HK37982A - Pharmaceutical formulations containing cis-platinum (ii) diamminedichloride - Google Patents

Abstract

A stable, sterile aqueous solution of cis-platinum (II) diamminedichloride (cisplatin) in a sealed container such as an ampule or vial in unit dosage form suitable for intravenous administration to man has a concentration of cisplatin in the range of from 0.1 to 1.0 mgm/ml. and a pH in the range of from 2.0 to 3.0, preferably about 5.5. The solution can also contain sodium chloride and mannitol.

Description

SPECIFICATIONPharmaceutical Formulations Containing Cis-Platinum (II) Diamminedichloride The present invention relates to stabilized aqueous solutions of cis-platinum (II) diamminedichloride (cisplatin), which is used by injection in the chemotherapy of cancer.

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 <RTI>1 965</RTI> and have since found to be potent antitumour agents in <RTI>animals.1,2</RTI> 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 of trans planar relationship.

Two of the more commonly studied platinum compounds are diagrammed below:

Cis-Platinum (II) Cis-Platinum <RTI>(IV)</RTI> Diamminedichloride Diamminetetrachloride As can be seen, the platinum compound, cis-platinum <RTI>(II)</RTI> diamminedichloride, selected for <RTI>cliriical</RTI> trials by the National Cancer Institute has the chloride and amino groups only in the horizontal plane. The cis form of the diamminechloride complex has been synthesized according to the following reaction:3

1. Rosenberg, B., VanCamp, L. and Krigas, T., Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature (London) 205: <RTI>698-699, 1965.</RTI>

2. Rosenberg, <RTI>K,</RTI> VanCamp, LTrosko, J. E. and Mansour, V. H., Platinum compounds: A new class of potent antitumour agents. Nature (London) 222: <RTI>385-386, 1969.</RTI>

3. Kauffman, G. B. in J. Kleinberg (ED.), <RTI>Inorganic</RTI> Synthesis, McGraw-Hill Book Co., Inc., New York, 1963.

The National Cancer Institute has been conducting clinical trails in cancer chemotherapy of the chemicat for which the United States Adopted Name (USAN) is now cisplatin. Certain information <RTI>regarding-its</RTI> chemistry and its pharmaceutical formulation are given in the publication titled C!inicalBrochure, Cis-platinum <RTI>(II)</RTI> Diamminedichloride (NSC-1 19875), H.Handelman et al., InvestigationalDrug Branch, CancerTherapy Evaluation Program, Division of Cancer Treatment, NationalCancer Institute (Revised, August 1974), on pages 1-5 and <RTI>31-32.</RTI> The iast two pages ofHandelman et al. concern the for formulation of cisplatin supplied gratis by the <RTI>N.C.I.</RTI> to clinicians for <RTI>their clìnical</RTI> evaluation in the chemotherapy of cancer and read as follows:Pharmaceutical Data SheetNSC-119875 Cis-Diamminedichloroplatinum (II)Dosage Formulation 10 mg./vial: The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial contains 10 mg. of NSC-1 19875; 90 mg. of Sodium Chloride; 100 mg. of Mannitol and Hydrochloric acid for pH adjustment.

Solution Preparation <RTI> 10 0 mg./vial: When reconstituted with 10 ml of Sterile Water for Injection, USP, each ml. of the</RTI> resulting solution will contain 1 mg. of <RTI>NSC-1 19875, 10</RTI> mg. of Mannitol, and 9 mg. of Sodium Chloride having <RTI>a-pH</RTI> range of 3.5-4.5.

Storage: The dry, unopened vials should be stored at refrigeration temperatures <RTI>(4--8 OC).</RTI>

Stability: Intact vials have a provisional stability of one year when stored at refrigeration temperature <RTI>(4-80C).</RTI> 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 (220C), when exposed to normal room illumination and not more than eight hours at room temperature <RTI>(22 OC.)</RTI> when protected from light. Reconstituted solutions may form a precipitate after one hour at refrigeration temperature <RTI>(4-80C).</RTI>

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

August, 1974Clinical Drug Distribution SectionDrug Development Branch Mention of this formulation and additional information on its clinical use is given, for example, inCancer Chemotheraphy Reports, Part <RTI>1.Vol.</RTI> 57, No.4, pages <RTI>465-471</RTI> (1973): Cancer <RTI>30:1451-1456(1972)</RTI> in reference to cisplatin states that "The drug material used in this study was manufactured by Ben Venue Laboratories <RTI>Inc.,</RTI> BedfordOhio. 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 NaCI.

