KR860000841B1 - Process of preparing stable concentrated solutions of cisplatin - Google Patents

Abstract

Stable concd. cis-platin(I) (esp. diaminodichloroplatinum or diaminotetrachloroplatinun) contg. 2.5 - 25 mg/ml cis-platin in a solvent comprising 30 - 90% polyethylene glycol(mol. wt. 150 9000), methoxy polyethylene(mol. wt. 300 - 6000), or mixts. of these contg. HCl or a chloride salt was prepd. Thus, 90 ml PEG 400 was mixed with a soln. of 1.0g NaCl in 10 ml H2O. I (900mg) and dissolved in 60 ml of this soln. by stirring in the dark for 5 hr. at room temp. The resulting soln. contained 15.8 mg I/ml and 10 mg NaCl/ml in 90% aq. PEG. The soln. is stable in storage and is used as an antiumor agent. Chloride ions include HCl, NaCl, CaCl2, MgCl2 or triethylamine hydrochrolide.

Description

Method for preparing a stabilized concentrated solution of cisplatin

The present invention relates to a stabilized concentrated solution of cisplation present in water-soluble polyethylene glycol, methoxy polyethylene glycol or mixtures thereof containing chloride ions.

Platinum compounds are unique compounds for the treatment of anti-neoplastic groups. The fact that these compounds have an antibiotic effect was first noted by Rosenberg and his colleagues in 1965 (Nature by Rosenberg, B., et al., 205, 698-699 (1965)). Antitumor therapy continues to be known by Rosenberg and his colleagues.

Nature (London), 222, 385-386 (1969) by Rosenberg, B. et al.

They are structurally represented as complexes in which the central atoms are formed of platinum and coordinated with various arrangements of chlorine or ammonia groups in cis or trans plane correlation. Two of the most widely studied platinum compounds are plotted as follows.

Cis-platinum (II), cis-platinum (IV), diaminechloride, diaminetetrachloride.

As shown above, both the chlorine and amino groups of the cis-platinum (II) diamine chloride compound are on one plane.

[참조 : Kauffman, G.B. 등에 의한 Inorganic Synthesis, J, Kleinberg(Ed.), pp. 239-245,McGraw-Hill Book Co., Inc., 뉴욕, 1963].The compound, named cisplatin by the United States Adopted Name (USAN), is synthesized according to the following reaction:

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

Breusva-Baidala, Y.G. Akademia Nauk SSSR No. 6, pp. 1230-1242 (June 1974) describes the conversion of cis-pratinium (II) diamine chloride to trans form by slow isomerization in aqueous solution.

Journal of the American Chemical Scciety 83, 2457-2462 (1961) by Reishus, JW and Martin, DS, describes the acid hydrolysis of cisplatin at 25 ° C and 35 ° C. These studies were carried out in aqueous solutions of 1.5 × 10 ⁻³ M, 2.5 × 10 ⁻³ M and 5.0 × 10 ⁻³ M concentrations corresponding to 0.45, 0.75 and 1.5 mg / ml, respectively. The authors say that it takes slightly 10 to 30 minutes for the sample to dissolve completely at such low concentrations, so that the origin of the hydrolysis curve (ie, "zero point") is a bit vague.

Annals of Internal Medicine 86, 803-812 (1977) by Rozencweig, M., et al., Have shown the results of various preclinical and clinical studies using cisplatin in experimental tumors in animals as well as tumors in various types of humans. Presenting.

The study drug is a vial containing 10 mg of cisplatin, 90 mg of sodium chloride, 100 mg of mannitol (USP), and hydrochloric acid to adjust the pH to facilitate licensed researchers at the Investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute. ), It was supplied as a lyophilized white powder. Each 1 ml of the resulting solution, when dissolved in 10 ml of sterile water for injection (U.S.P), contains 1 mg of cisplatin, 10 mg of mannitol, and 9 mg of sodium chloride.

Cancer Chemotherapy Reports by Tally, EW, et al., 57, 465-471 (1973), describe the results of their Phase I clinical study using cisplatin in the treatment of 65 patients with various neoplasms. . As in the aforementioned publication, the drug is in the form of a vial containing 10 mg of cisplatin, 90 mg of sodium chloride and 100 mg of mannitol, which has been injected from the patient by the National Cancer Institute, and 10 ml of sterile water is used as a solvent.

