CA1162479A - Pharmaceutical formulations containing cisplatin - Google Patents
Pharmaceutical formulations containing cisplatinInfo
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- CA1162479A CA1162479A CA000372499A CA372499A CA1162479A CA 1162479 A CA1162479 A CA 1162479A CA 000372499 A CA000372499 A CA 000372499A CA 372499 A CA372499 A CA 372499A CA 1162479 A CA1162479 A CA 1162479A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
ABSTRACT OF THE DISCLOSURE
Stable concentrated solutions of cisplatin in a solvent comprising polyethylene glycol or methoxy polyethylene glycol, or a mixture thereof, plus water and a nontoxic pharmaceutically acceptable source of chloride ion.
Stable concentrated solutions of cisplatin in a solvent comprising polyethylene glycol or methoxy polyethylene glycol, or a mixture thereof, plus water and a nontoxic pharmaceutically acceptable source of chloride ion.
Description
Background of the Invention 1. Field of the Invention _ This invention relates to stable, concentrated solutions of cisplatin in aqueous polyethylene glycol, methoxy polye~hylene glycol, or mixtures thereof, con-taining a source of chloride ion~
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 lRosenberg, B. et al., Nature (London), 205, 698-69g (1965)] and subsequently found by Rosenberg and his colleagues ~o be potent antitumor agents in animals [Rosenberg, B. et al , Nature (London), 222, 385-386 (1969)].
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:
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:
3--Cl NH3 Cl ¦ NH3 Cl NH3 Cl I NH3 Cl Cis-Platinum (II) Cis-Platinum ~IV) Diamminedichloride Diamminetetrachloride As can be seen, the compound cis-platinum tII~ diammine~-dichloride has all its chloro and amino gxoups in a single plane. This compound, now known by the United States Adopted Name (USAN) cisplatin, has been synthesized acGord-ing to the following reaction:
NH4Cl K2[PtC14~ + 2NH3 ~- ~ cis-~pt(NH332cl2] ~ 2KCl [see Kauffman, G. B~ et al., in Inor~anic Svnthesist J.
_ _ .. .
Kleinberg (Ed.), pages 239-245, McGraw-Hill Book Co., Inc., New York, 1963].
Breusova-Baidala, Y. G. et al., in Akademia Nauk SSSR, No. 6, pp. 1239-1242 (June 1974), discuss the slow isomerization of cis-platinum (II) diamminedichloride in aqueous solution to the trans form.
Reishus, J. W. and Martin, D. S~, in Journal of the American Chemical Society, 83, 2457-2462 (1961), describe the acid hydrolysis of cisplatin at 25C and 35C. These studies were conductPd in aqueous solutions at concentrations of 1.5 x 10 M, 2.5 x 10 M and 5.0 x 10 3 M, which correspond to 0.45~ 0.7S and 1.5 mg/ml, respectively. The authors state that there was some ~.6~
ambiguity in locating the origin (i.e "zero point") for the hydrolysis curves because the samples required from lO to 30 minutes to dissolve completely even at those low concentrations.
Rozencweig, M. et al., in Annals of Internal __ Medicine, 86, 803-812 (1977), review the results of various preclinical and clinical investigations of the use of cisplatin in experimental tumors in animals as well as various type~ of human tumors. They point out that the investigational drug, available to qualified investigators through the Investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute, was supplied as a white lyophilized powder in vials containing 10 mg of cisplatin, 90 mg of sodium chloride, lO0 mg of mannitol (U.S~P.) and hydrochloric acid for p~ adjustment. When reconstituted with 10 ml of sterile water for injection (U~S.P.), each ml of the resulting solution would contain 1 mg of cisplatin, lO mg of mannitol and 9 mg of NaCl.
Talley, R. W. et al., in Cancer Chemotherapy Reports, 57, 465-471 (1973), describe the results of their Phase I clinical stuay of the use of cisplatin in the treatment of 65 human patients with a wide variety of neoplasms. As in the preceding publication, the drug was supplied to them by the National Cancer Institute in vials containing lO mg of cisplatin, 90 mg sodium chloride and lO0 mg of mannitol, for reconstitution with lO ml of sterile water.
