FI66121C - FRAMEWORK FOR THE STABILIZATION OF A CABLE PLATE - Google Patents

Description

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Peteittl- js rekfatarihalllt Mii / 4A. _____ P * t * nt- och fgtatrrtyKl — n '' Min «3 ^ α * 31.05.84 (32) (33) (31) PyHttr folfc— lt« rd prtortwt 30.05.78 USA (US) 9IO325 ToteennSytetty-Styrkt ( 71) Bristol-Myers Company, 345 Park Avenue, New York, NY 10022, USA (72) Edmund S. Granatek, Syracuse, New York, Gerald M. Ziemba, Bridgeport,

New York, Frederick L. Grab, Fayetteville, New York, USA (74) Oy Kolster Ab (54) Method for preparing a permanent aqueous solution of cisplatin - Förfarande för framstälIning av en stabil vattenlösning av cisplatin

The invention relates to a process for preparing a stable, sterile aqueous solution of cisplatin. The solution is used in chemotherapy for cancer.

In the group of antineoplastic agents, the platinum compounds form their own special group. Rosenberg et al. found in 1965 that they have an antibiotic effect and later they are potent antitumor agents in animals. Rosenberg, B., Van-Camp, L. and Krigas, T., Inhibition of cell division in Escherichia coli by Electrolysis products from a Platinum electrode. Nature (London) 205: 698-699, 1965, and Rosenberg, B., VanCamp, L., Trosko, J.E. and Mansour, V.H., Platinum compounds: A new class of potent antitumor agents. Nature (London) 222: 385-386, 1969.

Structurally, they are complexes in which chlorine atoms or ammonia groups are attached to the central platinum atom in various ways around either the cis or trans position with respect to the plane.

The two most commonly studied platinum compounds can be described as follows: 2 66121

Cl NH3

Z /// pt //// Z \ - '[1 * H

Cl NH3 cis-platinum (II) diamine-cis-platinum (IV) diamine dichloride tetrachloride

In the platinum compound selected by the National Cancer Institute * for clinical trials, cis-platinum (II) diamine dichloride, the chloride and amino groups are all in the same horizontal plane. The cis form of diamine dichloride has been synthesized by the following reaction, Kauffman, G.B. in J. Kleinberg (Ed.), Inorganic Synthesis, McGraw-Hill Book Co., Inc.,

New York, 1963: nh4ci K2 ^ 1> tCl4.7 + 2NH3 -cis- / Pt (NH3) 2Cl2 ^ + 2KCl

The National Cancer Institute has conducted clinical kero-therapeutic trials with a chemical called (United States Adopted Name) USAN, cisplatin. For information on its chemistry and pharmaceutical compositions, see Clinical Brochure, CIS-PLATINUM (II) DIAMMINEDICHLORIDE (NSC-119875), H. Handelman et al., Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cander Treatment, National Cancer Institute (el. 1974), pages 1-5 and 31-32. Handelman et al. pages 31-32 relate to the cisplatin composition distributed by N.C.I free of charge to physicians for clinical cancer chemotherapy research and these pages disclose the following: NSC-119875 cis-diamine dichloroplatinum (II)

Dosage composition 10 mg / vial: Each 20 ml silicon vial contains an off-white lyophilised cake. Each vial contains 10 mg of NSC-119875, 90 mg of sodium chloride, 100 mg of mannitol and hydrochloric acid to adjust the pH.

66121

Preparation of the solution: 10 mg vial: Reconstituted with 10 ml of sterile water for injection (USP), the resulting solution contains 1 mg of NSC-119875, 10 mg of mannitol and 9 mg of sodium chloride per ml, and the pH of the solution is 3.5 -4.5.

Storage: Dry, unopened vials should be stored at refrigerator temperature (4-8 ° C).

Shelf life: Unopened vials have so far been considered to have a shelf life of one year when stored at refrigerator temperature (4-8 ° C). The stability recommendations may change after the end of the two-year storage period trial. Reconstitution as recommended gives a pale yellow solution that is stable for up to one hour at room temperature (22 ° C) under normal room lighting and up to 8 hours at room temperature (22 ° C) protected from light. A precipitate may form in the reconstituted solution after one hour of storage at refrigerator temperature (4-8 ° C).

Warning: Lyophilized dosage compositions do not contain preservatives and therefore it is recommended to discard the solutions 8 hours after reconstitution.

