CA1119954A - Aqueous solution of cisplatin - Google Patents

Abstract

PHARMACEUTICAL FORMULATIONS

ABSTRACT
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 is provided which has a concentration of cisplatin between about 0.1 and about 1.0 mgm./ml. and a pH in the range of 2,0 to 3.0 or preferably about 2.5. It can also contain sodium chloride and mannito1.

Description

~9~354 BACKGROUND OF TH~ 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 ~irst noted to have an antibiotic e~fect by Rosenberg and his colleagues in 1965 and have since been ~ound to be potent antitumor agents in animals.l'2 Structurally they represent a co~plex formed by a central atom o~ platinum and surrounded by various arrangements o~ chlorine atoms or ammonia groups in elther a cis or trans planar relationship. Two of the more com-monly studied platinum compounds are diagrammed belGw:
Cl ~ Cl ~NH3 Cl NH3 Cl Cis-Platinum (II) Cis-Platinum (IV) Diamminedichloride Di~mminetetrachloride As can be seen, the platinum compound, cis-platinum (II) diamminedichloride, selected for clinical trials by the Natlonal Cancer Institute has the chloride and amino groups only in the horizontal plane. The cis form o~ the diamminedichloride complex has been synthesized accord-ing to the following reaction:

' , NH4Cl K2[PtC14] ' 2N ~ ~cis-[Pt(N ~ )2C12] + 2KCl 1. Rosenberg~ B., VanC~mp, L. and Krigas, T., Inhibition of cell division in Escherichia coli by elec-trolysis products from a platinum electrodeG Nature (London) 205: 698_699, 1965.
2. Rosenberg, B., VanCamp~ L.,Trosko, J.E. and Mansour, V.H., Platinum compounds: A new class of potent antltumor agents. Nature (London) 222: 385-386, 1969.

3~ Kauf~man, G.B. in J. Kleinberg (Ed.), Inorganic Synthesis, McGraw-Hill Book Co., Inc., New York, 196~.
The National Cancer Institute has been conduct-ing clinical tr}als in cancer chemotherapy of the cnemical for which the United States Adopted Name (USAN) 1s now cisplatin. Certain information regarding its chemistry and its pharmaceutical formulation are given in the publication titled Cllnical Brochure, CIS-PLATINUM (II) DI~MMINEDICHLORIDE
(NSC-119875), H~ Handelman et al., Investiga-tional Drug Branch, Cancer Iherapy Evaluation Program, Division of Cancer Treat-ment~ Natlonal Cancer Institute (Revised, August, 1974), on pages 1~5 and 31-32. The last two pages of Handelman et al.
concern the ~ormulation of cisplatln supplied gratis by the N C I to clinicians for their clinical evaluation in the chemotherapy of cancer and read as follows:

s~

PHARMACEUTICAL DATA SHEET
NSC-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-119875; 90 mg. of Sodium Chloride;
100 mg. of Mannitol and H~drochloric acid for pH adjustment.
Solution Preparation 10 mg./vial : When reconstltuted with 10 ml. of Sterile Water ~or Injection, USP3 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 of 3.5-4-5-Stora~e : 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 recom-mendations may be adjusted pending com-pletion 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 a-t room tem-perature (22 C.) when exposed to normal room illuminatlon and not more than eight hours at room temperature (22 C ) when protected from light. Reconstituted so-s~

lutions may form a precipitate after one hour at re~rigeration temperature (4 8 C ) Caution : me 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 infor-mation on its clinical use is given, for example, in Cancer Chemotherapy Reports, Part 1, Vol. 57, No. 4, pages 465-471 (197~)-Cancer 30: 1451-1456 (1972) in reference to cisplatin states that "The drug material used in this study was manu~actured 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) o~ mannitol and 9 mg. (sic) of NaCl. The resulting yellowish white powder dissolved readily ln 8-10 ml. o~
sterile water and was injected immediately after preparation."
Annals of Internal Med. 86: 803-812 (1977) re-fers to cisplatin as "DDP" and states that " m e drug DDP is presently available as an investigational drug only to qualified specialists through the Investigational Drug 3~i~