Rossof, A. H. et al , in Cancer, 30, 1451-1456 (1972), describe the results o their use of cisplatin in the trea~ment of 31 human patients with a variety of tumor 7~
types. They state that the drug supplied by the Naticnal Cancer Institute was manu~actured by Ben Venue Laboratories, Inc. and contained, per vial, 10 mg of cisplatin, 10 mg ~sic) of mannitol and 9 mg (sic) of NaCl, and that the yellowish-white powder dissolved readily in 8-10 ml of sterile water.
Certain information concerning the chemistry and pharmaceutical formula~ion of cisplatin are given on pages 1-5 and 31-32 of the publication entitled "CLINICAL BROCHURE, CIS-PLATINUN ~II) DIAMMINEDICHLORIDE (NSC~119~75) ~
Haldelsman et al., Investigational Drug Branch9 Cancer Chemotherapy Evaluation Program9 Division of Cancer Traatment, National Cancer Institute (Revised Au~ust 1974).
Pages 31 and 32 thereof ~oncern 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:
PHARMACEUTICAL DATA S~EET
NSC-119875 Cis-Diamminedic~loroplatinum (II) Dosa~e Formulation 10 mg./vial : The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial con-tains 10 mg. of NSC-119875; 90 mg.
of Sodium Chloride; 100 mg. o Mannitol and Hydrochloric acid for pH adjustment, 7~3 --6~
501ution Preparation 10 mg./vial : When reconstituted wikh 10 ml. of Sterile Water for Injection, USP;
each ml. of the resulting solution will contain 1 mg. of ~SC-119875, 10 mg. of Mannitol, and 9 mg. of Sodium Chloride ha~ing a pH range o 3~5-4-5D
Storage : The dry, ~ vials should be stored at refri~eration temperatures (4-8~C.).
Stability : Intact vials have a provisional stability of one year when stored at refrigeration temperature (4-8C.). Stability recommendations may be adjusted pending completion of a two-year shelf~life studyO
Reconstitution as recommended results in a pale, yellow solution which is stable for not more than one hour at room temperature t22C.) when exposed to normal room illumina-tion and not more than eight hours at room temperature (22C.) when protected from light. Reconstituted solutions may form a precipitate after one hour a~ refrigeration temperature (4-8C.).
Caution : The lyophilized dosage formulations contain no preser~atives and therefore it is advised to discard solutions eight hours after reconstitution.
August, 1974 ClLnical Drug Distribution Section Drug ~evelopment Branch ~ 7 ~
Published Unitea Kingdom Patent Application No.
2021946~ describes stab7e aqueous solutions o cisplatin having a concentration of cisplatin between about 0.1 and lo O mg/ml and a pH in the range of 2.0 to 3.0, The solution~ may also contain a nontoxic, pharmaceutically acceptable, inorganic sourc2 of chloride ions, such as sodium chloride, and an excipient such as mannitol.
_omplete Disclosure This invention relates to stable, concen~rated, solutions of cisplatin ha~ing concentration~ o fr~m about 2.5 to about ~5 mg/ml. More particularly, the invention relates to stable, concentrated solutions of ci~platin in a solvent medium comprising from about 30% to about 95~ polyethylene glycol having an average molecular weight of from about lS0 to about 9000 or a methoxy polyethylene glycol haYing an average molecular weight o~ fro~ about 300 to about 6000, or a mixture thereof, and from about 5~ to about 70% water, said solutions also containing at least one nontoxic, pharmaceutically acceptable source of chloride ion in an amount whi~h is at least about equivalent to the amount of cisplatin pxesent in the solution, and said solutions having a cisplatin concentration of from about 2.5 to about 25 mg/mlO
Stable aqueous solutions of cisplat~n have been described in published United Kingdom Patent Application No. 2021946A. Although stable solutions containing cisplatin concentrations up to about 1 mg/ml may be obtained in such aqueous media at room temperature, crystallization of the cisplatin may occur in the cold at cisplatin concen~rations substantially above about 0.5 mgtml. Redissolving such crystallized cisplatin is not readily accomplished by shaking a~ room temperature, although a solution may be re-obtained by heating to about 37C. Since shipping and storage temperatures after sale cannot be controlled, and crystallization of oisplatin in the vials would create an undesirable problem for the administering physician, the maximum practical concentration of cisplatin in such aqueous media is a~out 0.5 mg/ml.
