DK149192B - PROCEDURE FOR PREPARING A STABLE CISPLATIN PREPARATION - Google Patents

Description

149192

The present invention relates to a process for preparing a stable, sterile aqueous solution of cis-platinum (II) -diammindi chloride, hereinafter called cis-platinum, in unit dosage form suitable for human administration, especially for injection into chemotherapy 05 of cancer.

The platinum compounds are a particular group of compounds among the antineoplastic agents. Rosenberg and colleagues first found in 1965 that they had an antibiotic effect, and they ·. have since been shown to be potent antitumor agents in animals, cf. B. Rosenberg, L.

10 Van Camp and T. Krigas, Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature (London) 205: 698-699, 1965, B. Rosenberg, L. VanCamp, J.E. Trosko and V.H. Mansour, Platinum compounds: A new class of potent antitumor agents. Nature: (London) 222: 385-386, 1969.

Structurally, these platinum compounds represent a canopy formed by a central platinum atom, surrounded by various arrangements of chlorine atoms or ammonia groups in either cis or transplanar relation. Two of the more commonly studied platinum compounds are shown below:

Cl 20 α_ ™ 3 y ~ \ - // Pty Pt yr

Cl NHo Cl I NHo

Cl J

Cis-platinum (II) - Cis-platinum (IV)

Diammindichloride Diammintetrachloride

Cisplatin (II) diamine dichloride, selected for clinical trials by the National Cancer Institute, has, as can be seen, the chloride atoms and amino groups arranged at the horizontal level only. The cis form of the diamine dichloride complex has been synthesized, cf. G.B.

30 Kaufmann in J. Kleihberg (Ed.) Inorganic Synthesis, McGraw Hill 2 149192

Book Co., Inc., New York, 1963, according to the following reaction: nh4ci K2 [PtCl4] + 2NH3 -> “Cis- [Pt (NH3) 2Cl2] + 2KC1

The National Cancer Institute has conducted clinical trials in 05 cancer chemotherapy with the compound whose official name in the United States (USÅN) is now cisplatin. Certain information regarding its chemistry and its pharmaceutical formulation is provided in the publication Clinical Brochure, CIS-PLATINUM (II) 10 DIAMMINEDICHLORIDE (NSC-119875), H. Handelman et al., Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute (revised August 1974) on pages 1 - 5 and 31-32.

Pages 31-32 of the brochure relate to the formulation of cisplatin for free delivery of N.C.I. to doctors for their clinical assessment in cancer chemotherapy and reads 15 in translation, as follows;

PHARMACEUTICAL DATA SHEET

NSC-119875 Cis-diammindichloroplatin (II),

Dose formulation 10 mg / vial: The contents of each 20 ml flint vial 20 appear as a greyish white lyophilised cake. Each vial contains 10 mg of NSC-119875, 90 mg of sodium chloride, 100 mg of mannitol and hydrochloric acid for pH adjustment.

Preparation of 25 solution_ 10 mg / vial: Upon reconstitution with 10 ml of sterile water for injection, USP, each ml of the resulting solution will contain 1 mg of NSC-119875, 10 mg of mannitol and 9 mg of sodium chloride having a pH range easily 3.5 - 4.5.

Storage: Store the dry, unopened vials at refrigerator temperature (4-8 ° C).

3 149192

Stability: Intact vials have a provisional stability of 1 year when stored at refrigerator temperature (4-8 ° C). The stability instructions can be adjusted after the completion of a two-year storage study. Reconstitution as recommended results in a pale yellow solution that is stable for a maximum of one hour at room temperature (22 ° C) when exposed to normal room lighting and at most eight hours at room temperature (22 ° C) protected from light. Reconstituted solutions may precipitate after one hour at refrigerator temperature (4-8 ° C).

Warning: The lyophilized dose preparations contain no preservatives and therefore it is recommended to discard solutions eight hours after reconstitution.

August, 1974

Clinical Drug Distribution Section 20 Drug Development Branch.

Discussion of this formulation and additional information on clinical use are e.g. given in Cancer Chemotherapy Reports, Part 1, Vol. 57, No. 4, pages 465-471 (1973).