Cancer, 30, 1451-1456 (1972) by Rossf, A.H., et al. Describe the results of the use of cisplatin in the treatment of 31 patients with various types of tumors. They are manufactured by Ben Venue Laboratories, Inc., and the drugs injected by the National Institute contain 10 mg of cisplatin, 10 mg of mannitol (Sic) and sodium chloride (9 mg) (Sic) per vial. It is described as rapidly dissolving in 8-10 ml of sterile water.

Information on the chemical and pharmaceutical structure of cisplatin can be found in Haldelsman et al. "CLINICAL BROCHURE, CISPLATIUM (II) DIAMMINEDICHLORIDE (NSC-119875)" Investigational Branch, Cancer Chemotherapy Evaluation Program, Division of Cancer Theatment, National Cancer Institute (1974). August revised), pages 1-5 and 31-32.

Faye 31 and 32 above relate to a formulation of cisplatin supplied free of charge to clinicians by N.C.I for the clinical evaluation of cancer chemotherapy, as follows:

Pharmaceutical Data Sheet

NSC-119875 cis-diamine dichloropratium (II)

Proper quantity

10 mg / vial: The contents of each 20 ml flint vial were lyophilized cake-like and bleached white.

Each vial contains NSC-119875 10 mg: sodium chloride 90 mg; It contains 100 mg of mannitol and hydrochloric acid for pH adjustment.

Solution combination

10 mg / vial: When reformed to 10 ml of injectable sterile water (U.S.P), the resulting solution contains NSC-119875, 1 mg mannitol 10 mg and 9 mg sodium chloride per ml, with a pH in the range 3.5-4.5.

Storage: Dry, closed vials should be stored at refrigeration temperatures (4-8 ° C).

Stability: A complete Bayer has a stability of one year when stored at refrigeration temperatures (4-8 ° C). Recommended stability is a shelf-life of about two years. The light yellow solution produced by dissolution as indicated is stable only for 8 hours or less when protected from light at room temperature (22 ° C) and only for 1 hour or less when exposed to room temperature (22 ° C) normal room light. The solution forms a precipitate after 1 hour at refrigeration temperature (4-8 ° C.).

Note: Lyophilized titrants do not contain preservatives and should be discarded after 8 hours of dissolution.

August 1974 Clinical Drug Distribution Section Drug Development Brancdh.

British Patent Application No. 2021946A describes a stable aqueous solution of cisplatin having a pH range of 2.0 to 3.0 and a cisplatin concentration of 0.1 to 1.0 mg / ml. The solution contains an excipient such as mannitol and a non-toxic pharmaceutically acceptable chlorine ion such as sodium chloride.

The present invention relates to a stable and concentrated solution of cisplatin with a concentration of 2.5 to 25 mg / ml. In particular, the present invention comprises a solvent comprising polyethylene glycol having an average molecular weight of 150 to 9000 or methoxypolyethylene glycol having an average molecular weight of 300 to 6000 or a mixture thereof of about 30% to 95% and about 5% to 70% water. The present invention relates to a stable and concentrated solution of cisplatin present in a commercial body, said solution being capable of producing a non-toxic and pharmaceutically acceptable source of chlorine ion in an amount approximately equal to the amount of cisplatin present in the solution. At least one, and the solution also has a cisplatin concentration of 2.5 to 25 mg / ml.

Stable aqueous solutions of cisplatin are described in British Patent No. 2021946A. Although stable solutions containing cisplatin at concentrations of up to about 1 mg / ml can be obtained in aqueous media at room temperature, substantially at concentrations of cisplatin above about 0.5 mg / ml, Crystallization may occur. Although the solution is recalculated by heating to about 37 [deg.] C., this redissolved crystallized cisplatin is not easily shaken at room temperature.

The actual maximum concentration of cisplatin in an aqueous medium is about 0.5 mg / ml since post-sale shipping and storage temperatures cannot be controlled and also the crystallization of cisplatin in vials causes undesirable problems when administered.

The cisplatin solution of the present invention contains up to 25 mg of cisplatin per ml with a good maximum concentration of about 15 mg / ml. The solution of the present invention containing 15 mg of cisplatin per ml is maintained at 4 ° C. for 12 months without crystallization of cisplatin. The solution is also frozen at −60 ° C. and then dissolved at room temperature without cisplatin precipitation.

Thus, the practical solution prepared according to the present invention has a cisplatin concentration 30 times higher than the practical aqueous solution prepared according to the preliminary process.