The cisplatin solutions of the present invention may contain up to about 25 mg of cisplatin per mlf although the preferred maximum is about 15 mg/ml. Solutions of the present invention containing 15 mg of cisplatin per ml have been maintained at a temperature of 4C for 12 months without crystallization of cisplatin. Such solutions have also been frozen at -60C and then thawed at room temperature with no e~idence of cisplatin pre-cipitation~ Thus, practical solutions prepared according to the present invention may have cisplatin concentrations at least 30 times higher than practical aqueous solu~ions prepared according to the prior art.
It will be appreciated that the concentrated solutions of cisplatin provided by the present invention will require lower shipping, storage and other cos~s per unit dose when compared to the known aqueous solutions~
Although the known lyophilized solid form also has lower shipping and storage costs, that saving is more than offset by the time and expenses invol~ed in lyophiliæation.
~ 7 ~
_g_ In a preerred embodiment of the present ~nvention, the solvent medium comprises from about 80%
to about 95% (and more preferably from about 85~ to about 90~) polyethylene glycol having an average molecular weight of from about 250 to about 1600 (and more prefer-ably from about 250 to about 650) and from about 5% to about 20~ (and more preferably from about 10~ to about 15%) water. In a most preferred embodLment the sol~ent medium comprises about 90% polyethylene glycol having an average molecular weight of from about 350 to about 450 and about 10% waterO
Preferably the solution contains from about 5 to about 20 mg of cisplatin per ml and most preferably from about 10 to about lS mg/ml. The nontoxic, pharma-ceutically acceptable source of chloride ion preferably is present in a concentration of at least about two equivalents per equivalent of cisplatin in the solution.
Concentrations as high as 50 equivalents or more of chloride ion per equivalent of cisplatin may be utilized, depending on the cisplatin concentration, the percentage of water present and the particular source of chloride ion, but such high concentrations of chloride ion usually are neither necessary nor desirable. It will be appreciated by those skilled in the art that, with a high cisplatin concentration and a low water content, it would not be possible to dissolve a suficient amount of a chloride ion source such as sodium chloride to provide 50 equiva~ents of chloride ion per equivalen~ of cisplatin~
Further, a saturated, or nearly saturated solution of an inorganic chloride salt would be undesirable because of the possibility of crystallizatiDn from the solution in the cold. In the situation set forth above, 50 equi~alents - ~ . ~
, of chloride ion per equivalent of cisplatin could be obtained by the use of hydr~chloric acid as the ~ource of chloride ion, but this might give a solution having an undesirably high acidity, ~.e. low pH~ We haYe found that excessively aciaic solutions are somewhat le~s stable than more moderately acidic solution~. The p~
range of the solutions preferably is from about 1.5 to about 4.5. We prefer to u~ilize from about 2 to about 10 equivalents of chloride ion per squivalent of cisplatLn~
and most preferably from abou~ 3 to about 7 equival~nts o~ chloride ion per e~uivalent of cisplatin.
The chloride ion may be provided by the addition of hydrochloric acîd, a nontoxic pharmaceutically metallic halide such as sodium chloride, potassium chloridet calcium chloride or magnesium chloride, or the hydxochloric acid addition salt of a nontoxic pharma-ceutically acceptable ~er~iary amine suGh as trie~hylamine, or by mixtures theraof~ The preferred source of chloride ~on is hydrochloric acid, sodium Ghloride or a mixture thereofO
Polyethylene glycols and me~hoxy polyethylene glycols have the general formulae H (OC~I2CEI;! ) ",OH and CH3 (CH2cH2 ) nC~3 respectively, and are commercially available as C~RBO~
Polyethylene Glycols and C~æX Methoxy Polyethylene GlycolsO We preer to utilize the SE~ Grades of CAR~OW~X Polyethylene Glycols, which are produced to meet U.S.P~, N. F. and F.C.C. specification5 ~or ~ood and dr~ applications. Typical molecular weight ranges ~or a vari~ty of C~RBOWAX Polyethylene Glycols and CAR~OWAX
, Trademark Methoxy Polyethylene Glycols are given in Tables 1 and 2 ~able 1 ~ ~ _ .