In August, 1974

Clinical Drug Distribution Section Drug Development Branch This formulation and further information on its clinical use is exemplified in Cancer Chemotherapy Reports, Part 1, Vol. 57, No. 4, pp. 465-471 (1973).

Cancer 30: 1451-1456 (1972) states with reference to cisplate: "The drug used in this study was manufactured by Ben Venue Laboratories Inc., Bedforf, Ohio. It was supplied by the Cancer Therapy Evaluation Branch of the National Cancer Institute in vials containing 10 mg of cis-diamine dichloroplatinum, 10 mg of dry mannitol, 9 mg of dry NaCl. The yellowish-white powder dissolved well in 8-10 ml of sterile water and was injected immediately after preparation. "

In Annals of International Med. 86: 803-812 (1977) discloses the following about cisplatin, referred to as DDP: 4 66121 "The drug DDP is only available to trained professionals for research purposes from the Investigational Drug Branch of the Cancer Therapy Evaluation Program, National Cancer Institute. The product is a white lyophilized powder in a vial. containing 10 mg DDP, 90 mg sodium chloride, 100 mg mannitol (USP) and hydrochloric acid to adjust the pH Reconstituted with 10 ml sterile water for injections (USP), each ml contains 1 mg DDP, 10 mg mannitol and 9 mg NaCl. The pH of the resulting solution is 3.4 to 4.5. The solution reconstituted at 22 ° C is stable for at least 8 hours ".

The solid compositions in vials described above are thus reported to require a refrigerator temperature (4-8 ° C) (i.e., prior to reconstitution), are difficult to reconstitute, and have a shelf life after reconstitution at room temperature (22 ° C) of only about 20 hours. Reconstruction itself, if done incorrectly, can cause problems and should be avoided. In addition, since the solubility of cis-platinum in water is only about 1 mg / ml, the preparation of dosage forms above 25 mg / vial by lyophilization becomes too expensive.

There is now a stable, therapeutically acceptable intravenous injectable dosage form of cisplatin that does not need to be lyophilized and reconstituted, that does not need to be refrigerated during transport and storage, and that provides doses greater than 50 mg.

The invention relates to a process for the preparation of a stable, sterile, preferably intravenous, aqueous solution of cisplatin containing 0.1 to 1 mg / ml, preferably 1.0 mg / ml of cis-platinum (II) diamine dichloride and optionally non-toxic, pharmaceutically acceptable a chloride ion source having a concentration corresponding to a sodium chloride concentration of 1 to 20 mg / ml, preferably about 9 mg / ml, and other additives such as mannitol, preferably at a concentration of 2 to 150 mg / ml, in particular 10 mg / ml, the pH adjusted to the acidic range by the addition of a non-toxic, therapeutically acceptable acid, preferably hydrochloric acid. The process is characterized in that the pH is adjusted to 2.0 to 3.0.

Cis-platinum (II) diamine dichloride (NSC 119875) is an inorganic compound that was first found to inhibit E. coli replication and was subsequently found to be anti-tumor active. The effect of the drug occurs by interfering with DNA synthesis by causing cross-linking of the complementary strands of DNA. The compound has activity on various tumor systems, e.g., L1210, Darcoma 180, Walker 256 carcinoma, DMBA-induced breast cancer, and ascites B16 melanosarcoma. The compound is of particular interest because it has synergism with several currently used chemotherapeutic agents. Extensive animal toxicity studies revealed renal tubular necrosis, inflammation of the bowel, bone marrow insufficiency, and lymphoid atrophy. Phase I studies showed the following toxic effects: spinal cord dysfunction, renal failure, high-frequency ear damage, and GI intolerance. The currently used doses with moderate toxicity are 60-100 mg / m given intravenously as a single dose or in divided doses over 3-5 days, repeated at 4-week intervals. Initial clinical trials have shown some effect on germ cell tumors, lymphoid tumors, connective tissue cancer, breast, head and neck carcinoma.

2

The dose of 60 mg / m is approximately the same as 1.5 mg / kg, which in turn corresponds to approximately 105 mg / kg for a patient weighing 70 kg.

The solutions prepared according to the invention are used in the same manner and for the same purpose as explained above and are disclosed in other relevant publications and in the extensive medical literature. As reported in the literature, the compound is often used in conjunction with other chemotherapists for best results. If desired, the solutions of the invention may be added immediately before use to a sterile, pharmaceutically acceptable aqueous diluent such as glucose or saline. The drug is administered either as a direct injection into a vein or as an intravenous infusion.