The resulting yellowish white powder dissolved readily in <RTI>8-10</RTI> ml. of sterile water and was injected immediately after preparation".

Annals of Internal Med. 86: <RTI>803-812</RTI> (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 <RTI>theCancerTherapy</RTI> Evaluation Program, National CancerInstitute. The product is supplied as a white lyophilized powder in vials containing 10 mg. of DDP, 90 mg. of sodium <RTI>chloride,100</RTI> 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 mg, of NACI. The pH of the resulting solution will be 3.4 to 4.5. At 220C., the reconstituted solution is stable for at least 8 h".

Thus the formulations described above are stated to require refrigeration <RTI>(4--8 OC.)</RTI> 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 <RTI>(220C).</RTI> 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 <RTI>mgmiml.,</RTI> the cost of preparing dosage forms containing more than 25 mgm./vial by lyophilization becomes prohibitive.

We have now developed a stable, therapeutically acceptable, intravenously injectable dosage form of cisplatin which does not require lyophilization and reconstitution, which does not require refrigeration during shipment and storage, and which can be supplied in dosages of 50 mg. or larger.

According to the present invention there is provided a stable, sterile aqueous solution of cisplatin in a sealed container such as an ampule or vial in unit dosage form suitable for intravenous administration to man, which solution has a concentration of cisplatin in the range of from 0.1 to 1.0 <RTI>mgm./ml.</RTI> and preferably about 1.0 mgm./ml. and a pH in the range of from 2.0 to 3.0, preferably in the range of from 2.3 to 2.7 and most preferably a pH of about 2.5, the pH being caused by the presence of an appropriate amount of a nontoxic, pharmaceutically and therapeutically acceptable acid.The acid is preferably a strong mineral acid and most preferably is hydrochloric acid; the solution optionally containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions at a concentration equivalent to that produced <RTI>bythe</RTI> presence of sodium chloride at a concentration in the range of from 1 to 20 mgm/ml. and most preferably about 9 <RTI>mgmjml.;;</RTI> the solution optionally also being either free of any other added chemicals or also containing a customary, harmless, physiologically acceptable excipient, which is preferably mannitol, at a concentration in the range of from 2 to <RTI>1 50</RTI> <RTI>mgm./ml.</RTI> and preferably a concentration of about 10 <RTI>mgm/ml.,</RTI> the solution exhibiting less than 10% (and usually less than 4%) loss of potency as measured by high performance liquid chromatography (HPLC) upon the storage for one month at 560C. Preservatives can be added if desired.

The present invention will be further described with reference to the following Examples.

Example 1 Cisplatin Injection 1 <RTI>Mg./MI.</RTI>

[1 Mg. Cis-diamminedichloroplatinum <RTI>(II)</RTI> per 1 Ml.] Formula <RTI>Per Ml.</RTI> Per Liter Cis-diamminedichloro-Platinum <RTI>(Il)</RTI> 0.0010 <RTI>gA</RTI> 1.000 g.A Sodium Chloride, U.S.P. 0.0090 g. <RTI>9.000</RTI> g.

Mannitol, U.S.P. <RTI>0.0100g.</RTI> <RTI>10.000g.</RTI>

Hydrochloric Acid Conc. U.S.P. q.s. to pH <RTI>2.0--3.08</RTI> q.s. to pH <RTI>2.0--3.OB</RTI>Water for Injection U.S.P. q.s. 1.0 Ml <RTI>q.s. 1000.0</RTI> MlNotes: <RTI>A. 100%</RTI> basis, adjust weight based on reported purity to provide 1.0 <RTI>g. 100%</RTI> cisdiamminedichloroplatinum <RTI>(II)</RTI> per liter.

B. Approximately <RTI>0.035-0.050</RTI> ml. of 37% hydrochloric acid required per gram of sodium chloride to obtain a pH of approximately 2.5.