CARBOWAX Typical Polyethylene Molecular Glycols . Weight Range _ _ ___ .
200 190 ~o 210 300 285 t~ 315 400 380 to ~20 , 600 570 to 630 1000 950 to 1050 15~0 1300 to 1600 4000 3000 to 37~0 6000 7000 to 9000 _ _ . ..
Table 2 _ ~, CARBOWAX Typical Methoxy Molecular Polyethylene Weight Glycols Range _ __ ~ . .
350 335 to 365 .
SS0 525 ~o 575 75~ 715 t~ 785 2000 . 1850 to 2150 _ __ _. . ,.
Polyethylene glycols are known to ~orm complexes with certai~ inorganic salts. Thus, the reaction of polyethylene glycols with ammonium cobalt thiocyanate ko form a blue complex is the basi~ o~ one color1metric method of determining the concentration o~ ~olyethylene glycols ~ ~6 ~ ~7 ~
in various mixtures. We believe that the unique stability of cisplatin in the solutions o~ the present invention may be due to a complex formed bet~een the cisplatin and the polyethylene glycol, but this is only theory and does not form a part of the invention. Evidence of complex formation has been noted in our TLC procedure. Using techniques described below, aqueous cisplatin produces a spot at about Rf 0.65~ However, a solution of cisplatin in 90~ Polyethylene Glycol 400 - 10% H20 (or 10% 0.5 N
HCl) gives a spot at about Rf 0.3 which streaks to about Rf 0.65. Dilution with ~ubstantial quantities of water appears to immediately break the complex, since dilution of the above PEG-H20 (or HCl) solution with five volumes of water then shows only a cisplatin spot at about R~ 0.65.
Thin Layer Chromato~raphy Apparatus and Rea~ents (a) TLC plates - EM Laboratories silica gel 60 plates, Catalog No. 57~3, or equivalent.
(b) Eluent - Acetone:l N HNO3 (9:1). Prepare fresh daily.
(c) Developer - Dissolve 5.6 gm of stannous chloride in 10 ml concentrated HC1. Add 90 ml of distilled water and 0.2 gm of KI. Mix well. Prepare fresh daily.
(d) Laboratory oven set to 100C.
Procedure (a) Dilute the sample with 5 volumes of dimethylformamide .
(DMFl ~Burdick and Jackson, distilled in glass].
(b) Spo~ ~ TLC plate with 5 rnicrolit~rs of the sample and 5 microliters of a standard solution containing cisplatin (and transplatinum and platinum B, if appropriate) at a concentration approximately th~
same as that expected in the sample being analyzed.
Develop a height of 10 cm in a TLC tank pre-equilibrated with the eluent. Spray the dried plate with freshly prepared developer solution and place it in a 100C oven fox 10 minutes. O~serve the yellow/
purple zones.
(c) Approximate Rf values:
0.65 - cisplatin 0~7~ - transplatinum O.9 - platinum Bo HPLC assays of the solutions of this invention for cisplatin content may ~e conducted according to the procedure described in our colleagues' published United Kingdom Patent Application No. ~021946A. The preferred mobile phase is ethyl acetate/methanol/dimethylformamide/
distilled water (~5/16/5/5). The standard preferably is cisplatin dissolved in dimethylformamide at a concentration of 1 mg/ml. Samples for analysis are diluted with dimethylformamide to an approximate cisplatin concentration of 1 mg/ml.
Although no particular advantage is obtained by their presence, tbe solutions of this invention may, i~
desired, contain a customary, physiologically acceptable excipient such as mannitol.
Based on stability studies to date, the pre dicted stability of the solutions of this invention (defined as a 10% loss of potency) i5 in excess of two years at room temperature.
