NZ189556A - Stabilised aqueous solutions of cisplatin - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 89556 189556 Priority Dat«(s}: .

Cormi©-a C;:ocificc.ticn Filed:A ClMS:«?« W/??; Publication Date: | P.O. Jouroe!, Ko: IliSlflili NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION PHARMACEUTICAL FORMULATIONS - _\v.. y<>ric . =T-/We, BRISTOL-MYERS COMPANY of 345 Park Avenue, New York,/lO 022, nA V United States of America a Corporation of the State of Delaware, United States of America hereby declare the invention for which—W we pray that a patent may be granted to mer/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 oUow>i?ci fcy BACKGROUND OF THE INVENTION 1. Field of the Invention.

This invention relates to stabilized aqueous solutions of a chemical (cisplatin) used by injection in the chemotherapy of cancer. 2. Description of the Prior Art.

The platinum compounds are a unique group of compounds in the antineoplastic group of agents. They were first noted to have an antibiotic effect by Rosenberg and his colleagues in 1965 and have since been found to be 1 2 potent antitumor agents in animals. ' Structurally they represent a complex formed by a central atom of platinum and surrounded by various arrangements of chlorine atoms or ammonia groups in either a cis or trans planar relationship. Two of the more commonly studied platinum compounds are diagrammed below: CI Cis-Platinum (II) Cis-Platinum (IV) Diamminedichloride Diamminetetrachloride As can be seen, the platinum compound, cis-platinum (II) diamminedichloride, selected for clinical trials by the National Cancer Institute has the chloride and amino groups only in the horizontal plane. The cis form of the diamminedichloride complex has been synthesized accord-ing to the following reactions 189556 NH.C1 4 K2/PtCl4_7" + 2NH3 ^cis-/Pt (NH3) 2C12_7 + 2KC1 1. Rosenberg, B., VanCamp, L. and Krigas, T., Inhibition of cell division in Escherichia coli by elec7 trolysis products from a platinum electrode. Nature (London) 205; 698-699, 1965. I 2. 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. 3. Kauffman, G.B. in J. Kleinberg (Ed.), Inorganic Synthesis, McGraw-Hill Book Co., Inc., New York, 241-242, 1963.

Three grams of ammonium chloride is dissolved in a solution containing 4.15g (0.01 mol) of potassium tetrachloro-platinate (II) and 2.5 ml. of concentrated hydrochloric acid in 75 ml. of water, contained in a 150 ml. beaker. About 10 ml. of 3 M aqueous ammonia is cautiously added until the solution is neutral to litmus. Two orie-hundredths mol of additional ammonia (6.75 ml. of 3 M solution) is then added. The solution is refrigerated until the precipitation of the greenish yellow solid appears to be complete and the supernatant liquid has changed from deep red to light yellow (24 to 48 hours). The precipitate, consisting of the cis isomer containing a small 189556 amount of tetraammineplatinum(II) tetrachloroplatinate(II) (Magnus' green salt), is separated by suction filtration and washed free of soluble salts with several 10 ml. portions of ice water. The precipitate is then transferred to a 250 ml. Erlenmeyer flask, and 0.1 N hydrochloric acid is added to bring the total volume to 150 ml. This mixture is heated to boiling and stirred until all the cis isomer dissolves, leaving a small residue of Magnus' green salt, which is removed by filtration. Crystallization of the isomer is prevented by use of a funnel heater or a jacketed Buchner funnel. The residue on the filter paper is washed with 10 to 20 ml. of boiling 0.1 N Hydrochloric acid and the washings are added to the filtrate. The latter is cooled in an ice bath until crystallization seems complete (1 to 2 hours)..

' The yellow crystals are separated by suction filtration, washed with several 10 ml. portions of ice water, and air-dried. The yield is 1.80 g. (60%, based on potassium hexachloroplatinate(IV)).

Anal. Calcd. for /Pt(NH3)2C12_7: Pt, 65.02; N,9.33; H, 2.01; CI, 23.62. Found: Pt, 65.23; N, 9.62, 9.81; H, 2.33; CI, 23.33.