Precautions: Cis-diamminedichloroplatinum <RTI>(II)</RTI> is a toxic substances and is listed on page 742 in the <RTI>1 976</RTI> edition of the "Registry of Toxic Effects of Chemical Substances". The OSHA Standard of TimeWeighted Average (TWA) is 2 meg./m3. 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 aClass <RTI>II</RTI> type 1 Safety Cabinet. Any cis-diamminedichloroplatinum <RTI>(II)</RTI> weighing, the working surface of the batching vessel, the filling, stoppering, and sealing must be provided with such protection.

Ail 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/m3. During the sterile liquid filling the sterile head/face cover, surgeon's gauze mask and goggles can repiace 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 thisProduce in Accordance with the Above Cannot be Overemphasized The prime bulk cis-diamminedichloroplatinum <RTI>(II)</RTI> must be protected from light. The processing and filling of vials described herein was conducted under diffused natural/fluorescent light.

EquipmentBatching Vessel Glass-lined, agitated, pressure vessel. A <RTI>31 6</RTI> SS agitator is permissible. Working volume must be consistent with batch size. A dipstick and calibration curve of tank 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 HosesTeflon <RTI>or Tygon</RTI> All stainless steel contacts should meet 316 <RTI>SS</RTI> 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 270C+20C. 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 <RTI>2.0-3.0</RTI> (preferably 2.5) with concentrated hydrochloric acid. See estimated amount under note "B" on the 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.

5. With good agitation and taking special precautions against dusting and exposure, add the cisdiamminedichloro-platinum <RTI>(II).</RTI> Rinse its container sufficiently with an appropriate amount of water for injection and add to the batch.

6. Agitate until completely dissolved. Approximately 60 to 90 minutes will be required for complete dissolution. Monitor pH and add additional concentrated hydrochloric acid if required to maintain at <RTI>2.0-3.0</RTI> (optimum 2.5).

7. Carefully adjust volume to theroetical 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: 10 Mg/Vial Sterile, Type I amber, 1 5 ml. vial; with a 1 O-ml. fill. Stopper with red, 20 mm Teflon-faced stoppers and seal with aluminium seals. Numbered as K93, 100 and 107 with nitrogen overlay andK94, 101 and 108 without nitrogen overlay.

25 Mg./Vial Sterile, Type I amber, 50 ml. vial with a <RTI>25-ml.</RTI> fill. Stopper with red, 20 mm Teflon-faced stoppers and seal, with aluminium seals. Numbered as K95, 102 and 109 with nitrogen overlay andK96, <RTI>1 03 and</RTI> <RTI>110</RTI> without nitrogen overlay.

50 Mg./Vial Sterile, Type I amber, 50 ml. vial with a <RTI>50-ml.</RTI> fill. Stopper with red, 20 mm Teflon-faced stoppers and seal with aluminium seals. Numbered as K97, 104 and <RTI>111</RTI> with nitrogen overlay and K98, 105 and <RTI>112</RTI> without nitrogen overlay.

These formulations were prepared in five groups (with the final pH given in parentheses) as follows: K93 <RTI>-96</RTI> (pH 2.4) K97 <RTI>-98</RTI> <RTI>(pH</RTI> 2.5) <RTI>K100-103</RTI> (pH 2.3) <RTI>K104-105</RTI> (pH 2.4) <RTI>K107-110</RTI> (pH 2.3) <RTI>Kill-i 12</RTI> (pH 2.4) Original potencies by HPLC assay were in the range of 099 to 1.00 <RTI>mgmiml.</RTI>

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: 560C 450C One Month Two Months One Month K93 4.0 K94 2.0 4.0 K95 0.0 <RTI>1.0*</RTI> K96 1.0 4.0 0.0 K97 3.0 K98 4.0 2.0 K100 3.0 K101 3.0 5.0 <RTI>K102</RTI> 3.0 K103 5.0 4.0 K104 0.0 <RTI>1.0*</RTI> K105 0.0 5.0 0.0 <RTI>K107</RTI> 1.0 0.0 K108 2.0 5.0 1.0 K109 3.0 <RTI>K110</RTI> 3.0 <RTI>-K111</RTI> 7.0 K112 7.0 *Negative sign means assay showed 1.0% increase in potency The above-described solutions, with and without nitrogen cover, thus have shown 7% or less loss in potency after storage at 560C and 450C with the majority showing a loss of potency of 3% or less.