Cancer 3: 1451-1456 (1972) states with respect to cisplatin 25 in translation that "the drug material used in this study was manufactured by Ben Venue Laboratories Inc., Bedford,

Ohio. It was provided by the Cancer Therapy Evaluation Branch of the National Cancer Institute in vials containing 10 mg of cis-diammindichloroplatin, 10 mg (sic) mannitol and 9 mg (sic) NaCl. The resulting yellowish white powder was readily dissolved in 8-10 ml of sterile water and injected immediately after preparation. "

Annals of Internal Med. 86: 803-812 (1977) refers to cis-platinum as "DDP" and states in translation that "The drug DDP is currently only available as a trial drug for qualified specialists 05 through the Investigational Drug Branch of Cancer Therapy.

Evaluation Program, National Cancer Institute. The product is supplied as a white lyophilized powder in vials containing 10 mg DDP, 90 mg sodium chloride, 100 mg mannitol (U.S.P.) and hydrochloric acid for pH-10 adjustment. When reconstituted with 10 ml of sterile water for injection (U.S.P.), each ml of the resulting solution will contain 1 mg of DDP, 10 mg of mannitol and 9 mg of NaCl. The pH of the resulting solution will be 3.4 to 4.5. At 22 ° C, the reconstituted solution is stable for at least 8 hours. "

Thus, the above-described compositions are stated to require cooling (4-8 ° C) while in the solid state vials (ie, prior to reconstitution), are difficult to reconstitute and have a useful life of only about 20 hours at room temperature (22 ° C) after reconstitution.

Reconstitution itself can cause problems if performed incorrectly and is best avoided. Furthermore, because the aqueous solubility of cisplatin is only about 1 mg / ml, the cost of preparing dosage forms containing 25 more than 25 mg per ml. vials for lyophilization, prohibitive.

The present invention provides a process for preparing a stable, sterile aqueous solution of cisplatin in unit dosage form suitable for human administration. The solution thus prepared, like the known 30 cis-platinum preparations, is suitable for intravenous injection, but it does not require lyophilization and reconstitution, nor does it require refrigeration during shipping and storage, and it can be delivered in doses of 50 mg or more, preferably in a sealed container such as a vial or unit dose vial.

The process of the invention is characterized by dissolving cis-platinum in a sterile aqueous medium containing a non-toxic pharmaceutically acceptable inorganic source of chloride ions at a concentration equivalent to that provided by the presence. of sodium chloride at a concentration in the range of 1 to 20 mg per ml. and, optionally, a conventional, harmless, physiologically acceptable excipient 05 at a concentration in the range of 2 to 150 mg per ml. to a cis-platinum concentration of between ca. 0.1 and approx. 1.0 mg per and with hydrochloric acid adjust the pH in the range of 2.0 to 3.0.

According to the invention, it is preferred that the pH be adjusted to 10 in the range of 2.3 to 2.7, in particular to approx. 2.5. Within this preferred pH range, it is preferred that the cis-platinum be dissolved to a concentration of approx. 1.0 mg per ml.

Furthermore, in this embodiment of the invention, it is preferred that the inorganic source of chloride ions be provided by the fact that the medium contains sodium chloride at a concentration of approx. 9 mg per and that the medium further contains mannitol at a concentration of approx. 10 mg per ml. It has been found that such a solution exhibits less than 10% strength loss (usually less than 4%) measured by high performance liquid chromatography (HPLC) after storage for one month at 56 ° C.

The solution of cis-platinum according to the invention can be used to inhibit malignant tumors that are affected by cis-platinum by intravenous administration.

The process of the invention is elucidated in the following Examples.

6 149192

Example. _j. Cisplatin injection 1 mg / ml [1 mg cis-platinum (II) -diammine dichloride per 1 ml]

Rule

Pr · pr. liter

Cisplatin (II) diamine dichloride 0.0010 gA 1,000 gA

05 Sodium Chloride, U.S.P. 0.0090 g 9,000 g

Mannitol, ϋ.S.P. 0.0100 g 10,000 g

Hydrochloric acid wife. U.S.P GS to pH q.s. to pH

2.0 - 3.0 2.0 - 3.0B

Water for Injection, U.S.P. q.s 1.0 ml q.s. 1000.0 ml 10 NOTES: A. 100% basis, the weight being adjusted on the basis of the stated purity to 1.0 g of 100% cis-diammine-dichloroplatin (II) per day. liter.