The National Cancer Institute has been conducting clinical trials in cancer chemotherapy of the chemical for which the United States Adopted Name (USAN) is now cisplatin. Certain information regarding its chemistry and its pharmaceutical formulation are given in the publication titled Clinical Brochure, CIS-PLATINUM (II) 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. The last two pages of Handelman et al. concern the formulation of cisplatin supplied gratis by the N.C.I, to clinicians for their clinical evaluation in the chemotherapy of cancer and read as follows: 189556 PHARMACEUTICAL DATA SHEET NSC-119875 Cis-Diamminedichloroplatinum (II) Dosage Formulation mg./vial ; The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial contains 10 mg. of NSC-119875; 90 mg. of Sodium Chloride; 100 mg. of Mannitol and Hydrochloric acid for pH adjustment.

Solution Preparation mg./vial : When reconstituted with 10 ml. of Sterile Water for Injection, USP, each ml. of the resulting solution will contain 1 mg. of NSC-119875j 10 mg. of Mannitol, and 9 of Sodium Chloride having a pH range of 3-5-4.5.

Storage : The dry, unopened vials should be stored at refrigeration temperatures (4-8° C.).

Stability : Intact vials have a provisional stability of one year when stored at refrigeration temperature (4-8° C.). Stability recommendations may be adjusted pending completion of a two-year shelf-life study. Reconstitution as recommended results in a pale, yellow solution which is stable for not more than one hour at room temperature (22° C.) when exposed to normal room illumination and not more than eight hours at room temperature (22° C.) when protected from light. Reconstituted so- 189556 lutions may form a precipitate after one hour at refrigeration temperature (4-8° C.).

Caution : The lyophilized dosage formulations contain no preservatives and therefore it is advised to discard solutions eight hours after reconstitution.

August, 1974 Clinical Drug Distribution Section' Drug Development Branch Mention of this formulation and additional information on its clinical use is given, for example, in Cancer Chemotherapy Reports, Part 1, Vol. 57, No. 4, pages 465-471 (1973).

Cancer 30: 1451-1456 (1972) in reference to cisplatin states that "The drug material used in this study was manufactured by Ben Venue Laboratories Inc., Bedford, Ohio. It was supplied by the Cancer Therapy Evaluation Branch of the National Cancer Institute in vials containing 10 mg. of cis-diamminedichloroplatinum, 10 mg. (sic) of mannitol and 9 mg. (sic) of NaCl. The resulting yellowish white powder dissolved readily in 8-10 ml. of sterile water and was injected immediately after preparation." Annals of Internal Med. 86: 803-812 (1977) refers to cisplatin as "DDP" and states that "The drug DDP is presently available as an investigational drug only to qualified specialists through the Investigational Drug Branch of the Cancer Therapy Evaluation Program, National Cancer Institute. The product is supplied as a white lyophylized powder in vials containing 10 mg. of DDP, 90 mg. of sodium chloride, 100 mg. of mannitol (U.S.P.), and hydrochloric acid for pH 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 MS* 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 h." Thus the formulations described above are stated to require refrigeration (4-8° C.) while in vials in the solid state (i.e., before reconstitution), they are difficult to reconstitute and they have a useful life of only about twenty hours at room temperature (22° C.) following reconstitution. The very act of reconstitution can cause problems if improperly performed and is better avoided. In addition, because the aqueous solubility of cisplatin is only about 1 mgm./ml., the cost of preparing dosage forms containing more than 25 mgm./vial by lyophilization becomes prohibitive.

It was the object of the present invention to provide a stable, therapeutically acceptable, intravenously injectable dosage form of cisplatin which would not require lyophilization and reconstitution, which would not require refrigeration during shipment and storage, and which could be supplied in dosages of 50 mg. or larger.

These objectives were achieved by the present invention as described in detail below. 1 SUMMARY OF THE INVENTION There is provided by the present invention a stable, sterile aqueous solution of cisplatin in a sealed container such as an ampul or vial in unit dosage form suitable for intravenous administration to man, said solution having a con- centration of cisplatin betweeniabewt 0.1 and /afeeurfr 1.0 J h w r- *- " mgm./ml. and preferably of about 1.0 mgm./ml. and a pH in the range of 2.0 to Ji.O and preferably in the range of 2.3 to 2.7 and most preferably a pH of about 2.5, said pH ^ being caused by the presence of the appropriate amount of a nontoxic, pharmaceutically and therapeutically acceptable acid, said acid preferably being a strong mineral acid and most preferably being hydrochloric acid; said solution optionally containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml. and most preferably about 9 mgm./ml.; said solution optionally also being either free of any other added chemicals or also containing a customary, harmless, physiologically acceptable excipient, which is preferably mannitol, in a concentration in the range of 2 to 150 mgm./ml. and preferably a concentration of about 10 mgm./ml., said solution exhibiting less than 10$ (and usually less than b%) loss of potency as measured by high performance liquid chromatography (HPLC) upon storage for one month at 56° C. Preservatives can be added if desired.