Example 1

Solution for injection containing 1 mg / ml cisplatin (1 mg cis-diamine dichloroplatinum (II) in 1 ml solution) 6,661 21

Composition

ml per liter per liter A A

cis-diamine dichloroplatinum (II) 0.0010 g 1,000 g sodium chloride, U.S.P. 0.0090 g 9,000 g

Mannitol, U.S.P. 0.0100 g 10,000 g Concentrated hydrochloric acid. U.S.P. q.s. To adjust the pH q.s. To adjust the pH

B B

To 2.0-3.0 to 2.0-3.0

Water for injections U.S.P. 1.0 ml to 1000 ml

Note.

A. Lacquered at 100%. Based on the analysis, cisplatin is added in an amount to give 1.0 g of 100% cis-diaramine dichloroplatinum (II) per liter.

B. 37% hydrochloric acid per gram of sodium chloride is required to adjust the pH to about 2.5 to about 2.535-0.050 ml.

precautions

Cis-diamine dichloroplatinum (II) is a toxic substance listed on page 942 of the 1976 edition of the Register of Toxic Effects of Chemical Substances. The Time Weighted Average (TWA) of the OSHA standard is 2 mcg / m. Refer to the literature references listed above, applicable local notices and regulations, and publications: the National Cancer Institute Safety Standards for Research Involving Chemical Carcinogens and the National Institute of Health Specifications for a Class II type 1 Safety Cabinet. Weighing of cis-diamine dichloroplatinum (II), treatment of the surface of the manufacturing vessels, filling of the solution, closing of the medicinal containers must be carried out using protective equipment.

Personnel who come into contact with the manufacture of the product must wear full nylon head / face protection, protective suits, rubber gloves and respirators equivalent to MSA-Ultra Filter Respirator protective equipment designed for use in conditions where contaminants, vapors and mists are exposed to 3 volumes. with a TWA of less than 50 pg / m. During sterile fluid filling i 66121, the respirator may be replaced with a sterile head / face shield, a surgeon's respirator, and a protective shield. Protective suits spilled with larger amounts of product should be stored in closed metal containers and then incinerated.

The importance of protecting the personnel involved in the handling, manufacture and testing of this product, as described above, cannot be overemphasized.

The stock solution made of cis-diamine dichloroplatinum (II) must be protected from light. The preparation described below and the filling of the vials are performed in twilight daylight or fluorescent light.

Hardware

Tableware

The preparation vessel was a glass-lined pressure vessel equipped with a stirrer. The material of the mixer is 316 SS stainless steel. The size of the batch must correspond to the working volume. A dipstick and a tank calibration curve are required to determine the volume.

Millipore membrane filter holders 316 SS. Filter surface and necessary pre-filters and a sterile filter of 0,22 μm for final filtration.

Silrtoletkut

Teflon or tygonia

All stainless steel contact points should be 316 SS grade. The rest of the equipment should be suitable for producing a sterile, pyrogen-free and particle-free product.

Instructions for preparation A. These instructions apply to the preparation and filling phase of a batch to be carried out within 8 hours. The storage of the product before filling had not been studied at the time of issuing this instruction.

B. During the entire preparation and filtration steps, the temperature is maintained at 27 ° C + 2 ° C.

1. 80% of the water for injection required in the batch is placed in a suitable container, U.S.P.

2. Sodium chloride is added with stirring. Stirring is continued for 10 minutes, or until the salt is dissolved.

3. With constant stirring, the sodium chloride solution is carefully adjusted to 2.0-3.0 (preferably 66121 8 2.5) with concentrated hydrochloric acid. The estimated amount is in section B of the composition instructions. After the last addition, mix for 10 minutes. The pH is then checked.

4. Add mannitol with good stirring and continue stirring for 10 minutes, or until the mannitol is dissolved.

5. Add cis-diamine dichloroplatinum (II) with good stirring, taking particular care not to allow it to affect the worker in the form of dust or otherwise. Its container is rinsed with a sufficient amount of water (for injection purposes) and added to the batch.

6. Stir until all is dissolved. It takes about 60-90 minutes for complete dissolution. The pH is measured and, if necessary, concentrated hydrochloric acid is added to the solution to maintain the pH at 2.0 to 3.0 (preferably 2.5).