B. Approx. 0.035 - 0.050 ml of 37% hydrochloric acid is required per g of sodium diloride to obtain a pH of approx. 2.5.

WARNINGS:

Cis-diammindichloroplatin (II) is a toxic compound listed on page 942 of the 1976 issue of "Registry of Toxic Effects of Chemical Substances". The so-called "OSHA Stan-20 dard of Time Weighted Average" (TWA) is 2 µg / m. It is recommended to consult the references cited above, relevant local publications and regulations and publications such as the "National Cancer Institute Safety Standard for Research Involving Chemical Carcinogens" and "The National Institute of Health Specifications for a Class II Type 1

Safety Cabinet "Any handling of cis-diammindichloroplatin (II) must be carried out under the specified protective measures.

7 149192

All personnel involved in the preparation of this product must be protected with complete nylon head / face coverage, total protective clothing, rubber gloves and a respirator designed for a 05 milieu contaminated with dust, smoke and fog with a

ISLAND

"TWA" value of less than 50 µg / m During the sterile fluid filling, the sterile head / face cover, surgical mask and goggles may replace the respirator. Any suits that are heavily contaminated due to spills etc. must be stored in a closed metal container until they can be burned.

THE IMPORTANCE OF PROTECTING THE STAFF WHEN HANDLING, MANUFACTURING AND TESTING THIS PRODUCT UNDER 15 OF THE ABOVE CANNOT BE UNDERLINED NOK.

The main portion of cis-diamminedichloroplatin (II) must be protected from light. The reprocessing and filling of vials as described here was performed under diffuse daylight / fluorescent tube light.

20 APPARATUS

Filling tank.

A glass-lined pressure vessel with stirring. The work volume must correspond to the portion size. A dipstick and calibration curve for tank volume are needed to determine the volume.

25 "Millipore" Membrane Filter Containers

Filter area with the required pre-filters and 0.22 µm final sterilization filters.

Transfer Tubes.

Teflon or vinyl plastic of the TYGON type.

Preparation Instructions 30 A. These instructions relate to an eight-hour charge-to-fill operation with quantities as specified in the regulation. Storage of the product before filling has not been investigated at this time.

8 149192 B. 27 ° C - 2 ° C temperature conditions are maintained throughout the charge and filtration operation.

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

05 2. With stirring, the sodium chloride is added. Stir for 10 minutes or until dissolved.

3. With good stirring, the pH of the sodium chloride solution is carefully adjusted to 2.0 - 3.0 (preferably 2.5) with concentrated hydrochloric acid, see estimated amount under note "B" 10 of the regulation. Stir ten minutes after the last addition. The pH is checked again.

4. With good stirring, mannitol is added and stirred for ten minutes or until dissolved.

5. Under good agitation and under special measures 15 against dust and exposure, add the cis-diaminindichloroplatin (II). Rinse the container sufficiently with an appropriate amount of water for injection and add to the batch.

6. Stir to complete dissolution. Ca. 60 - 90 mi-20 nuts are required for complete dissolution. The pH is measured and additional concentrated hydrochloric acid is added if necessary to hold 2.0 - 3.0 (optimal 2.5).

7. The volume is carefully adjusted to the theoretical 25 volume of water for injection. A final pH check is made.

8. The solution is passed through a clean, sterile 0.22 μπ "Mil-lipore" filter to the sterile filling line.

30 9. Make up as indicated below for the following products 10 mg / ml. vials

Sterile, type I amber, 15 ml vial with 10 ml filling. Plugging with red 20mm Teflon-coated plugs and sealing with aluminum seal. Numbering as K93, 100 and 107 with nitrogen coverage and K94, 101 and 108 without nitrogen coverage.

9 mg per 25 mg vials

. IN

Sterile, Type I amber 50 ml vial with 25 ml filling. Sealing with red 20mm Teflon-coated plugs and aluminum seal. Numbering as K95, 102 05 and 109 with nitrogen coverage and K96, 103 and 110 without nitrogen coverage.

50 mg per vial.

Sterile, Type I amber 50 ml vial with 50 ml filling.

Plugging with red 20mm Teflon-coated plugs and sealing with aluminum seal. Numbering as K97, 104 and 111 with nitrogen coverage and K98, 105 and 112 without nitrogen coverage.

These preparations were prepared in five groups (with the final pH indicated in parentheses) as follows: 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)

Klll-112 (pH 2.4) 20 The initial strengths of the HPLC study ranged from 0.99 to 1.00 mg / ml.