There is further provided by the present invention a method for inhibiting the growth of a malignant tumor susceptible to cisplatin which comprises intravenously administering to a human afflicted with such a malignant tumor an amount effective to inhibit the growth of said tumor of is 9556 a stable, sterile aqueous solution of cisplatin, from a sealed container such as an ampul or vial in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin between substantially 0.1 and substantially 1.0 mgm./ml. and preferably of about 1.0 mgm./ml. and a pH in the range of 2.0 to 3.0 and preferably in the range of 2.3 to 2.7 and most preferably a pH of about 2.5, said pH being caused by the presence of the appropriate amount of a nontoxic, pharmaceutically and therapeutically acceptable acid, said acid preferably being a strong mineral acid and most preferably being hydrochloric acid; said solution optionally containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml. and most preferably about 9 mgm./ml.; said solution optionally also being either free of any other added chemicals or also containing a customary, harmless, physiologically acceptable excipient, which is preferably mannitol,.in a concentration in the range of 2 to 150 mgm./ml. and preferably a concentration of about 10 mgm./ml., said solution exhibiting less than 10$ (and usually less than 4$) loss of potency as measured by high performancie liquid chromatography (HPLC) upon storage for one month at 560 C. p.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Cisplatin Injection 1 Mg./Ml. fl Mg. Cis-diamminedichloroplatinum (II) per 1 M1.1 Formula Per Ml. Per Liter Cis-diamminedichloro- . . platinum (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.

Hydrochloric Acid, Cone. U.S.P q.s. to pH q.s. to pH 2.0-3.0B 2.0-3.0B Water for Injection, U.S.P q.s. 1.0 Ml. q.s. 1000.0 Ml.

NOTES: A. 100$ basis, adjust weight based on reported purity to provide 1.0 g. 100$ cis-diamminedichloroplatinum (II) per liter.

B. Approximately 0.035-0.050 ml. of 37$ hydrochloric acid required per gram of sodium chloride to obtain a pH of approximately 2.5.

PRECAUTIONS Cis-diamminedichloroplatinum (II) is a toxic substance and is listed on page 9^2 in the 1976 edition of the "Registry of Toxic Effects of Chemical Substances." The OSHA Standard of Time Weighted Average (TWA) is 2 mcg./m-5.

Consult the above, listed references, pertinent local publications and regulations and such publications as 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. Any cis-diamminedichloroplatinum (II) weighing, the working surface of the batching vessel, the filling, stoppering, and sealing must be provided with such protection.

All personnel involved with compounding of this product must be protected with full nylon head/face cover, coveralls, rubber gloves and a respirator equivalent to the MSA Ultra Filter Respirator rated for environments contaminated with dusts, fumes and mists having a TWA rating of less than 50 mcg./m^. During the sterile liquid filling the sterile head/face cover, surgeon's gauze mask and goggles can replace the respirator. Any uniforms grossly contaminated due to spills, etc. should be stored in a closed metal container until burned.

THE IMPORTANCE OF PROTECTING PERSONNEL DURING THE HANDLING, MANUFACTURING AND ASSAYING OF THIS PRODUCT IN ACCORDANCE WITH THE ABOVE CANNOT BE OVEREMPHASIZED.

The prime bulk cis-diamminedichloroplatinum (II) must be protected from light. The processing and filling of vials described herein was conducted under diffused natural/fluorescent light.

EQUIPMENT Batching Vessel Glass-lined, agitated, pressure vessel. A 316 SS agitator is permissible. Working volume must be consistent with batch size. A dipstick and calibration curve of tank 189556 volume is required for determining volume.

Millipore Membrane Filter Holders 316 SS. Filter area with necessary pre-filters and 0.22 micron final sterilizing filter.

Transfer Hoses Teflon or Tygon.

All stainless steel contacts should meet 316 SS requirements. All other equipment should be appropriate to produce a sterile, non-pyrogenic, particulate-free product.

Manufacturing Instructions A. These instructions are written for an eight-hour batching to filling operation. Storage of this product before filling has not been investigated at this writing.