The concentrated solution of cisplatin produced by the present invention has very low shipping, storage and other costs per unit capacity compared to known conventional aqueous solutions. Although the known lyophilized solid forms have lower shipping and storage costs, the cost savings from this process are greater than the cost and time offset associated with lyophilization.

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

Preferred solutions contain 5-20 mg cisplatin per ml, most preferably at 10-15 mg / ml.

It is preferred that there is a non-toxic, pharmaceutically acceptable source of chlorine ion in the solution at a concentration of at least 2 equivalents per equivalent of cisplatin.

Depending on the concentration of cisplatin, the percentage of water present and the specific chlorine ion generator, chlorine ions may be used in concentrations of 50 equivalents or more per equivalent of cisplatin, but the high concentrations of these ions are generally not necessary. Neither is it desirable. Those skilled in the process should provide sufficient amounts of chlorine ion generators (e.g. sodium chloride) to provide 50 equivalents of chloride ions per equivalent of cispratin in solutions with high concentrations of cisplatin and low water content. You will see that it is impossible to dissolve. Moreover, saturated or nearly saturated inorganic chloride solutions are undesirable because of the possibility of crystallization from the solution upon refrigeration. As mentioned above, 50 equivalents of chlorine ion per equivalent of cisplatin can be obtained by using hydrochloric acid as the source of chlorine ions, but leads to solutions with undesirable high acidity (ie low pH).

Excessively acidic acid solutions are known to be less stable than moderate acid solutions. The preferred pH range of the solution is about 1.5 to 4.5. Preferably, 2 to 10 equivalents of chlorine ion per equivalent of cisplatin, and most preferably 3 to 7 equivalents of chlorine ion per equivalent of cisplatin.

Chlorine ions are hydrochloric acid, non-toxic pharmaceutically acceptable metal halides such as sodium chloride, potassium chloride, calcium chloride or magnesium chloride, or non-toxic pharmaceutically acceptable tertiary amines such as triethylamine. By addition of addition salts or mixtures thereof.

Preferred chlorine ion generators are hydrochloric acid, sodium chloride or mixtures thereof. Polyethyleneglycols and methoxypolyethyleneglycols are compounds having the structures of H (OCH ₂ CH ₂ ) n OH and CH ₃ (OCH ₂ CH ₂ ) nOCH ₃ , respectively, and are commercially available as CARBOWAX polyethylene glycol and CARBOWAX methoxy polyethylene glycol. Can be used.

It is preferable to use SENTRY Grades of CARBOWAX polyethylene glycols, which are described in U.S.P., N.E. And F.C.C. to meet the specifications. Typical molecular weight ranges for various CARBOWAX polyethylene glycols and CARBOWAX methoxypolyethylene glycols are specified in Tables (1) and (2) below.

TABLE 1

TABLE 2

Polyethylene glycol is known to form complexes with inorganic salts. Therefore, the reaction of ammonium cobaltthiocyanate with polyethylene glycol to form a blue complex compound follows the colorimetric method for determining the concentration of polyethylene glycol in various mixtures.

The specific stability of cisplatin in the solution according to the invention is believed to be due to the complex formed between cisplatin and polyethylene glycol, but this is only a theory and does not form part of the invention. Evidence of complex formation was determined by Applicants by TLC. Using the method described below, it can be seen that the water-soluble cisplatin produces a spot at Rf 0.65. However, a solution of cisplatin in 90% polyethylene glycol 400,10% H ₂ O (or 10% 0.5 N HCl) forms a spot at Rf 0.3 leading to Joules up to Rf 0.65. Dilution with a sufficient amount of water immediately destroys the complex, indicating that cisplatin spots appear only at Rf 0.65 when the REG-H ₂ O (or HCl) solution is diluted with 5 volumes of water.

Thin layer chromatography

Device and Indicator

(a) TLC plate-EM Laboratories Silica Gel 60plate, Catalog No. 5763 or the like.

(b) eluent-acetone: 1N HNO ₃ (9: 1). Manufactured every day.

(c) 5.6 g of tin chloride are dissolved in 10 ml of concentrated HCl. 90 ml of distilled water, 0.2 g of potassium iodide are added. Mix well. Newly manufactured daily.

(d) Fix the experiment oven to 100 ° C.

How to proceed

(a) Dilute the sample with 5 volumes of dimethylformamide (DMF). [Burdick and Jackson, distilled from glass].

