / ml) in 90% polyethylene glycol 600 - 10% 0.5 η HCl

To a solution of 2.5 ml of purified water (ü.SP) / 2.5 ml of 1 η HCl and 45 ml of polyethylene glycol 600 is added 500 mg of cisplatin and the mixture is stirred in the dark for 5 hours at room temperature to obtain a clear solution , TLC of the freshly prepared solution gives only one cisplatin stain. Samples of the freshly prepared solution are diluted with 1, 2, 3, 4, 5 and 9 volumes of purified water (ü.SP); crystallization does not occur at these temperatures after 16 hours at room temperature or 4 ^° C. Samples of the freshly prepared solution are sealed in brown 17 ml ampoules as described in Example 3 and tested for storage stability at several temperatures. After standing at 37 ^° C. and 45 ^° C. for 3 months, the TLC shows 1% platinum B and no transplatin. After a month

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Storage at 56 ⁰ C, the TLC shows the presence of 3.4% platinum B and no transplatin. Diluting the aged specimens with purified water (USP) to a concentration of 2 mg / ml cisplatin gives clear solutions which clear after 24 hours at room temperature.

Example 8

Preparation of a stable concentrated solution of cisplatin (10mg / ml) plus NaCl (10mg / ial) in 90% polyethylene glycol 400 10% 0.2 η HCl

To a solution of 0.5 g of NaCl in 4 ml of purified water (U.S.P.), 1 ml of 1 N HCl and 45 ml of polyethylene glycol 400 is added 250 mg of cisplatin and the mixture is stirred in the dark

4 hours at room temperature, giving a clear solution. TLC of the freshly prepared solution shows only one cisplatin stain. Dilution of the freshly prepared solution with 1, 2, 3, 4, 5 and 9 volumes of purified water gives clear solutions which remain clear after standing at room temperature for 24 hours. The on 1, 2, 3/4 and

5 volumes of dilute solutions zeigea no crystallization when they stand for 24 hours at 4 ⁰ C. Portions of the freshly prepared solutions are sealed in brown 17 ml ampoules as described in Example 3 and exposed to storage stability tests at various temperatures. After storage for 3 months at 37 ^° C., TLC shows the presence of 1% platinum B with a possible trace of transplatin.

After three months storage at 45 ° C, TLC shows the presence of 5% platinum B with a possible trace of transplatin. After one month of storage at 56 ^° C., TLC shows the presence of 2 to 3% platinum B and no transplatin. Dilute the aged samples with purified

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Water (U.S.P.) to a concentration of 2 mg / ml cisplatin, clear solutions are obtained which remain clear after standing at room temperature for 24 hours.

example

Preparation of a stable concentrated solution of cisplatin (2.5 mg / ml), NaCl (9 mcj / ml) and mannitol (12.5 mg / ml) in acidified 31% (w / v) aqueous polyethylene glycol 6000

0.9 g of sodium chloride, 1.25 g of mannitol and 31.3 g of polyethylene glycol 6000 is dissolved in so much water that gives 100 ml of solution and the solution is acidified with 0.7 ml of 1 η HCl to pH 2.2 , Cisplatin is added to the mixture at 255 mg and stirred in the dark for 3 days at room temperature to give a clear solution. TLC of the freshly prepared solution shows only one cisplatin zone. Samples of the freshly prepared solution are sealed, as described in Example 3, in brown 17 ml ampoules and subjected to storage stability tests at 45 ° C. and 56 ^° C. After two months storage at 45 ^° C. and 56 ^° C., TLC shows less than 1% platinum B and no transplatin. Diluting the aged samples with an equal volume of purified water (USP) gives clear solutions, which remain clear after standing for 24 hours at room temperature.

Example 10

(15.8 mg / ml)

Preparation of a stable concentrated solution of cisplatin plus NaCl (10 mg / ml) in 90% aqueous polvethylenhylene glycol 400

90 ml of polyethylene glycol are dissolved in a solution of 1.0 g of NaCl in 10 ml of purified water (U.S.P.). To 60 ml of the resulting solution is added 900 mg of cisplatin and stirred

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Blend in the dark for five hours at room temperature, giving a clear solution. TLC of the freshly prepared solution shows only one cisplatin zone; HPLC analyzes show that it contains 15.8 mg cisplatin per ml. Diluting the freshly prepared solution with four volumes of purified water (USP) gives a clear solution that remains clear after standing at room temperature for 24 hours. Samples of the freshly prepared solution are sealed in brown 17 ml vials as described in Example 3 and subjected to stability tests at various temperatures. After two months of storage at 45 ^° C., the TLC shows 1.5% platinum B and no transplatin. After one month storage at 56 ^° C., the TLC shows 2% platinum B and no transplatin. The samples aged at 56 ^° C. are diluted to a concentration of 2 mg / ml with sterile water suitable for injections, and the samples aged at 45 ^° C. are also adjusted to concentrations of 2.5 and 5 with sterile water suitable for injection. 0 mg / ml cisplatin diluted. They all form clear solutions, which remain clear after standing for 24 hours at room temperature.