Branch of the Cancer m erapy Evaluation Programg National Cancer Institute. The product is supplied as a white lyophylized powder in vials containing 10 mg. of DDP, 90 mg. o~ sodium chloride, 100 mg. of mannitol (U.S.P.), and hydrochloric acid ~or pH adjustment. When re-constituted with 10 ml. o~ sterile water for in-aection (U.S.P.), each ml. of the resulting solu-tion will contain 1 mg. o~ DDP, 10 mg. of manni-tol, and 9 mg. of NaCl. The pH of the resulting solution will be 3.4 to 4.5. At 22 C., the recon-stltuted solution is stable for at least 8 h."
Thus the formulations described above are sta-ted to require re~rigeration (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 te~perature (22 C.) following reconsti-tution. The verg act o~ reconstitution can cause problems if i~properly performed and is better avoided. In addition, be-cause 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 obâect o~ the present invention to pro-vide a stable~ therapeutically acceptable, intravenously in~ectable dosage form o~ cisplatin which would not require lyophilization and reconstitution, which would not require re-~rigeration during shipment and storage, and which could be supplied in dosages o~ 50 mg. or larger.
These obaectives were achieved by the present in-vention as described in detail below.

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SUMMARY OF THE INVENTICN
There is provided by the present invention a stable, sterile aqueous solution of cisplatin in a sealed container such as an ampul or ~ial in unit dosage ~orm suitable ~or intra-venous administration to man, said solutlon having a con- -centration of cisplatin between about 0.1 and about 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 accept-able acid, said acid pre~erably being a strong mineral acid and most preferably being hydrochloric acid; said solution optionally containing in addition a nontoxic, pharmaceutically acceptable, inorganic source o~ chloride ions in a concentration equi~alent to that produced by the presence of sodium chloride in a concentration in -the range of 1 to 20 mgm./m-. and most pre~erably about 9 mgm./ml.;
said solution optionally also being either ~ree of any other added chemicals or also containing a customary, harm-less, physiologically acceptable excipient, which is prefer-ably mannitol, in a concentratlon in the range o~ 2 to 150 mgm./ml. and preferably a concentration o~ about 10 mgm./ml., said solution exhibiting less than 10~ (and usually less than 4~) loss of potency as measured by high per~ormance liquid chromatography (HPIC) upon storage ~or one month at 56 C. Preservati~es can be added i~ desired.
There is further provided by the present inventlon a method ~or inhibiting the growth o~ a malignant tumor susceptible to cisplatin which comprises intravenously ad-ministering to a human af~licted with such a malignant tumor an amount ef~ective to inhibit the growth of said tumor o~

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a stable, sterile aqueous solution of cisplatin in a sealed container such as an ampul or vial in unit dosage form suitable for intravenous admlnistration to man~ said solution havin~ a concentration of cisplatin between about 0.1 and about 1.0 mgm./ml. and preferably of about 1.0 mgm./ml. and a pE in the range of 2.0 to ~.O and preferably in the range of 2.3 to 2.7 2nd most preferably a pE o~ about 2.5, said pH
being caused by the presence of the appropriate amount of a nontoxlc~ pharmaceutically and therapeutically accept-able acid~ ~id acid pre~erably being a ~trong mineral acid and most preferably being hydrochloric acid; said solution optionally containing in addition a nontoxic, pharmaceutically ~cceptable, 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 option~lly also being either free of any other added chemicals or also contalning a customa:ry, harm-less, physiologically acceptable excipient~ which is prefer-ably 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 th~n 10~ (and usually less than 4%) loss of potency as measured by high perform~lce liquid chromatography (HPLC) upon storage for one month at 56 C.

_8--~995~

DESCRIPTION OF THE PREFERRED EMBODIMENTS

~ For~ula : Per Ml. Per Liter ~ Cis-diamminedichloro- A A
: platinum (II) . . ~ . . . 0.0010 g. l.OOO g.
; Sodium Chloride, U.S.P... . 0.0090 g. 9~000 g.
Mannitol, U.S.P. ~ . . . . 0.0100 g. lO.OOO g.