(b) Five microliters of sample and 5 microliters of standard solution containing cisplatin (if applicable, also transplatinium and platinum B) at approximately the same concentrations expected in the sample to be analyzed. It is developed to a height of 10 cm in a TLC tank previously equilibrated with a spot eluent. The newly prepared developing solution is sprayed onto the dried plate and left to stand at 100 ° C. for 10 minutes. Yellow / violet bands are observed.

(c) Approximate Rf value: 0.65-cisplatin, 0.76-transpratinium, 0.9-pratinium B.

HPLC analysis of the solution of the present invention to determine the cisplatin content can be carried out according to the method described in British Patent Specification No. 202194A. Preferred fluidized beds are ethyl acetate / methanol / dimethylformamide / distilled water (25/16/5/5). Preferred standard solutions are cisplatin dissolved in dimethylformamide at a concentration of 1 mg / ml.

The analytical sample is diluted with dimethylformamide so that the cisplatin concentration of 1 mg / ml is about 1 mg / ml.

Although no particular benefit is obtained, physiologically acceptable excipients such as mannitol may be included in the solution of the present invention.

Based on the stability studies for elapsed time, the predicted stability (defined as 10% loss of titer) of the solution of the present invention is at least 2 years at room temperature.

In a preferred embodiment of the invention, the solution is sterile, pyrogenic and packaged in a sterile, pyrogen free container. Thereafter, the above solution was used as a sterile water for injection U.S.P. Or diluted with normal physiological sterilization solution U.S.P., etc. and administered intramuscularly or intravenously. Methods of sterilizing these solutions are known in the present process. The solution is preferably passed through a sterile, pyrogen-free 0.22 micron Millipore filter using aseptic techniques under sterile nitrogen pressure. Millipore, a membrane filter, is a registered trademark of Millipore Corporation. Sterile filtrate is collected in a sterile, pyrogen-free container and is finally filled in an appropriate sterile, pyrogen-conjugated vial into a vial containing a sterile, pyrogen-free cap (Teflon coated Good) and sealed with a sterile aluminum seal.

For use in the treatment of cancer, the concentrated solution is diluted with sterilized water USP, normal physiological sterilized solution USP, or glucose sterilized solution to a desired concentration (typically 1 mg cisplatin per ml) and prepared in conventional cisplatin. Intramuscular or intravenous injection or intravenous infusion as known in the art. The dose with moderately acceptable toxicity used recently is intravenous administration of 60-100 mg / M ² in a single dose or in divided doses over 3-5 days, preferably repeated every four weeks. The dosage of 60 mg / M ² is equal to 1.5 mg / kg, usually equivalent to 105 mg / 70 kg of the patient. For best results, treatment is usually done concurrently with other chemotherapeutic agents.

As used herein and in the claims, "equivalent" of chlorine ion per "equivalent" of cispratin means molar equivalents.

For example, when a range of 3 to 7 equivalents of chlorine ion per equivalent of cisplatin is used, it means that 3 to 7 moles of NaCl per mole of cisplatin or 1.5 to 3.5 moles of CaCl ₂ per mole of cisplatin are used. .

Platinum B, optionally used herein for use as an acid reaction product of cisplatin, is one half of the known magnus thread complex and may be represented temporarily by the following structure:

Example 1

Stable concentrate of cisplatin (10 mg / ml) in 90% polyethylene glycol 400-10% 1N HCl

Cisplatin (500 mg) is slurried in a solution of 5 ml, 1N HCl and 45 ml of polyethylene glycol 400.

After stirring for 2.5 days at room temperature (in a container protected from light as aluminum foil), a clear yellow solution is obtained. A portion of the solution is placed in a 17 ml yellow vial, covered with a Teflon coated stopper, sealed with an aluminum cap and subjected to storage stability experiments at various temperatures. After two weeks of storage at 45 ° C., thin layer chromatography (TLC) showed trace amounts of transpratinium and about 1% of platinum B present. After two weeks of storage at 56 ° C., TLC showed less than 1% of transpratinium and about 3% of platinum B. Samples stored for two weeks at 56 ° C. are diluted with 4,9 and 19 volumes of water to obtain clear solutions containing 2,1 and 0.5 mg / ml cisplatin, respectively. The diluted sample is left at room temperature for 18 hours to produce some cloud points.

Example 2

Stable concentrated solution of cisplatin (10 mg / ml) in 90% polyethylene glycol 400-10% 0.5N HCl

After mixing 5 ml of purified water U.S.P. and 5.0 ml of 1N HCl, 90.0 ml of polyethylene glycol 400 is added.