7. The solution is passed through a clean, sterile 0.22 μm Millipore filter into a sterile filling line.

9. The various products are filled as follows: 10 mg / vial

Sterile, type I, brown, 15 ml vial with a fill volume of 10 ml. Stopper: red, 20 mm Teflon-colored stopper, capsule: aluminum capsule. Products with numbers K93, 100 and 107 are protected with nitrogen, products K94, 101 and 108 are without nitrogen shielding gas.

25 mg / vial

Sterile, type I, brown 50 ml vial with a fill volume of 25 ml. Plug: red 20 mm Teflon plug; capsule: aluminum capsule. Products with numbers K95, 102 and 109 are protected with nitrogen, products K96, 103 and 110 are without nitrogen shielding gas.

50 mg / vial

Sterile type I 50 ml vial with a fill volume of 50 ml. Plug: red 20 mm Teflon plug; capsule: aluminum capsule. Products with numbers K97, 104 and 111 are protected with nitrogen gas, products K98, 105 and 112 are without nitrogen shielding.

These compositions were prepared in five groups (final pH in parentheses) as follows: 9 66121 K93-96 (pH 2.4) K97-98 (pH 2.5) K100-103 (pH 2.3) K104-105 (pH 2, 4) K107-110 (pH 2.3) K111-112 (pH 2.4)

Initial concentrations according to HPLC analysis ranged from 0.99 to 1.00 mg / ml. The percentage reductions in concentration after 1 or 2 months of storage at the indicated temperature as determined by HPLC were as follows:

56 ° C_45 ° C

1 month 2 months 1 month K93 4.0 K94 2.0 4.0 K95 0.0 -1.01 K96 1.0 4.0 0.0 K97 3.0 K98 4.0 2.0 K100 3.0 K101 3.0 5.0 K102 3.0 K103 5.0 4.0 K104 0.0 -1.01 K105 0.0 5.0 0.0 K107 1.0 0.0 K108 2.0 5.0 1.0 K109 3.0 K110 3.0

Kili 7.0 K112 7.0

A minus sign indicates that the concentration increased by 1.0%.

ίο 66121

Thus, in the solutions described above, a maximum of 7% of active substance was lost when stored at 56 ° C and 45 ° C, with or without a shielding gas, and for the most part a loss of up to 3%. The pH of the solutions remained at 2.4 to 2.7.

After one month of storage at 56 ° C, no physical changes were observed in the solutions. The solutions remained clear and colorless. At the beginning of the experiment, the mean Klett readings were 8-12, after one month at 56 ° C and 45 ° C the mean readings were 6-15.

No changes or differences were observed between the samples in the nitrogen shielding gas and the unprotected samples.

One sample of all products was taken at each temperature for the experiment to determine the effect of the Teflon-coated stopper.

Sample bottles, both with and without nitrogen shielding gas, were placed inside out at 56 ° C for one month. Monthly storage at 56 ° C did not affect stability, the loss of active substance was only 1-2%.

The crystallization of cis-diamine dichloroplatinum (II) was studied by storing the samples at 4 ° C. No crystallization was observed within a month. Observations were made only on randomly selected samples and not on all samples. In one batch of 10 mg / vial and 25 mg / vial, some crystals were found to be formed at 4 ° C in random samples. Crystallization was observed in all batches containing 50 mg / vial, but not all crystals were present. In one sample stored at 4 ° C, the crystals were not allowed to dissolve when heated and stirred at 37 ° C. The result was therefore not entirely satisfactory. It appears that these products cannot be stored under refrigerator conditions because redissolution of the crystals also presents difficulties.

Determination of cis-diamine dichloroplatinum by high performance liquid chromatography (HPLC) _

Method

Cis-diamine dichloroplatinum is chromatographed on a Water's yu-Bonda-pak-NH2® column using a loop injection technique. The results are obtained from a monitor with a UV absorbance of 313 nm and cantation is performed by measuring the height of the peak and comparing with the calibration curve.

This method can be used to measure raw material powders and solid dosage compositions containing NaCl and mannitol. Method 11 66121 makes it possible to distinguish between cis and trans isomers and the obvious decomposition products (effect of moisture, acids, bases, heat and light).