Hydrochloric Acid~
Conc. U.S.P.. . . . . . ~ q.s. to pH q.s. to pH
2.0-3.0 2 0-3 0B
Water ~or Injection, U.S.P.. . . . . . . . . . q.s. l.O Ml. q.s. lOOO.O Ml.

NOTES:
A. lOO~ basis, adjust weight based on reported purity to provlde l.O g. lOO~ Cis-diammlnedichloroplatinum (II) per liter B. Approximately 0.035 0.050 ml. of 37~ hydrochloric acid required per gram of sodium chloride to obtaln a p~ of approximately 2.5.
PRECAUTlONS
Cis-diamminedichloroplatinum (II) is a toxic sub-stance and is listed on page 942 in the 1976 edition of the "Registr~ of Toxlc E~ects o-f Chemical Substances~" The OSHA Standard of Time Weighted A~erage (TWA) ls 2 mcg./m3.

_g _ Consult the above, listed references, pertinent local pub-lications 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-dia~minedichloroplatinum (II) weighing, the working surface of the batching vessel, the filling, stoppering9 and sealing must be provided with such protec-tion.
All personnel invol~ed 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 contaml-nated 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 contami-nated due to spills, etc. should be stored in a closed meta container until burned.
THE IMPORTANCE OF PROTECTING PERSONNEL DURING T~E
HANDLlNG, MANUFACTURING AND ASSAYING OF THIS PRODUCT IN

_ _ _ . _ _ _ _ _ _ ACCORDANCE WITH THE ABOVE CANNOT BE O-~EREMPHASIZED.
_ The prime bulk cis-dia~minedichloroplatinum (II) must be protected from light. The processing and filling of vials described herein was conducted under diffused natural/fluorescent light.

Batching ~essel Glass-lined, agitated, pressure ~essel A ~16 SS
agitator is permissible. Working volume must be consistent with batch size. A dipstick and calibration cur~e of tank J~

~ 5 ~

volume is requlred for determining volume.

Milli~ore Mem~rane Filter Holders 316 SS. Fllter area with necessary pre-filters and 0.22 micron final sterilizing f~lter.

Transf * *
Teflon or Tygon.
All stainless s-teel contacts should meet 316 SS
requirements. All other equipment should be appropriate to produce a sterlle, non-pyrogenic, particulate-free product.

Manufacturing Instructions A. m ese instructions are written for an eight-hour batchin~ to filling operation. Storage o~ this product before filling has not been in~estigated 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 Injec-tion, U.S.P. in a suitable vessel.
2. With agita-tion add the sodium chloride. Agitate ten minutes or until dissolved.
~ . With good agitation carefully ad~ust the pH of the sodium chloride solution to 2.0-3.0 (pre~erably 2.5) with concentrated hydrochloric acid. See estimated amount under note "B" on formula sheet. Agitate ~or ten minutes a~ter last addition. Recheck pH~

4. With good agitation add the mannitol and agita-te ten mlnwtes or untll dissolved.

5~ With good agitation and tak~ng special precautions against dusting and exposure, add the cis-diamminedichloro-*Trade Marks platinum (II). Rinse its container sufficiently wi-th an appropriate amount of water for injection and add to the batch.

6. Agitate until completely dissolved. Approximately 60-go minutes will be required for co~plete dissolution.
Monitor pH and add additional concentrated hydrochloric acid if required to maintain at 2.0-3.0 (optim~n 2.5).

7. Carefully adjust volume to theoretical batch ~olume wlth 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 ~mber, 15 ml. vial, with a 10-ml. fill.
Stopper with red, 20mm Teflon-~aced stoppers and seal with aluminum seals. Numbered as K93, 100 and 107 with nitrogen overlay and K94, 101 and 108 without nitrogen overlay.
2~ ~ ial 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 M~./Vial 5terile, 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 K9~, 105 and 112 without nitrogen overlay.