After adding 500 mg of cisplatin to 50 ml of the solution, the mixture is protected from light by aluminum foil and stirred at room temperature for 24 hours to give a clear solution. TLC on the freshly prepared solution shows a trace amount of transpratinium. 2 ml aliquots of solution are placed in 17 ml yellow vials, sealed with Teflon-coated stoppers, sealed with aluminum caps and tested for storage stability at various temperatures. One sample vial is frozen in ice-acetone bath for 1 hour and then left at room temperature. Clear solution free of precipitate is obtained. After 3 months of storage at 37 ° C and 45 ° C, the presence of 1-2% platinum B and traces of transpratinium can be achieved by TLC.

After a month of storage at 56 ° C., TLC showed the presence of 5% -10% of platinum B and traces of transpratinium. Diluting the sample stored at 37 ° C and 45 ° C for 3 months and the sample stored at 56 ° C with 4 volumes of purified water USP yielded a clear solution when the concentration of cisplatin was 2 mg / ml. It stays clear even if left standing for 24 hours.

Example 3

Stable concentrated solution of cisplatin (10mg / ml) + CaCl "_2under" (20mg / ml) in 90% polyethyleneglycol 400-10% 0.5N HCl

2 g of anhydrous CaCl ₂ are dissolved in a mixture of 5 ml of purified water USP and 5 ml of 1N HCl. Polyethylene glycol 400 (89 ml) is added to bring the volume to 100 ml.

After adding 550 mg of cisplatin to 50 ml of this solution, the mixture is protected from light using aluminum foil and stirred at room temperature for 24 hours to obtain a clear solution. TLC on the prepared solution reveals the presence of traces of transpratinium and cisplatin. 2 ml of each sample solution is placed in 17 ml yellow vial, sealed with Teflon-coated stopper, sealed with an aluminum cap, and tested for storage stability at various temperatures. One sample vial is left in ice-acetone bath for 0.5 hours and frozen in clear gel. Keeping the solution at room temperature yields a clear solution. After 3 months of storage at 37 ° C., TLC showed that 1-2% of platinum B and traces of transpratinium were present. After 3 months storage at 45 ° C., TLC showed that about 5% of platinum B and traces of transpratinium were present. After 1 month of storage at 56 ° C, TLC showed that the presence of platinum B and traces of transpratinium was present. Samples stored at 37 ° C. and 45 ° C. for 3 months and at 56 ° C. for 1 month were transferred to purified water. Dilution to 4 volumes yields a clear solution when the concentration of cisplatin is 2 mg / ml. The solution remains clear even when left at room temperature for 2 hours.

Example 4

Stable concentrated solution of cisplatin (about 22 mg / ml) in 90% polyethylene glycol 400-10% 0.5N HCl

In 3 ml of a solution of 90% polyethylene glycol 400 and 10% 0.5N HCl, 45 mg of cisplatin is added and the mixture is stirred at room temperature for 1 hour to obtain a clear solution. An additional 30 mg of cisplatin (total 25 mg / ml) and the mixture are stirred at 45 ° C. for 1 hour and at room temperature for 18 hours to obtain a nearly complete solution. Small amounts of insoluble matter are removed by filtration. TLC on the filtrate confirms the presence of trace pratium and cisplatin. The remaining filtrate is placed in a 17 ml vial, closed with a Teflon-coated stopper, sealed with an aluminum cap, and left standing at 45 ° C. for 3 months. After 3 months of aging at 45 ° C., TLC can confirm the presence of 1-2% platinum B and the absence of trans platinum. Diluting the aged solution with purified water U.S.P. results in a clear solution when the concentration of cisplatin is 2 mg / ml. The solution remains clear even after standing at room temperature for 24 hours.

Example 5

Stable Concentrated Solution of Cisplatin (12mg / ml) + NaCl (10mg / ml) in 90% Polyethyleneglycol 400-10% 0.5N HCl

Sodium chloride (100 mg) is dissolved in a solution of 5 ml purified water U.S.P. and 5 ml 1N HCl. 90 ml of polyethylene glycol 400 is added to this solution and the mixture is stirred for 15 minutes. To 50 ml of this solution, 500 mg of cisplatin is added and the mixture is stirred for 3 days in a dark place at room temperature to give a clear solution. TLC of the prepared solution shows cisplatin spot. High preparative liquid chromatography (HPLC) analysis of the prepared solution shows that it contains 120 mg of cisplatin per ml. Samples are sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at various temperatures. After 3 months of storage at 37 ° C, TLC showed less than 1% of platinum B and no transpratinium. After storage for one month at 56 ° C., it can be seen by TLC that 1-2% platinum B is present and free of transpratinium.