In a preferred embodiment of this invention~
the solutions are sterile and pyrogen-free, and are packaged in sterile, pyrogen-free containers. Such ~olutions may then be diluted with, for example, Sterile Water for Injection~ U.g.P., or Sterile Normal Saline Solution, U.S.P., and administered by the intramuscular or intravenous route. Means for sterilizing these solutions are well known in the art. W8 prefer to pass the solutions through a ~teril~, pyrogen-free 0.22 micron Millipore filter, using aseptic techniques, under sterile nitrogen pressure. Millipore is a registered trademark of the Millipore Corporation for membrane filters~ The sterile iltrate is collected in sterile, pyrogen-free containers and is ultimately filled, in the desired amount, into suitable sterile, pyrogen-free vials, stoppered with sterile, pyrogen-free stoppers (preferably teflon coated) and sealed with sterile aluminum seals.
For u~e in the treatment of cancer, the concen-trated solutions are diluted to the desired concentration ~typically 1 mg ci~platin per ml) with, for example, Sterile Water for Injection, U.S~P~, 5terile Normal Saline Solution, U.S.P., or Sterile Glucose Solution and used by intramuscular or LntraVenOUs injection, or intravenous ,.
infusion as known for prior art cispla~in preparationsO
Currently used dosages with mild to moderately acceptable toxicity are in the range of 60-100 mg/M2 intravenously as a single dose or divided over 3-5 days, to be repeated at 4-week intervals. A dosage of 60 mg/M2 is roughly equal to 1.5 mg/kg which in turn is roughly equal ~o 105 mg~patient weighing 70 ky. Frequently, use is made of concurrent therapy with other chemothera-peutic agents for best results.
As used herein and in the claims, references to "equivalents" of chloride ion per "equivalent" of cisplatin means molar equivalents. Thus, for example, when utilizing the preferred range of f~om about 3 to about 7 equivalents of chloride ion per equivalent of cisplatin, one would utilize from about 3 to about 7 moles of NaCl per mole of cisplatin but from about 1. 5 to about 3 . 5 moles of CaC12 per mole of cisplatin, etc.
Platinum B is an arbitrary designation used herein for an a~id reaction product of cisplatin which is one-half of the known Magnus red complex and has been tentatively assigned the following structure:
rH4 ~ Cl C1~3 \ Pt /
H3N / \ Cl This invention is illustrated by, but i~ in no way l~mited to, the following Examples.
Example 1 Stable Concentrated Solution of Ci~platin ~lO mg/ml~ in 90% Polyethylene Glycol 400 - 10% lN HCl Cisplatin (500 mg) was slurried in a solution o~
5 ml of lN HCl and 45 ml of Polyethylene Glycol 400.
After 2.5 days of stirring at room temperature (with the container protected from light with aluminum foil) a clear yellow solution was obtained. Aliquots of the solution were placed in 17 ml amber vials, stoppered with teflon coated stoppers, sealed with aluminum caps and placed on storage stability tests at various temperatures. After two weeks' storage at 45~C, thin layer chromatography (TLC) indicated the presence of a txace of transplatinum and approximately 1~ platinum B. Aftsr two weeks' storage at 56C, TLC indicated the presence of <1% transplatinum and approximately 3% platinum B. Samples stored for two weeks at 56C were diluted with 4, 9 and 19 volumes of water to give clear solutions containing 2, 1 and 0. 5 mg/ml, respectively, of cisplatinl A slight cloudiness developed in each of the diluted samples after standing approximately 18 hours at room temperature.
~ 7 Example 2 Stable Concentrated Solution of Cis~latin (10 m~/ml3 in 90% Pol~ethylene Glycol 400 - 10~ 0.5N HCl Five ml of purified water U~S.P. and 5.0 ml of lN Hcl were mixed and 90.0 ml of Polyethylene Gly~ol 400 was added. To 50 ml of the above solution was added 500 mg of cisplatin and the mixture was protected from light with aluminum foil and stirred at room temperature for 24 hours to produce a clear solu~ion. TLC of the freshly prepared solution showed only a cisplatin zone with a possible trace of transplatinum. ~o ml aliquots o~ the solution were placed in 17 ml amber vials~ stoppered with teflon coated stoppers, sealed with aluminum caps and placed on storage stability tests at various temperatures.