I~ese formulations were prepared in ~ive groups (with the final pH given ln parentheses) as follows:
K9~-96 (pH 2~4) K97-98 (pH 2.5) K100-103 (pH 2.3) K104-105 (p~ 2.4) K107~110 (pH 2.~) K111-112 (p~ 2.4) Original potencies by HPLC assay were in the range o~ 0.99 to 1.00 mgm./ml.
m e percentage loss in potency after storage ~or one or two months at the indicated -temperature was ~ound by ; HPIC assay to be as follows:
: 56 C. - 45o C
One Two One Month Months Month K93 -~F~5~
K94 2.0 4.0 K95 o,o -1.0*
K96 1.0 4.0 0.0 K97 .3 K98 4.0 2.0 K100 3.0 K101 ~.0 5.0 K102 3.0 K103 5.0 4-K104 0,0 -I.O*
K105 0.0 5~
K107 1.0 0.0 K108 2.0 5.0 1.0 K109 3.0 KllO 3.0 Klll 7.0 K112 7.0 *Negative sign means assay showed 1.0~ increase in potenc~.
,.

~995~

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 show-ing a loss of potency of ~ or less. The pH of the solu-tions 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 No changes or differences are noted between samples with or without N ~.

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 N2 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-di~mminedichloroplatinum (II). No crystals were obser~ed until one month and it was only noted randomly, not in every sample. Only one lot o~ the 10 mg~/~ial and 25 mg./vial products show some crystals forming rand~mly at 4 ~. Crystallization is noted through-out 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 solu-tion to 37 C. with agita-tion. Only partial success was obtained. It appears these products cannot be stored under refrigerated cond.itions as even redissolving of crystallized products was difficult.

Cis-platinum (II) diamminedichloride (NSC 11987~) is an inorganic compound ~irst noted to prevent replication of E. coli and subsequently ~ound to possess antitumor _.
activity. The drug exerts its effect of interfering with DNA synthesis by causlng cross-linking of complementary strands o~ DNA. It has activity in a variety of tumor sys-tems including L1210, Sarcoma 180, Walker 256 carcinosarcoma~
DMBA induced mammary tumors and ascitic B16 melanosarcoma.
The compound is especially interesting in that i-t 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 fol-lowîng toxicities: myelos~ppression, renal insufficiency, high frequency ototo~icity and GI intolerance. Currently u~ed dosages with mild to moderately acceptable toxicity are in the range o~ 60-100 mg/m2 IV as à 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/m2 is roughly equal to 1.5 mgm/kg which in turn is roughly equal to 105 mgm/patient weighing 70 kg.
The solutlons 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 volumlnous medical literature on this sub~ect. As stated therein, frequent use is made of concurrent therapy with other chemotherapeutic agents for best results. ~hen desired~ the solu-tions of -the prese~t invention may be added immediately before use to a 95~

sterile, pharmaceutically acceptable aqueous diluent such as glucose or saline. Administration is either by direct intravenous injection or by intravenous infusion.

:

- ' ' 35~L

cis-Diamminedichloro~latinum.

Method Cis-diammined~chloroplatin~ is chromatographed on a Water's ~-Bondapak-NH2 column using a loop inaection technique. Detection is achieved by monitoring the U.V.
absorbance at 313 r~ and quantitation is acco~plished by peak height measurement with external calibration, This method is applicable to bulk powders and solid dose for-mulations containing NaCl and mannitol. Specificity has been demonstrated by separation o~ the cis and trans isomers, and apparent degradations (moisture~ acid, base, heat and accelerated light).
NH7 Cl Cl NH

/ \ / 3 Pt Pt /\' /\
NH3 Cl 3 Cl Cis-(NH3)2 C12 Pt II ( 3)2 2 r,~ rD-Column - Water's Micro Bondapak-NH2 (300 MM X 4.0 MM ID) 027386 or equivalent.
obile Phase - Ethyl acetate/methanol/dimethyl~ormamide/
distilled water (25/16/5/5). Use Burdick and Jackson distilled in glass spectro-quality reagents. ~egas the wa-ter prior to use and the solution after mixing.
etector - Water's Model 440 Absorbance Detec~orO
avelength - 313 ~m (U.V.).