HPLC analyzes of the three months at 45 ^° C., 6 months at 37 ^° C. and 8 months storage at room temperature show efficacy losses of 7.6%, 7.6% and 0%, respectively.

Example 11

Preparation of a stable concentrated solution of cisplatin (15 mg / ml) plus CaCl ₂ (25 mg / ml) in 90% aqueous polyethylene glycol 400

To a solution of 2.5 g of CaCl ₂ in 10 ml of purified water (USP) is added 90 ml of polyethylene glycol 4 00, and the resulting solution is stirred for 10 minutes. To 50 ml of the above solution is added 750 mg of cisplatin and stirred

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Mixture in the dark for 5 hours, giving a clear solution. TLC of the freshly prepared solution shows only one cisplatin zone. Dilutions of the freshly prepared solution with 1/2, 5 and 10 volumes of purified water (USP) give clear solutions. Samples of the freshly prepared solution, as described in Example 3, sealed in 17 ml vials and brown at 45 ⁰ C and 56 ° C examined for storage stability. After two months of storage at 45 ^° C., TLC shows the presence of 1.5% platinum B and no transplatin. After one month storage at 56 ^° C., TLC shows the presence of 2.5 to 5% platinum B and no transplatin. The sample aged at 56 ^° C. is diluted to a concentration of 2 mg / ml and the sample aged at 45 ° C. is diluted to concentrations of 2.5 and 5.0 mg / ml of cisplatin with sterile water suitable for injection. They form clear solutions that remain clear after standing for 24 hours at room temperature.

Example 12

Kerstelluno a sterile, stable, concentrated solution before. Cisplatin in 90% polyethylene glycol 400 - 10% 0.5 η HCl (the label indicates 15 mg / ml cisplatin activity)

Note : Cisplatin is a potential carcinogen. Protective clothing, gloves, masks, goggles and headgear must be worn throughout the procedure. All work areas and equipment must be thoroughly cleaned to prevent subsequent contamination.

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formulation

per ml per 10.0 ml

Cisplatin 0.015 g ⁽¹⁾ 0.150 g

Sodium chloride 0.015 g 0.150 g

(2)

0.5 η hydrochloric acid 0.10 ml 1.0 ml

Polyethylene glycol 400

as much as necessary to 1.0 ml 10.0 ml

* This cisplatin weight is said to be effective

1000 mcg / mg. The following formula is used to calculate the amount of cisplatin required:

1000 x 0.015 g

= Grams of needed

Effectiveness of cisplatin mcg / mg cisplatin

'One liter of 0.5 η hydrochloric acid is prepared as follows:

1) Place 957.25 ml sterile sterile water suitable for injection into a clean 1 liter Erlenmeyer flask.

2) With rapid stirring, slowly and carefully add 42.75 ml of conc. Hydrochloric acid and stirred for a further 10 minutes. Then close with a clean butyl rubber stopper.

Preparation instructions for one liter of sterile solution

1) Add 100 ml of 0.5 N hydrochloric acid to a clean, calibrated, 1-liter conical flask containing a suitable stirrer, e.g. a 6 cm long Teflon-coated magnetic stir bar.

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2) With slow stirring add 15.0 g of sodium chloride and stir until the salt is completely dissolved.

3) With rapid stirring, then 750 ml of polyethylene glycol 400 (SENTRY Reinehit) and stirred for 5 minutes.

4) Then carefully remove the stir bar and return excess liquid to the flask.

5) Then cisplatin is added cautiously according to an efficacy of 15.0 g.

6) Give Polyethylene Glycol 400 up to the 1 liter mark

to (a total of 880 ml Polyäthylgenlycol 400 is required).

7) Return the Teflon stirrer to the mixture and close with a pure butyl rubber stopper.

8) Wrap the flask in aluminum foil to completely shield against light.

9) It is stirred rapidly for 24 to 48 hours room temperature, whereby a clear solution should be obtained. If there is no clear solution after 48 hours, the mixture can be heated at 37 to 40 ° C for 2 to 6 hours with the exclusion of air and light to facilitate the dissolution of the remaining cisplatin. Then it is cooled to 23 to 27 ⁰ C from.

19) By aseptically working, pass the dark yellow solution under sterile nitrogen flow through a suitable sterile, pyrogen-free 0.22 micron Millipore filter. The sterile filtrate is collected in a sterile, pyrogen-free Erlenmeyer flask and sealed with a sterile pyrogen-free butyl rubber stopper. The solution can be stored in the dark.

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11) Fill the required amount of sterile solution into sterile, pyrogen-free brown ampoules, seal with a sterile, pyrogen-free Teflon stopper and seal with sterile aluminum caps.