Diluting the aged sample with purified water U.S.P. to a concentration of cisplatin of 2 mg / ml produces a clear solution, which remains clear even after standing at room temperature for 24 hours. HPLC analysis of samples stored for 3 months at 45 ° C., 6 months at 37 ° C., and 8 months at room temperature showed 6.6%, 6.1% and 2.3% of efficacy, respectively.

Example 6

Stable, concentrated solution of cisplatin (10 mg / ml) + NaCl (10 mg / ml) in 90% polyethylene glycol 400-10% water

To a solution of 50 mg of NaCl dissolved in 5 ml of purified water U.S.P. and 45 ml of polyethylene glycol 400 was added 500 mg of cisplatin, and the mixture was stirred for 6 hours at room temperature to obtain a clear solution.

TLC of the prepared solution showed only cisplatin spot and HPLC analysis indicated that it contained 11.4 mg of cisplatin per ml. The aliquots were sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at various temperatures. After 3 months of storage at 37 ° C. and 45 ° C., TLC showed 1% platinum B present and no transpratinium present. After a month of storage at 56 ° C., TLC showed the presence of 2-3% platinum B and no transpratinium. Diluting the aged sample with purified water U.S.P. to a concentration of cisplatin of 2 mg / ml yields a clear solution, which remains clear even after standing for 24 hours.

HPLC analysis of the samples stored for 3 months at 45 ° C., 6 months at 37 ° C. and 7 months at room temperature showed loss of potency of 6.1%, 7.0% and 0.9%, respectively.

Example 7

Stable Concentrated Solution of Cisplatin (10mg / ml) in 90% Polyethyleneglycol 600-10% 0.5N HCl

To a solution of 2.5 ml of purified water U.S.P., 2.5 ml of 1N HCl and 45 ml of polyethyleneglycol 600, 500 mg of cisplatin is added and the mixture is stirred for 5 hours in the dark at room temperature to give a clear solution. TLC on the prepared solution shows only cisplatin spot. Samples of the prepared solution were diluted with 1,2,3,4,5 and 9 volumes of purified water U.S.P., where the diluted solution was free of crystallization after standing for 16 hours at room temperature or 4 ° C.

Samples of the solution are sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at various temperatures. After 3 months of storage at 37 ° C and 45 ° C, TLC showed that 1% of platinum B is present and free of transpratinium. After 1 month of storage at 56 ° C., TLC showed 3.4% platinum B present and no transpratinium present. Diluting the aged sample with purified water U.S.P. to a concentration of cisplatin of 2 mg / ml yields a clear solution, which remains clear even after standing at room temperature for 24 hours.

Example 8

Stable concentrated solution of cisplatin (10 mg / ml) + NaCl (10 mg / ml) in 90% polyethylene glycol 400-10% 0.2N HCl

To a solution of 0.5 ml NaCl in 4 ml of purified water U.S.P., 1 ml 1N HCl and 45 ml polyethylene glycol 400 was added 250 mg of cisplatin and the mixture was stirred for 4 hours at room temperature in the dark to obtain a clear yellow solution. Cisplatin spots can be identified by TLC on the prepared solutions. A solution prepared with 1,2,3,4,5 and 9 volumes of purified water was diluted to obtain a clear solution which remained clear even after standing at room temperature for 24 hours. Dilutions of 1,2,3,4 and 5 volumes of material do not crystallize when left at 4 ° C for 24 hours. Samples of the prepared solutions are sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at various temperatures. After 3 months of storage at 37 ° C., TLC showed that traces of trans platinum and 1% platinum B were present. After 3 months of storage at 45 ° C., TLC showed that traces of transpratinium and 5% platinum B were present. After 1 month of storage at 56 ° C., TLC showed that 2-3% platinum B was present and no transpratinium was present. Diluting the matured sample with purified water U.S.P. yields a clear solution when the concentration of cisplatin is 2 mg / ml. The solution remains clear even after standing at room temperature for 24 hours.