~ 5 Sensitivity - O.1 AUFS.
In~ector - A 20 microliter loop injector.
The Loop Injector - A Valco 7000 psi stainless steel valve (CV -6-UHPa-C20).
Injection Volume - 20 mlcroliter.
Solvent Delivery System - Water's Model 6000A pump.
Flow 2.0 ml~/minute, Retention - 2.8 minutes (appro~.).
Recorder Heath Model SR-2~B.
Chart Speed - O.5 inch~mln.
Range - 10 milli~olt.

Using the conditions above, obtain chromatograms o~ the standard and sample preparations in duplicate.
Re~erence Standard of cis diamminedichloro-platinum (DDP):

Lot No, = 78F7 (Matthey Bishop Lot No. AM7702) Asslgned Purity = 99.8~
501vents - Burdick and Jackson (distilled in glass) spec-troquality.
Standard - Weigh accurately 25 mg. of cis-diamminedichloro~
platinum (DDP) into a 25-ml. ~olumetric ~lask.
Dissolve in and dilute to volume with dimethyl-~ormamide.
L~ophll~zed In~ection - Reconstitute vial contents with 10.0 ml. o~ dimethylformamide ~ld mechanically shake ~or 5 minutes (alternately a sonic bath may b~ used for 2 minutes). Filter 5.0 ml. of the sample solution (Millipore Filter Kit or *Trade Mark ~1 95~

equivalent) discarding the first ml.
ontent Uniformity - Prepare 10 vials as described above and assay, Calculations __ STANDARD FACTOR (SF) = AV~RAGE PEAK HEIGHT ST~NDARD

MG DDP/GRAM = SF X AVERAGE PEAK ~EIGHT SAMPLE X 25 MG. DDP/VI~L = SF X AVERAGE PEAK HEIGHT SAMPLE X 10 For assay, average results obtained for 10 vials from content uniformity test.

Me The method of assay for cisplatin described above is applied to aqueous solutions (dose formulations) con taining NaC1 and mannitol after making the changes indicated below.

~PLC Conditions _ _ _ obile Pha~e - Acetonitrile/distilled water (75/25, v/v).

Use Burdick and Jackson distilled in gla~s 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.).

H ~
Sta~dard - Weigh accurately 25 mg. of cis-diamminedichloro-platinum (DDP)~ 225 mg. sodium chloride and 250 mg.

mannitol into a 25-ml. volumetric flask. Dissolve in and dilute to vol~me with distilled water, Pipet 5 . O ml, of the resulting solution into a 25,-ml. volumetric flask, add 2.0 ml, of dis-tilled water and take to volume with ac etonitrile .
Sample (1 mg./ml.) Pipet 5.0 ml. of the sample into a 25 ml. volumetric flaskg add 2.0 ml. of d~stilled water and take to ~olume with acetonitrile.

Calculations ____ , STANDARD FACTOR (SF) =
MG, DDP/ML. = SF X AVERAGE PEAK HEIGHT SAMPIE X 25 This invention is capable of industrial ~pplication.

c.O~

Claims (12)

WE CLAIM:

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 about 0.1 and about 1.0 mgm./ml. and a pH in the range of 2.0 to 3Ø

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 about 0.1 and about 1.0 mgm./ml. and a pH in the range of 2.0 to 3Ø

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 about 0.1 and about 1.0 mgm./ml. and a pH in the range of 2.3 to 2.7.

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 about 0.1 and about 1.0 mgm./ml. and a pH of about 2.5.

5. 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 2.0 to 3Ø

6. A stable, sterile aqueous solution according to claim 4 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.

7. A stable, sterile aqueous solution according to claim 4 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.

8. 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 nontoxic, therapeutically acceptable acid; said solution containing in addition a nontoxic, pharmaceutically accept-able, 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.

9. 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./m1. 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 pro-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 pro-duced 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.

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 l to 20 mgm./ml.; said solution also con-taining a customary, harmless, physiologically acceptable excipient in a con-centration 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 hydrochloric 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 as measured by high performance liquid chromatography upon storage for one month at 56° C.