One sample vial was frozen in a dry ice-acetone bath for one hour and then allowed to come to room temperature. A
clear solution was obta~ned, with no evidence o a pre-cipitate. After three months' storage at both 37C and 45C, TLC indicated the presence of 1-2% platinum B and a possible trace of transplatinum. After one month storage at 56~C, TLC indicated the presence of more than 5~ but less than 10% of platinum B and a trace of trans-platinum. Samples stored at 37C and 45C for three months and at 56C for one month were diluted with four volumes of purified water U.S~P. to give clear solutions containing 2 mg/ml of cisplatin. The diluted solutions remained clear after standing 24 hours at room temperature.
.
Stable Concentrated Solution of Cisplatin (lO m~/ml) Plus CaCl2 (20 mg/ml) in 90% Polyethylene Glycol 400 - 10% 0.5N
HCl ~ wo gms of reagen~ grade anhydrous CaCl~ wa~
dissolved in a mixture o~ 5 ml purified water U.S.P. and 5 ml lN HCl. Polyethylene Glycol 400 (89 ml) was added to bring the volume to lO0 ml, To 50 ml of this solution was added 550 mg of cisplatin, and the mixture was protected from light with aluminum foil and stirred at room temper ature for 24 hours to give a clear solution. T~C o t~e freshly prepared solution indicated only a cisplatin zone with a possible trace of transplatinum. Two ml aliquots of the solution were placed in 17 ml amber vials, stoppered with teflon coated stoppers, sealed with aluminum caps and placed on storage stability tests at various t~mperatures~
One sample vial was placed in a dry ice-acetone bath for 0.5 hour and froze to a clear gel. It was then allowed to come to room temperature and a clear solution was ob tained. After three months' storage at 37C, TLC indi-cated the presence of 1~2% platinum B and a possible trace of transplatinum. After three months' storage at 45C, TLC indicated the presence of approximately 5~ platinum B
and a possible trace of transplatinum. After Qne month storage at 56C, TLC indicated the presence of 8-10%
platinum B and a trace of transplatinum. Samples stored at 37C and 45C for three months and at 56C for one month were diluted with four volumes of purified water U.S.P. to give clear solutions containing 2 mg/ml of cisplatinO The diluted solutions remained clear after standing 24 hours at room temperature.
.. . . .
.
t~
Example 4 Stable oncentrated Solution of Cisplatin (A~roxLmatel~
22 mg/ml) Plus CaCl~ (25 mg/ml) in 90% Polyethylene Glycol -10% 0.5N ~Cl To three ml of a solution of 90~ Polyethylene Glycol 400 and 10~ 0.5N HCl was added 45 mg of cisplatin, and the mixture was stirred for about one hour at room temperature to o~tain a clear solution. An additional 30 mg of cisplatin was added (to~al of 25 mg/ml) and the mixture was stirred at about 45C for one hour and then at room temperature for 18 hours to produce a nearly complete solution. The small amount of insolubl~ material was removed by filtration. TLC of the filtrate showed only a cisplatin zone with a possible trace of trans-platinum. The remainder Gf the filtrate was placed in a 17 ml am~er vial, stoppered with a teflon coated stopper, se~led with an aluminum cap and held at 45C for three months~ After aging three months at 45C, TLC indicated the presence of 1-2~ platinum B and no transplatinumO
Dilution of the aged solution with purified wate~ U.S.P.
to a concentration of 2 mg/ml of cisplatin gave clear solutions, which remained ~lear after standing at room temperature for 24 hours.
Example S
Stable Concentrated Solution of Cis latin (12 mq/ml) Plus _ P ~
NaCl (10 m~/ml) in 9o~ Polyethylene Glycol 400 - 10~ 0.5N.