B. Maintain 27° C. ± 2° C. temperature conditions throughout entire batching and filtering operations. 1. Place 80% of the batch volume of Water for Injection, U.S.P. in a suitable vessel. 2. With agitation add the sodium chloride. Agitate ten minutes or until dissolved. 3. With good agitation carefully adjust the pH of the sodium chloride solution to 2.0-3.0 (preferably 2.5) with concentrated hydrochloric acid. See estimated amount under note "B" on formula sheet. Agitate for ten minutes after last addition. Recheck pH. 4. With good agitation add the mannitol and agitate ten minutes or until dissolved.

. With good agitation and taking special precautions against dusting and exposure, add the cis-diarnminedlchloro- 1 platinum (II)- Rinse its container sufficiently with an appropriate amount of water for injection and add to the batch. 6. Agitate until completely dissolved. Approximately 60-90 minutes will "be required for complete dissolution. Monitor pH and add additional concentrated hydrochloric acid if required to maintain at 2.0-3.0 (optimum 2.5). 7. Carefully adjust volume to theoretical batch volume with water for injection. Make final pH check. 8. Pass the solution through a clean, sterile 0.22 micron Millipore Filter into the sterile filling line. 9. Fill as directed below for the following products: Mg./Vial Sterile, Type I amber, 15 ml. vial, with a 10-ml. fill. Stopper with red, 20mm Teflon-faced stoppers and seal with aluminum seals. Numbered as K93, 100 and 107 with nitrogen overlay and K94, 101 and 108 without nitrogen overlay.

Mg./Vial Sterile, Type I amber, 50 ml. vial with a 25-ml. fill. Stopper with red, 20mm Teflon-faced stoppers and seal with aluminum seals . Numbered as K95* 102 and 109 with nitrogen overlay and K96, 103 and 110 without nitrogen overlay. 50 Mg./Vial Sterile, Type I amber, 50 ml. vial with a 50-ml, fill. Stopper with red, 20mm Teflon-faced stoppers and seal with aluminum seals. Numbered as K97* 104 and 111 with nitrogen overlay and K98, 105 and 112 without nitrogen overlay. 189556 These formulations were prepared in five groups (with the final pH given 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-H0 (pH 2.3) Klll-112 (pH 2.4) Original potencies by HPLC assay were in the range of 0.99 to 1.00 mgm./ml.

The percentage loss in potency after storage for one or two months at the indicated temperature was found by HPLC assay to be as follows: K93 One Month 4.0 Two Months One Month K94 2.0 4.0 K95 0.0 -1.0* K96 1.0 4.0 0.0 K97 3.0 K98 4.0 2.0 K100 3-0 K101 3.0 -0 K102 3.0 K103 .0 4.0 K104 0.0 -1.0* K105 0.0 -0 0.0 K107 1.0 0.0 K108 2.0 .0 1.0 K109 3.0 K110 3.0 Kill 7-0 K112 7.0 *Negative sign means assay showed 1.0$ increase in potency. _1 ■*_ 189556 The above-described solutions, with and without nitrogen cover, thus have shown 7$ or less loss in potency after storage at 56° C. and 45° C. with the majority showing a loss of potency of J>tfo or less. The pH of the solutions remained between 2.4 and 2.7.

Physically, no change is apparent at 56° C. or 45° C. after one month. Solutions remain clear and colorless. Initial Klett readings averaged 8-12; one-month 56° C. and 45° C. readings averaged 6-15. Wo changes or differences are noted between samples with or without Ngf.

One sample at each temperature station for all products was tested inverted exposing the solution to the Teflon-coated plug stopper. Samples from inverted products were assayed from 56° C. at one month with and without N2t exposure. Stability was not affected at one month 56° C. as samples showed only 1-2$ loss of potency.