High performance liquid chromatography (HPLC) for cis-diamminedichloroplatin.

Method

Cis-diammindichloroplatin is chromatographed on a "Water's γ-Bondapak-NH2" column using a loop injection technique. The detection is done by measuring U.V. absorbance at 313 nm, and quantitative determination is done by 30 height measurement of apexes with external calibration. This method can be applied to · charge powders and solid dose preparations containing NaCl and mannitol.

xo 149192 HPLC conditions.

Column - "Water's Micro-Bondapak-NH2" (300 mm x 4.0 mm ID) 05 027386 or its equivalent -

Mobile phase - ethyl acetate / methanol / dimethylformamide / distilled water (25/16/5/5) '. Spectro quality reagents of the type "Burdick and Jackson" distilled in glass are used. The water is degassed before use 10 and the solution after mixing.

Detector- "Water's Model 440 Absorbance Detector".

Wavelength - 313 nm (U.V.)

Sensitivity - 0.1 AUFS

Injector - A 20 microlitre loop injector, 15 loop injector - A "Valco" 7000 psi stainless steel valve (CV-6-UHPa-C20)

Injection volume - 20 microliters

Solution Delivery System - Water's Model 6000 A Pump Flow - 2.0 ml / minute 20 Retention - 2.8 minutes (approximate)

Recorder - Heath model SR-255B Curve speed - 12.7 mm per minutes Interval - 10 millivolts HPLC analysis 25 Using the above conditions, chromatograms of the standard and sample preparations are obtained in duplicate.

Reference Standard of cis-diammindichloroplatin (DDP):

Serving # = 78F7 (Matthey Bishop portion # AM7702)

Assigned Purity = 99.8%.

30 Solvents - "Burdick and Jackson" (distilled in glass) spectro quality

Standard - Weigh exactly 25 mg of cis-diammindichloro-platinum (DDP) into a 25 ml volumetric flask.

Dissolve in and dilute to volume with dimethylformamide.

149192 11

Lyophilized Injection - The contents of the vials are reconstituted with 10.0 ml of dimethylformamide and shaken mechanically for 5 minutes (alternatively, a sound bath can be used for 2 minutes). Filter 5.0 ml of the sample solution Q5 (Millipore filter set or equivalent) and discard the first ml.

Content uniformity - 10 vials are prepared as described above and examined.

Calculations 10 STANDARD FACTOR (SF) = __MS STANDARD / ML_

AVERAGE TOP HEIGHT OF STANDARD

MG DDP / GRAM = SF X AVERAGE HEAD OF SAMPLE X 25 WEIGHT OF SAMPLE (G) MG DDP / Vials = SF X AVERAGE HEAD OF HEIGHT X 10 15 For the test, average results obtained from the test are used for the 10 cap test.

Method

The above-described study method of cisplatin is applied to aqueous solutions (dose preparations) containing NaCl 20 and mannitol after making the changes listed below.

HPLC Conditions

Mobile phase - acetonitrile / distilled water (75/25, v / v).

Spectro grade reagents of the type "Burdick and Jackson" distilled in 25 glasses are used. The water is degassed before use and the solution after mixing.

Injector - A 100 microlitre loop injector.

Injection volume - 100 microliters.

Retention - 2.0 minutes (approximate) 149192 12 • HPLC Analysis 05 Standard - Weigh exactly 25 mg of cis-diammindi dichloroplatin (DDP), 225 mg of sodium chloride and 250 mg of mannitol in a 25 ml volumetric flask.

Dissolve in and dilute to volume with distilled water. Pipette 5.0 ml of the resulting solution into a 25-ml volumetric flask, add 2.0 ml of distilled water and make up to volume with acetonitrile.

Sample (1 mg / ml) - Pipette 5.0 ml of the sample into a 25-ml volumetric flask, add 2.0 ml of distilled water and make up to volume with ace tonitrile.