H
Sodium chloride (100 m~) was dissolved in a solution of 5 ml purified water U~S~P~ and 5 ml lN
~.3.~7~3;
HCl. To this solution was added 90 ml of Polyethylene Glycol 400 and the mixture was stirred for 15 minutes.
To 50 ml of the latter solution was added 500 mg of cisplatin, and the mixture was stirred in the ~ark at room ~emperature for 3 days to produce a clear solution.
T~C o the freshly prepared solution showed only a cisplatin spot. High performance liquid chromatography (HPLC) assay of the freshly prepared solution showed it to contain 12 mg of cisplatin per ml~ Aliquots were sealed in 17 ml amber vials as described in Example 3 and put on storage stability tests at various ~emperatures.
After storage at 37~C for three months, TLC indicated the presence of less than 1% platinum B and no trans-platinum. After storage at 56C for one month, TLC
indicated the presence of 1~2% platinum B an~ no transplatinum. Dilution of the aged samples with purified water U.S.P. to a concentration of 2 mg/ml of cisplatin gave clear solutions, whic~ remained clear after standing at room temperature for 24 hours.
HPLC assays of samples stored 3 months at 45C, 6 months at 37C and 8 months at room temperature showed potency losses of 6.6%, 6.1~ and 2. 3%, respecti~ely.
. .. . .. . . .
Example 6 Stable Concentrated Solution of Clsplatin (11.4 mg/ml Plus NaCl (10 mg/ml) n 90% Polyethylene Glycol 400 - 10% Water To a solution of 50 mg NaCl in 5 ml of purified water U.S.P. and 45 ml Polyethylene Glycol ~09 was added 500 mg of cisplatin; and the mixture was stirred in the dark at room temperature ~or 6 hours to give a elear solution. TLC of the freshly prepared solution showed . .
r7 91 ~ 2:L ~
only a cisplatin spot; HPLC assay showed it to contain 11.4 mg of cisplatin per ml. Aliquots were sealed in 17 ml amber vials as described in Example 3 and put on storage stability tests at various temperatures. After storage at 37C and 45C for 3 monthst TLC indicated the presence of 1% platinum B and no transplatinum. After storage at 56C for one month, TLC indicated the presence of 2-3% platinum B and no transplatinum~ Dilution of the aged samples with purified water U.S.P. to a concentration of 2 mg~ml of cisplatin gave clear solutions, which remained clear after standing at room temperature for 24 hours.
HPLC assays of samples stored 3 months at 45C, 6 months at 37C and 7 months at room temperature showed potency losses of 6.1%, 7.8% and 0O9%~ respectively.
. . .
ExamEIle 7 Stable Concentrated Solution of Cis~latin (lO mg/ml) in 90% Polyethylene Glycol 600 - 10% 0.5N HCl To a solution of 2.5 ml of purified water U7SoP~
2.5 ml of lN HCl and 45 ml of Polyethylene Glycol 600 was added 500 mg of cisplatin, and the mixture was stirred in the dark at room temperatuxe for S hours to obtaLn a clear solution. TLC of the freshly prepared solution showed only a cisplatin spot. Samples of the freshly prepared solution were diluted with 1, 2, 3, 4, 5 and 9 volumes o puriied~.~ater U.5.P.; these diluted solutions showed no crystallization after standing for 16 hours at room tèmperature or 4C. Aliquots of the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and were put on storage stability tests at various temperatures. After storage at 37C and 45C for 3 months, TLC indicated the presence of 1% platinum B
and no transplatinum. After storage at 56C for one ~ ~ ~ ?4,~?9 month, TLC indicated the presence of 3.4% platinum B
and no transplatinum. Dilution of the aged samples with purified water U~S.P. to ~ concentra~ion of 2 mg/ml of cisplatin gave clear solutions, which remained clear after standing at ro~m temperature for 24 hours.
Example 8 .