At two weeks 4° C. samples were observed for crystallization of cis-diamminedichloroplatinum (II). No crystals were observed until one month and it was only noted randomly, not in every sample. Only one lot of the 10 mg./vial and 25 mg./vial products show some crystals forming randomly at 4° C. Crystallization is noted throughout all lots of 50 mg./vial products but again not in all samples. One sample from 4° C. with crystals could not be redissolved by warming the solution to 37° C. with agitation. Only partial success was obtained. It appears these products cannot be stored under refrigerated conditions as even redissolving of crystallized products was difficult. 189556 Cis-platinum (II) diamminedichloride (NSC 119875) is an inorganic compound first noted to prevent replication of E. coli and subsequently found to possess antitumor activity. The drug exerts its effect of interfering with DNA synthesis by causing cross-linking of complementary strands of DNA. It has activity in a variety of tumor systems including L1210, Sarcoma 180, Walker 256 carcinosarcoma, DMBA induced mammary tumors and ascitic Bl6 melanosarcoma. The compound is especially interesting in that it exhibits synergism with a large number of currently-used chemothera-peutic agents. Large animal toxicology studies showed renal tubular necrosis, enterocolitis, bone marrow hypoplasia and lymphoid atrophy. Phase I studies have demonstrated the following toxicities: myelosuppression, renal insufficiency, high frequency ototoxicity and GI intolerance. Currently used dosages with mild to moderately acceptable toxicity are in the range of 60-100 mg/m IV as a single dose or divided over 3-5 days, to be repeated at four-week intervals. Early clinical trials show some responses to the drug in germinal cell tumors, lymphomas, sarcomas, breast and head and neck carcinomas.

A dosage of 60 mgm/m is roughly equal to 1.5 mgm/kg which in turn is roughly equal to 105 mgm/patient weighing 70 kg.

The solutions of the present invention are used in the same manner and for the same purpose as stated above and in the other publications and in the voluminous medical literature on this subject. As stated therein, frequent use is made of concurrent therapy with other chemotherapeutic agents for best results. When desired, the solutions of the present invention may be added immediately before use to a 1 8 95 5 6* sterile, pharmaceutically acceptable aqueous diluent such as glucose or saline. Administration is either by direct intravenous injection or by intravenous infusion. t 89556 High Performance Liquid Chromatography (HPLC) Assay for cis-Pi^Tmni nedichloroplatinum.

Method Cis-diamminedichloroplatinum is chromatographed on a Water's H--Bondapak-NHg column using a loop injection technique. Detection is achieved by monitoring the U.V. absorbance at 313 nm and quantitation is accomplished by peak height measurement with external calibration. This method is applicable to bulk powders and solid dose formulations containing NaCl and mannitol. Specificity has been demonstrated by separation of the cis and trans isomers and apparent degradations (moisture, acid, base, heat and accelerated light).

Cis-(NH5)2 Cl2 Pt II Trans-(NH^)2 Cl2 Pt II HPLC Conditions Column - Water's Micro-Bondapak-NHg (300 MM X 4.0 MM ID) 027386 or equivalent.

Mobile Phase - Ethyl acetate/methano1/dimethyIformami de/ distilled water (25/16/5/5). Use Burdick and Jackson distilled in glass spectro-quality reagents. Degas the water prior to use and the solution after mixing.

Detector - Water's Model 440 Absorbance Detector. Wavelength - 313 nm (U.V.). 189556 Sensitivity - 0.1 AUFS.

Injector - A 20 microliter loop injector.

The Loop Injector - A Valco 7000 psi stainless steel valve (CV -6-UHPa-C20).

Injection Volume - 20 microliter.

Solvent Delivery System - Water's Model 6000A pump.

Flow - 2.0 ml./minute.

Retention - 2.8 minutes (approx.).

Recorder - Heath Model SR-255B.

Chart Speed - 0.5 inch/min.

Range - 10 millivolt.

HPLC Analysis Using the conditions above, obtain chromatograms of the standard and sample preparations in duplicate.

Reference Standard of cis-diamminedichloro- platinum (DDP): Lot No. = 78F7 (Matthey Bishop Lot No. AM7702) Assigned Purity = 99-8$ Solvents - Burdick and Jackson (distilled in glass) spec-troquality.

Standard - Weigh accurately 25 mg. of cis-diamminedichloroplatinum (DDP) into a 25-ml. volumetric flask. Dissolve in and dilute to volume with dimethyl-formamide.

Iyophilized Injection - Reconstitute vial contents with 10.0 ml. of dimethylformamide and mechanically shake for 5 minutes (alternately a sonic bath may be used for 2 minutes). Filter 5-0 ml. of the sample solution (Millipore Filter Kit or 189556 mannitol into a 25-ml. volumetric flask. Dissolve in and dilute to volume with distilled water.

Pipet 5'0 ml. of the resulting solution into a 25.-ml. volumetric flask, add 2.0 ml. of distilled water and take to volume with acetonitrile.

Sample (1 mg./ml.) - Pipet 5.0 ml. of the sample into a -ml. volumetric flask, add 2.0 ml. of distilled water and take to volume with acetonitrile.