The pH of the solutions remained between 2.4 and 2.7.

Physically, no change is apparent at <RTI>560C.</RTI> or <RTI>450C.</RTI> after one month. Solutions remain clear and colorless. Initial Klett readings averaged <RTI>8-12;</RTI> one-month <RTI>560C.</RTI> and <RTI>450C.</RTI> readings averaged 6 <RTI>1 5.</RTI> No changes or differences are noted between samples with or without N2t.

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 <RTI>560C.</RTI>

at one month with and without N2t exposure. Stability was not affected at one month <RTI>560C.</RTI> as samples showed only <RTI>12%</RTI> loss of potency.

At two weeks <RTI>4"C.</RTI> samples were observed for crystallization of cis-diamminedichloroplatinum <RTI>(II).</RTI> 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 40C.

Crystallization is noted throughout all lots of 50 mg/vial products but again not in all samples. One sample from <RTI>40C.</RTI> with crystals could not be <RTI>redissoived</RTI> by warming the solution to <RTI>370C.</RTI> 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.

Cis-platinum <RTI>(II)</RTI> diamminedichloride (NSC <RTI>11 9875)</RTI> is an inorganic compound first noted to prevent replication of E. coli and subsequently found to possess antitumour 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 tumour systems including <RTI>L121 0,</RTI> Sarcoma 180, Walker 256 carcinosarcoma, DMBA induced mammary tumours and ascitic B1 6 melanosarcoma. The compound is especially interesting in that it exhibits synergism with a large number of currently used chemotherapeutic agents. Large animal toxicology studies showed renal tubular necrosis, <RTI>enterocolitis,</RTI> bone marrow hypoplasia and lymphoid atropy. 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 <RTI>60-100</RTI> mg/m2 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 tumours, lymphomas, sarcomas, breast and head and neck carcinomas.

A dosage of 60 mgm/m2 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 purposes 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 sterile, pharmaceutically acceptable aqueous diluent such as glucose or saline. Administration is either by direct intraveneous injection or by intravenous infusion.

High Performance Liquid Chromatography (HPLC) Assay for Cis-Diamminedichloroplatinum.

Method Cis-diamminedichloroplatinum is chromatographed on a Water's <RTI>y-Bondpak-NH2</RTI> column using a <RTI>loop injection technique. Detection is achieved by monitoring the U.V. absorbance at 313- nm and</RTI> quantitation is accomplished by peak height measurement with external calibration. This method is applicable to bulk powders and solid dose formulations containing NaCI and mannitol. Specificity has been demonstrated by separation of the cis and trans isomers and apparentdegradations (moisture, acid, base, heat and accelerated liyht).

HPLC Conditions Column-Water's Micro-Bondpak-NH2 (300 mmx4.0 mm ID) 027386 or equivalent.

Mobile Phase-Ethyl acetate/methanol/dimethylformamide/distilled water (25/16/5/5). Use Burdick and Jackson distilled in glass spectroquality reagents. Degas the water prior to use and the solution after mixing.

<RTI>Detector-Water's</RTI> Model 440 Absorbence Detector.

<RTI>Wavelength-313</RTI> nm (U.V.) <RTI>Sensitivity-0.i</RTI> AUFS.

<RTI>Injector--A</RTI> 20 microliter loop injector.

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

Injection <RTI>Volume-20</RTI> microliter.

Solvent Delivery <RTI>System-Water's</RTI> Model 6000A pump.

<RTI> FIow-2.0 ml./minute.</RTI>

<RTI>Retention-2.8</RTI> minutes (approx).

<RTI>Recorder-Heath</RTI> Model SR-255B.

Chart <RTI>Speed-0.5</RTI> inch/min.

<RTI>Range-lO</RTI> 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 <RTI>Purity=99.8%</RTI> <RTI>Solvents-Burdick</RTI> and Jackson (distilled in glass) spectroquality.

<RTI>Standard-Weight</RTI> accurately 25 mg. of cis-diamminedichloro-platinum (DDP) into a 25 ml.

volumetric flask. Dissolve in and dilute to volume with dimethylformamide.

<RTI>Lyophilized.lnjection-Reconstitute</RTI> vial contents with 10.0 ml. of <RTI>dimethylformamide</RTI> 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 equivalent) discarding the first ml.