Calculations STANDARD FACTOR (SF) = _ MG STANDARD / ML_

AVERAGE TOP HEIGHT OF STANDARD

2o MG DDP / ML = SF X AVERAGE TOP HEIGHT OF SAMPLE x 25

The percent loss in strength after storage for one or two months was determined by HPLC examination at the indicated temperatures to the following: 13 149192

56 ° C 45 ° C

month months month K93 4.0 K94 2.0 4.0 05 K95 0.0 -1.0 * K96 1.0 4.0 0.0 K97 3.0 K98 4.0 2.0 K100 3.0 10 K101 3.0 5.0 K102 3.0 K103 5.0 4.0 K104 0.0 -1.0 * K105 0.0 5.0 0.0 15 K107 1.0 0.0 K108 2.0 5 , 0 1.0 K109 3.0 K110 3.0

Kill 7.0 20 K112 7.0 * Negative sign means that the sample showed a 1.0% increase in strength.

Thus, the above described information with and without nitrogen cover 25 has shown 7% or less loss in strength after storage at 56 ° C and 45 ° C with the majority exhibiting a strength loss of 3% or less. The pH of the solutions remained between 2.4 and 2.7.

Physically, no change is seen at 56 ° C or 45 ° C after one month. The solutions remain clear and colorless. Initial "Klett" readings averaged 8 - 12, and after a month at 56 ° C and 45 C readings averaged 6-15. No changes or differences are seen between samples with and without N2 cover.

149192 14

A sample at each temperature for all products was inversely tested by exposing the solution to the teflon coated plug. Reverse product samples were examined at 56 ° C for one month with and without N2 cover. Stability was not affected at one month at 56 ° C, as the samples showed only 1-2% strength loss.

After two weeks at 4 ° C, samples were observed for any crystallization of cis-diamminedichloroplatin (II). No crystals were observed until after a month in which crystallization was observed only in individual samples. Only one portion of the products "10 mg per vial" and "25 mg per vial" showed random crystals at 4 ° C. Crystallization was observed on all portions of 50 mg / ml. vial products, but again not in all samples. A sample at 4 ° C with crystals could not be redissolved at 15. Heating the solution to 37 ° C gains stirring. Only partial success was achieved. It appears that these products cannot be stored under cooled conditions as redissolution of crystallized products was difficult.

Cis-platinum (II) diamine dichloride (NSC 119875) is an inorganic compound which was first observed to prevent the propagation of E.coli and was subsequently found to possess antitumor activity. The compound exerts its interfering effect on DNA synthesis by causing cross-linking of complementary strands of DNA. It has activity in a variety of 25 tumor systems including L1210, Sarcoma 18.0, Walker 256 carcinomas, DMBA-induced gland tumors, and ascitic B16 melanosarcoma. The compound is particularly interesting in that it exhibits synergism with a large number of chemotherapeutic agents used so far. Large animal toxicology studies showed 30 renal tubular necrosis, enterocolitis, bone marrow hypoplasia and lymphoid atrophy. Phase I studies have shown the following toxicities: myelosuppression, renal insufficiency, high-frequency oto-toxicity and GI intolerance. The doses currently used with mild to moderately acceptable toxicity are in the range

Claims (2)

2 1A 919 2 60-100 mg / m IV as a single dose or divided over 3-5 days for repetition at 4 week intervals. Early clinical trials show certain responses of the compound to germinal cell tumors, lymphomas, sarcomas, breast, 05 head and neck carcinomas. Λ A dose of 60 mg / m is roughly equivalent to 1.5 mg / kg, which in turn is roughly equivalent to 105 mg per kg. patient weighing 70 kg. The solutions in question are used in the same way and for the same purposes as stated above and in other publications and in the comprehensive medical literature on this subject. As stated there, there is frequent use of concurrent therapy with other chemotherapeutic agents to achieve the best results. If desired, the present solutions 15 may be added immediately before use to a sterile, pharmaceutically acceptable aqueous diluent such as glucose or saline solution. Administration is either by direct intravenous injection or by intravenous infusion. A process for preparing a stable, sterile aqueous solution of cis-platinum (II) -diammine dichloride, called 20 cisplatin, in unit dosage form suitable for human administration, characterized by dissolving cisplatin in a sterile aqueous medium which contains a non-toxic pharmaceutically acceptable inorganic source of chloride ions at a concentration equivalent to that provided by the presence of sodium chloride at a concentration ranging from 1 to 20 mg per ml. and / or, optionally, a usually harmless physiologically acceptable excipient at a concentration in the range of 2 - 150 mg per ml. to a cis-platinum concentration of between ca. 0.1 and approx. 1.0 mg per with hydrochloric acid 30 sets the pH in the range of 2.0 to 3.0.