12) The ampoules should be marked as follows as a warning:

Not for direct intramuscular or intravenous administration *

* The polyethylene glycol-400 solution can be diluted with 14 parts sterile sterile water for injection (USP) or sterile 1N saline (USP) to give a solution of 1 mg / ml cisplatin. If higher concentrations are needed, add тгщ correspondingly less sterile water or saline solution. The diluted solutions can be administered intravenously and are stable at room temperature (22-26 ^° C.) for at least 48 hours. The diluted solutions must not be cooled, otherwise crystals could form.

13) The ampoules should be stored dark.

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Example 13

Preparation of a stable, concentrated solution of cisplatin (2.5 mg / ml), NaCl (9 mg / ml), CaCl ₃ (15 ng / ml) and mannitol

(10 mg / ml) in acidified 31% aqueous ethylene glycol

0.9 g of sodium chloride, 1.5 g of CaCl ₃ and 1.0 g of mannitol are dissolved in a mixture of 31.25 ml of polyethylene glycol 400 and 40 ml of purified water (USP). The solution is acidified to pH 2.2 with 0.4 ml of 1 N HCl, 255 mg of cisplatin are added, the volume is increased to 100 ml with purified water and the mixture is stirred in the dark at room temperature for 5 hours to give a clear Solution receives. TLC of the freshly prepared solution shows only one cisplatin zone.

Example 14

The procedure is as described in Example 5, with the exception that the sodium chloride used is replaced by an equivalent amount of magnesium chloride, thereby obtaining a stable, concentrated cisplatin solution,

Example 15

The procedure is as described in Example 5, with the exception that the sodium chloride used is replaced by an equivalent amount of triethylamine hydrochloride, and receives a stable, concentrated cisplatin solution.

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Example 16

The procedure is as described in Example 5, with the exception that the polyethylene glycol used 4 00 is replaced by an equal volume of polyethylene glycol 200 or 300, and receives stable, concentrated cisplatin solutions.

Example 17

The procedure is as described in Example 9, with the exception that the polyethylene glycol 6000 used in this case is replaced by an equal weight amount of polyethylene glycol 1000 or 4000, and obtains stable, concentrated cisplatin solutions.

Claims (5)

M / 22 079 - 29 - invention claim A process for preparing a stable, concentrated solution of cisplatin in a solvent medium, characterized by reacting in a solvent containing from about 30% to about 95% of polyethylene glycol having an average molecular weight of from about 150 to about 9,000, or a methoxypolyethylene glycol having an average of Molecular weight of about to about 6000, or mixtures thereof, and about 5% to about 70% water, so much cisplatin dissolves to give a cisplatin concentration of 2.5 to about 25 mg / ml and at least one non-toxic, adding a pharmaceutically acceptable source of chloride ion in an amount at least approximately equivalent to the amount of cisplatin contained in the solution, and optionally transferring the resulting solution to a sterile container, preferably an ampoule, sterilizing and sealing. 2. The method according to item 1, characterized in that the solvent used is a medium comprising about 80% to about 95% of a polyethylene glycol having an average molecular weight of about 250 to about 1600, or a Methoxypolyäthylenglycols having an average molecular weight of about 300 to about BOO, or a mixture thereof, and about 5% to about 20% water, which solution is also at least one non-toxic, pharmaceutically M / 22 079 - 30 - contains an acceptable source of chloride ion, which is about one equivalent to about ten equivalents per cisplatin equivalent contained in the solution, and as much cisplatin admits that the solution contains about 5 to about 20 mg / ml of cisplatin. 3. The method according to item 1 or 2, characterized in that one uses as non-toxic, pharmaceutically acceptable chloride ion source, hydrochloric acid, sodium chloride, calcium chloride, magnesium chloride or triethylamine hydrochloride or a mixture thereof. A process according to any one of the preceding claims, characterized by using as solvent a medium containing from about 85% to about 90% of polyethylene glycol having an average molecular weight of from about 250 to about 650 and from about 10% to about 15% water, and this solution also contains a source of chloride ion selected from hydrochloric acid, sodium chloride and mixtures thereof, in an amount of about two to about seven equivalents, per equivalent of cisplatin contained in the solution, and so much cisplatin admits that the solution has a cisplatin content of about 10 to about 15 mg / ml. 5. The method according to item 4, characterized in that in a solvent system consisting of about 90% polyethylene glycol having an average molecular weight of about 350 to about 4 50 and about 10% water, about 10 to about 15 mg cisplatin per ml M / 22 079 - 31 - and dissolve about 10 to about 15 mg NaCl per ml. Process according to item 5, characterized in that, in a solvent system consisting of about 90% polyethylene glycol having an average molecular weight of about 350 to about 40 and about 10% of dilute hydrochloric acid having a concentration of up to 0.5 n, about 10 to Dissolve about 15 mg cisplatin per ml and about 10 to about 15 mg NaCl per ml.