Example 9

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

Sodium chloride (0.9 g), mannitol (1.25 g) and polyethylene glycol 6000 (31.3 g) are sufficiently dissolved in purified water U.S.P. to make a 100 ml solution, acidified to pH 2.2 with 1N HCl (0.7 ml). Cisplatin (225 mg) is added and the mixture is stirred for 3 hours in the dark at room temperature to obtain a clear solution. The cisplatin band can be determined by TLC on the prepared solution. Samples of the prepared solutions are sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at 45 ° C and 56 ° C. After 2 months of storage at 45 ° C and 56 ° C, TLC showed that less than 1% of platinum B was present and there was almost no platinum. Diluting the aged sample with the same volume of purified water U.S.P. yields a clear solution which remains clear even after standing for 24 hours at room temperature.

Example 10

Stable concentrated solution with cisplatin (15.8 mg / ml) + NaCl (10 mg / ml) in 90% aqueous polyethylene glycol 400

Polyethylene glycol 400 (90 ml) is dissolved in 10 ml purified water U.S.P. in which 1.0 g of NaCl is dissolved.

To 57 ml of the resulting solution is added 900 mg of cisplatin and the mixture is stirred for 5 hours in the dark at room temperature to obtain a clear solution. TLC of the prepared solution showed only the cisplatin band and the HPLC sample showed that 15.5 mg of cisplatin per ml. The clear solution obtained by diluting the solution prepared with 4 volumes of purified water U.S.P. is kept at room temperature for 24 hours to maintain the clear color. Samples of the prepared solutions are sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at various temperatures. After two months of storage at 45 ° C., TLC showed 1.5% platinum B present and no transpratinium present. In addition, after 1 month storage at 56 ℃, by TLC it can be seen that the presence of 2% platinum B and no trans platinum. Samples aged at 56 ° C. are also diluted to sterile water for injection at a concentration of 2 mg / ml and samples aged at 45 ° C. are diluted to cisplatin concentrations of 2.5 and 5.0 mg / ml. Each clear solution formed remained clear even after standing at room temperature for 24 hours. HPLC analysis on samples stored for 3 months at 45 ° C., 6 months at 37 ° C. and 8 months at room temperature showed loss of efficacy of 7.6%, 7.6% and 0%, respectively.

Example 11

Stable concentrated solution of cisplatin (15 mg / ml) + CaCl "_2" (25 mg / ml) in 90% aqueous polyethylene glycol 400

90 ml of polyethylene glycol 400 is added to a solution of 10 ml of purified water USP in which 2.5 g of CaCl ₂ is dissolved, and the resulting solution is stirred for 10 minutes. 750 mg of cisplatin is added to 50 ml of the solution, and the mixture is stirred in a dark place at room temperature for 5 hours to obtain a clear solution. TLC of the prepared solution shows only the cisplatin band.

The prepared solution is diluted with 1,2,5 and 10 volumes of purified water U.S.P. respectively to obtain a clear solution. Samples of the formed solution are sealed in 17 ml yellow vials as described in Example 3 and tested for storage stability at 45 ° C and 56 ° C. After storage at 45 ° C. for less than 2 months, it can be seen by TLC that 1.5 platinum B is present and no trans platinum is present. After 1 month of storage at 56 ° C., TLC showed 2.5-5% of platinum B and no trans platinum. Sterile water for injection is diluted to 2 mg / ml for samples aged at 56 ° C. and 2.5 and 5.0 mg / ml for samples aged at 45 ° C. The resulting clear solution remains clear even after standing for 24 hours at room temperature.

Example 12

Sterile, Stable Concentrated Solution of Cisplatin (15mg / ml) in 90% Polyethyleneglycol 400-10% 0.5N HCl

Note: Cisplatin is a carcinogen. Protective clothing, gloves, masks, blindfolds and hats must be worn during the process. All work areas and equipment must be clean enough to avoid contamination with any other material.

Formulation

Polyethylene glycol 400 Add up to 1.0ml Add up to 10.0ml (SENTRY grade)

(1): The weight of cisplatin is assumed to be a titer of 1000 mcg / mg. The following formula is used to determine the amount of cisplatin needed for use.

는 다음과 같이 제조된다 :(2): 0.5 N hydrochloric acid 1

Is manufactured as follows:

의 삼각플라스크에 주사용 멸균수 U.S.P. 957.25ml를 넣는다.1. Clean 1

Put USP 957.25ml sterile water for injection into the Erlenmeyer flask.

2. While stirring rapidly, slowly add 42.75 ml of concentrated hydrochloric acid. Stir for 10 minutes and cover with clean butyl rubber stopper.