Calculations ^TAWTlA'RT) FACTOR — MG. STANDARD/ML. blAiMDAitU rALiUK - AVERAGE PEAK height STANDARD MG. DDP/ML. = SF X AVERAGE PEAK HEIGHT SAMPLE X 25 This invention is capable of industrial application. \. 189556 equivalent) discarding the first ml.

Content Uniformity - Prepare 10 vials as described above and assay.

Calculations STANDARD FACTOR (SF) = AVERAGE pEAK HEIGHT^STANDARD SF X AVERAGE PEAK HEIGHT SAMPLE X 25 MG. DDP/GRAM WT. SAMPLE (GM. ) MG. DDP/VTAL = SF X AVERAGE PEAK HEIGHT SAMPLE X 10 For assays average results obtained for 10 vials from content uniformity test.

Method The method of assay for cisplatin described above is applied to aqueous solutions (dose formulations) containing NaCl and mannitol after making the changes indicated below.

HPLC Conditions Mobile Phase - Acetonitrile/distilled water (75/25, v/v).

Use Burdick and Jackson distilled in glass spec-troquality reagents. Degas the water prior to use and the solution after mixing.

Injector - A100 microliter loop injector.

Injection Volume - 100 microliter.

Retention - 2.0 minutes (approx.).

HPLC Analysis Standard - Weigh accurately 25 mg. of cis-diamminedichloro- platinum (DDP), 225 mg. sodium chloride and 250 mg. 1895

Claims (11)

WHAT WE CLAIM IS:

1. A stable, sterile aqueous solution of cisplatin in unit dosage form suitable for administration to man, said solution having a concentration of cisplatin between substantially 0.1 and substantially 1.0 mgm./ml. and a pH in the range of 2.0 to 3.0, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid.

2. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin between substantially 0.1 and substantially 1.0 mgm./ml. and a pH in the range of 2.0 to i 3.0, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid.

3. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin between substantially 0.1 and substantially 1.0 mgm./ml. and a pH in the range of 2.3 to 2.7, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid.

4. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin between substantially 0.1 and substantially 1.0 mgm./ml. and a pH of about 2.5, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid.

5. A stable, sterile aqueous solution of 189556 cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ml. and a pH in the range of 2.0 to 3.0, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid.

6. A stable, sterile aqueous solution according to claim 5 of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ ml. and a pH in the range of 2.3 to 2.7, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid.

7. A stable, sterile aqueous solution according to claim 5 of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ ml. and a pH of about 2.5, said pH being caused by the presence of the appropriate amount of a non-toxic, pharmaceutically and herapeutically acceptable acid.

8. A stable, sterile aqueous solution according to claim 6 of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ml. and a pH in the range of 2.3 to 2.7, said pH being caused by the presence of the appropriate amount of a non-toxic, therapeutically acceptable acid; said solution containing in addition a non-toxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml. 189556

9. A stable, sterile aqueous solution according to claim 6 of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ml. and a pH in the range of 2.3 to 2.73 said pH being caused by the presence of the appropriate amount of hydrochloric acid; said solution containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that pro- I duced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml. !

10, A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ml. and a pH in the range of 2.3 to 2.7* said pH-being caused by the presence of the appropriate amount of hydrochloric acid; said solution containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml.; said solution being free of any other added chemical. -23- 189556

11. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said . ✓ solution having a'concentration of cisplatin of about 1.0 mgm./ml. and a pH in the range of 2-3 to 2.7, said pH being caused by the presence of the appropriate amount of hydrochloric acid; said solution containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration / in the range of 1 to 20 mgm./ml.; said solution also containing a customary, harmless, physiologically acceptable f excipient in a concentration in the range of 2 to 150 mgm./ml. 12, A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, said solution having a concentration of cisplatin of about 1.0 mgm./ml. and a pH in the range of 2.3 to 2.7, said pH being caused by the presence of the appropriate amount of hydro'chloric acid; said solution containing in addition sodium chloride in a concentration of about 9 mgm./ml.; said solution also containing mannitol in a concentration of about 10 mgm./ml., said solution exhibiting less than 10$ loss of potency a£ measured by Jiigh performance liquid chromatography . upon storage for one month at 56° C. ■ - o\ 24 - v ,>9 MAY! 981 . — - • -• • % 1 89556 13- A stable sterile aqueous solution according to claim 1 and substantially as hereinbefore described with particular reference to example 1. DATED THIS 3O-ll DAY OF A. J. /SON AGE Mm ^APPLICANTS "2 1 - 25 -