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

Calculations Mg. Standard/ml Standard Factor (SF)= Average Peak Height Standard SFxAverage Peak Height <RTI>Samples 25</RTI> Mg. DDP/Gram= Wt. Sample (Gm) Mg. DDP/Vial=SFxAverage Peak Height Sample x 10 For assay, 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 NaCI and mannitol after making the changes indicated below.

HPLC Conditions Mobile <RTI>Phase-Acetonitrile/distilled</RTI> water (75/25, v/v). Use Burdick and Jackson distilled in glass spectroquality reagents. Degas the water prior to use and the solution after mixing.

<RTI>lnjector--A100</RTI> microliter loop injector.

Injection <RTI>Volume--100</RTI> microliter.

<RTI>Retention-2.0</RTI> minutes (approx).

HPLC Analysis <RTI>Standard-Weight</RTI> accurately 25 mg of cis-diamminedichloro-platinum <RTI>(DDP), 225</RTI> mg. sodium chloride and 250 mg. mannitol into a <RTI>25-ml.</RTI> volumetric flask. Dissolve in and dilute to volume with distilled water. Pipet 5.0 ml. of the resulting solution into a <RTI>25-ml.</RTI> volumetric flask, add 2.0 ml. of distilled water and take to volume with acetonitrile.

Sample (1 <RTI>mg/mi)--Pipet</RTI> 5.0 ml. of the sample into a <RTI>25-ml.</RTI> volumetric flask add 2.0 ml. of distilled water and take to volume with aceonitrile.

Calculations Mg. Standard/ml.

Standard Factor <RTI>(SF)</RTI> Average Peak Height Standard Mg. DDP/ml.=SFxAverage Peak Height Samplex25 This invention is capable of industrial application.

Claims (15)

1. Claims
2. 1. A stable, sterile aqueous solution of cisplatin in unit dosage form suitable for administration to man, which solution has a concentration of cisplatin in the range of from 0.1 to 1.0 mgm./ml. and a pH in the range of from 2.0 to 3.0.
3. 2. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, which solution has a concentration of cisplatin in the range of from 0.1 to 1.0 mg./ml. and a pH in the range of from 2.0 to 3.0.
4. 3. A solution as claimed in claim 2 which has a pH in the range of 2.3 to 2.7.
5. 4. A solution as claimed in claim 2 or claim 3 which has a pH of about 2.5.
6. 5. A solution as claimed in any one of claims 2 to 4 which has a concentration of cisplatin of about 1.0 <RTI>mgmiml.</RTI>
7. 6. A solution as claimed in any one of claims 2 to 5 wherein the pH is caused by the presence of an appropriate amount of a nontoxic pharmaceutically acceptable acid.
8. 7. A solution as claimed in claim 6 wherein the pharmaceutically acceptable acid is hydrochloric acid.
9. 8. A solution as claimed in any one of claims 2 to 7 which additionally contains a nontoxic pharmaceutically acceptable inorganic source of chloride ions at a concentration equivalent to that produced by the presence of sodium chloride at a concentration in the range of from 1 to 20 mgm/ml.
10. 9. <RTI>A</RTI> solution as claimed in claim 8 which is free from any other added chemical.
11. 10. A solution as claimed in any one of claims 1 to 8 which additionally contains a pharmacologically accepable excipient at a concentration in the range of from 2 to 15 mgm/ml.
12. <RTI>ii:</RTI> A solution as claimed in claim 10 wherein the excipient is mannitol.
13. <RTI>1 2.</RTI> A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, which solution has a concentration of cisplatin of about 1.0 mgm/ml. and pH in the range of from 2.3 to 2.7, the pH being caused by the presence of an appropriate amount of hydrochloric acid; the solution containing in addition sodium chloride at a concentration of about 9 mgm/ml and mannitol at a concentration of about 10 mgm./ml. the solution exhibiting less than 10% loss of potency when measured by high pressure liquid chromatography upon storage for one month at <RTI>560C.</RTI>
14. 13. A solution as claimed in claim 1 or claim 2 substantially as hereinbefore described.
15. 14. A solution as claimed in claim 2 substantially as hereinbefore described with reference to the

    Example.