의 무균용액을 제조하는 방법One

To prepare a sterile solution

의 삼각플라스크에 0.5N의 염산 100ml를 넣는다.1. A clean 1 containing a suitable stirrer such as a 6 cm magnetic pole and a Teflon-coated stirring rod.

Put 100 ml of 0.5 N hydrochloric acid into the Erlenmeyer flask.

2. Add 15.0 g of sodium chloride while stirring at an appropriate rate and stir until the salt is completely dissolved.

3. Add 750 ml of polyethylene glycol 400 (SENTRY grade) with rapid stirring and stir for 5 minutes.

4. After removing the magnetic stir bar, place excess fluid back into the flask.

5. Carefully add 15.0 g of cisplatin.

가 될때까지 첨가한다(총 880ml 폴리에틸렌글리콜 400이 필요).6. Polyethylene glycol 400 (SENTRT grade) 1

Add until (a total of 880 ml polyethylene glycol 400 is required).

7. Place the Teflon stir bar back into the mixture and close it with a clean butyl rubber stopper.

8. Wrap aluminum foil around the flask to block all light.

9. Stir rapidly at ambient temperature for 24-48 hours. A clear solution is obtained. If no clear solution is obtained within 48 hours, the mixture is warmed to 39-40 ° C. for 2-6 hours in the absence of air and light to promote the remaining solution of cisplatin. Cool to.

10. Using aseptic technique, pass dark yellow solution through a sterile, pyrogen-free 0.22 micron Millipore filter under a suitable sterile nitrogen pressure. Sterile filtrate is collected in a sterile flask with sterile pyrogen. Sterile, pyrogen-free butyl rubber stopper. Store this solution in the dark.

11. Put the required amount of sterile solution into sterile, vial-free yellow vial. Sterile, pyrogen-free Teflon plugs. Seal with sterile aluminum sutures.

12. In Bayer the following cautions are recorded:

Do not use directly intramuscularly or intravenously *

* PEG-400 solution is diluted with 14 parts of sterile water for injection (U.S.P.) or steril normal solution (U.S.P.) to obtain a 1 mg / ml solution of cisplatin. If higher concentrations are required, use less sterile water or saline solution. The diluted solution is administered intravenously and is stable for at least 48 hours at ambient temperature (22-26 ° C.). Cryodiluted solutions as crystals are not frozen.

13. Store this vial in a dark place.

Example 13

Stable concentrated solution of cisplatin (2.5 mg / ml), NaCl (9 mg / ml), "CaCl_2" "" (15 mg / ml) and mannitol (10 mg / ml) in acidified 31% aqueous polyethylene glycol 400

Sodium chloride (0.9 g), CaCl 2 (1.5 g) and mannitol (1.0 g) are dissolved in a mixture of 31.25 ml of polyethylene glycol 400 and 40 ml of purified water U.S.P. Add 1N HCl (0.4 ml) to the solution to acidify the pH to 2.2, add 255 mg of cisplatin, add purified water USP until the total volume is 100 ml and mix the mixture in the dark at room temperature. Stirring for a time gives a clear solution. The band of cispratin can be confirmed by TLC on the prepared solution.

Example 14

Instead of the sodium chloride used in Example 5, the same amount of magnesium chloride can be used to repeat the process of Example 5 to obtain a stabilized concentrated solution of cisplatin.

Example 15

Instead of the sodium chloride used in Example 5, the same amount of triethylamine hydrochloride can be used to repeat the process of Example 5 to obtain a stabilized concentrated solution of cisplatin.

Example 16

Instead of the polyethylene glycol 400 used in Example 5, using the same volume of polyethylene glycol 200 and 300, respectively, the process of Example 5 was repeated to obtain a stabilized concentrated solution of cisplatin.

Example 17

The process of Example 9 was repeated using polyethylene glycol 1000 and 4000 of the same weight instead of the polyethylene glycol 6000 used in Example 9 to obtain a stabilized concentrated solution of cisplatin.

Claims (1)

Non-toxic pharmaceuticals such as polyethylene glycol having an average molecular weight of about 150-9000 or methoxypolyethylene having an average molecular weight of 300-6000 or mixtures thereof 30-90%, water 5-70% and cisplatin A method for producing a stabilized concentrated solution of cisplatin, characterized in that a sufficient amount of cisplatin is dissolved in a solvent medium composed of chlorine ions to allow the concentration of the spratin to be 2.5-22 mg / ml.