NH_ ^^ Cl Cl nh3 '^ "Cl NH3' ^^ ^^ Cl

cis- (NH3) 2 Cl2 Pt II trans- (NH3) 9 Cl2 Pt II

The HPLC test conditions

Column - Water Micro-Bondapak-NH2 (300 mm x 4.0 mm ID) 027386 or equivalent.

Mobile phase - ethyl acetate / methanol / dimethylformamide / distilled water (25/16/5/5). Burdick & Jackson glass-distilled spectrograph-grade reagents are used. The water is degassed before use and the solution after mixing.

Detectors - Water’s Model 440 Abdorbance Detector.

Wavelength - 313 nm (UV).

Sensitivity - 0.1 AUFS.

Injector - 20 μΐ loop injector,

Loop Injector - Valco 7000 psi stainless steel valve (CV-6-UHPa-C2 0).

Injection volume - 20 μΐ.

Solvent dosing device - Water’s Model 6000A pump.

Flow - 2.0 ml / min.

Duration - 2.8 min (approx.).

Plotter - Heath Model SR -255B.

Paper speed - 12.5 mm / min.

Range - 10 mV.

HPLC analysis

Under the above conditions, chromatograms of the standard sample and preparations are determined in duplicate.

Cis-diamine dichloroplatinum (DDP) reference standard:

Lot No. 78F7 (Matthey Bishop Lot No AM7702). Reported purity = 99.8%.

Solvents - Burdick & Jackson (distilled in glassware) spectrograph grade.

12,661 21

Standard - Weigh accurately 25 mg of cis-diamine dichloroplatinum (DDP) into a 25 ml graduated flask. DDP is dissolved in dimethylformamide and at the same time diluted to 25 ml as solvent.

Lyophilised preparation for injection - The contents of the vial are dissolved in 10 ml of dimethylformamide by shaking the vial for 5 minutes (alternatively, a 2-minute ultrasound treatment may be used). Filter 5.0 ml of the sample solution (Millipore Filter Kit or equivalent), discarding the first ml.

Homogeneity of contents - 10 vials are prepared for testing as described above.

Invoice Payments

Standard factor (SF) = mg standard / ml_ mean standard peak height mg DDP / g = SF x mean peak height of sample x 25 sample weight (g) mg DDP / vial = SF x mean peak height of sample x 10.

From the content homogeneity test, 10 vials of drug were used to obtain an average result.

Method

The experimental procedure described above was applied to aqueous solutions (dosage compositions) of cisplatin containing NaCl and mannitol, following the changes shown below.

The HPLC test conditions

Mobile phase - acetonitrile / distilled water (75/25, v / v). Betrick & Jackson glass-distilled spectrograph-grade reagents are used. The gases are degassed before use and the solution after mixing,

Injector - 100 pl loop injector.

Injection volume - 100 pl.

Duration - 2.0 min (approx.).

HPLC analysis

Standard - Weigh accurately 25 mg of cis-diamine dichloroplatinum (DDP), 225 mg of sodium chloride and 250 mg of mannitol into a 25 ml graduated flask. The substances are dissolved in distilled water and the solution is diluted with distilled water to 25 ml. Pipette 5.0 ml of the resulting solution into 25 ml

Claims (3)

13 661 21 in a graduated flask, add 2.0 ml of distilled water and dilute the solution to 25 ml with acetonitrile. Sample (1 mg / ml) - Pipette 5 ml of the sample into a 25 ml graduated flask, add 2.0 ml of distilled water and dilute the solution to 25 ml with acetonitrile. Calculations Standard factor (SF) = mg standard / ml_ mean peak height of the mg mg DDP / ml = SF x mean peak height of the sample x 25. A process for the preparation of a stable, sterile, preferably intravenous, aqueous solution of cisplatin containing 0.1 to 1 mg / ml, preferably 1.0 mg / ml of cis-platinum (II) diamine dichloride and optionally non-toxic, pharmaceutically acceptable an acceptable chloride ion source having a concentration corresponding to a sodium chloride content of 1-20 mg / ml, preferably about 9 mg / ml, and other additives such as mannitol, preferably at a concentration of 2-150 mg / ml, especially 10 mg / ml, The pH is adjusted to the acidic range by the addition of a non-toxic, therapeutically acceptable acid, preferably hydrochloric acid, characterized in that the pH is adjusted to 2.0 to 3.0. Process according to Claim 1, characterized in that the pH is adjusted to 2.3 to 2.7. Process according to Claim 1 or 2, characterized in that the pH is adjusted to about 2.5.