Stable Concentrated Solution of Cisplatin (10 m~ml) Plus NaCl (lO ma/ml) in 90% PolvethYlene G1YCO1 k00 - 10%
.~ , _ 0.2N HCl To a solution of O.S gm NaCl in 4 ml of purified water U.SOP., l ml of lN ~Cl and 45 ml of Polyethylene Glycol 400 was added 250 mg of cisplatin, and the mixture was stirred in the dark at room temperature for 4 hours to give a clear yellow solution. TLC of the freshly prepared solution showed ~nly a cisplatin spot. Dilutions of the freshly prepared solution with 1, 2, 3, 4, 5 and 9 volumes of purified water gave clear solutions which remained clear after standing at room temperature for 24 hours. The 1, 2, 3, 4 and 5 volume dilutions showed no crystallization when held at ~C for 24 hours. Aliquots of the freshly , , ...................... _ . . . . .
prepared solution were sealed in 17 ml ambPr vials as described in Example 3 and were puk on storage stability tests at various temperatures. After storage at 37C
for three months, TLC indicated the presence of 1%
platin~n B with a possible trace of transplatinum. After storage at 45C for three months, TLC indicated the presence of 5% platinum B with a possible trace o trans-pla~inum. After storage at 56C for one month, TLC
indicated the presence of Z-3% platinum B and no trans-platinum. Dilution of the aged samples with purified water U.S.P. to a concentration o~ 2 mg/ml of cisplatin gave clear solutions which remained clear after standing ~23 for 24 hours at room temperature, Example 9 Stable Concentrated Solution of CisE~atin (2.5 m~ml), NaCl ~9 m~/ml) and Mannitol (12.5 mg/ml) in Acidified 31% (w/v) A~ueous Polyeth~lene Gl~ol 6000 - Sodium chloride (0.9 gm), mannitol (1.25 gm~
and Polyethylene Glycol 6000 (31.3 ~m5~ were dissolved in sufficient purified water U~S.P. to make 100 ml of solution, and the solution was then acidified to pH 2.2 with 1 N HCl (0O7 ml~. Cisplatin (255 mg) was added and the mixture was stirred in the dar~ for 3 days at room temperature to obtain a clear solution. TLC of the freshly prepared solution showed only a cisplatin zone. Aliquots o~ the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and were put on storage stability tests at 45C and 56C. After storage for two months at 45C and 56C, TLC showed less than 1%
platinum B and no transplatinum. Dilutivn of the aged samples with an equal volume of purified water U.S.P.
gave c1ear solutions which remained clear after standing at room temperature for 24 hours.
Stable Concentrated Solution of Cisplatin (15.8 mq/ml) Plus NaCl (10 mg~ml) in 90% A~ueous Polyethylene_Glycol 400 Polyethylene Glycol 400 ~90 ml) was dissolved in a solution of 1.0 gm NaCl in 10 ml purified water U.S.P.
To 60 ml of the resulting solutio~ wa5 added 900 mg of cisplatin, and the mixture was stirred in the dark for five hours at room temperature to obtain a clear solutio~.
TLC of the freshly prepared solution showed only a cisplatin zone; ~P~C assay showed it to contain 15 . ~ mg of cisplatin per ml~ ~lu~ion of the ~reshly prepared solution with four volumes of purified water U.S.P. gave a clear solution which remained clear after standing at room temperature for 24 hours. ~liquots of the freshly prepared solution wRre sealed in 17 ml am~er vials as described in Example 3 and put on storage stability tests at various temperatures. A~ter two months' storage at 45C, TLC indicated 1.5% platinum B and no transplatinum.
Ater one month storage at 56C, TLC indicated 2~
platinum B and no transplatinum. The sample aged at 56C was diluted to a concentration of 2 mg/ml with sterile water for injection and the sample aged at ~45C was diluted to concentrations of 2.5 and 5.0 mg/ml of cisplatin with sterile water for injection. They each formed clear solutions which remained clear after standing at room . .
~ temperatuxe for 24 hours.
~ PLC assays of samples stored 3 months at 45C, 6 months at 37C and 8 months at room temperature showed potency losses o 7.6%, 7.6~ and %t resp~ctively.
Example_ll Stable Concentrated Solution of Cisplatin (15 m /ml) Plus _... . _g_ CaC12 (25 mg/ml) in 90% A~ueous Polyethylene Glycol 400 .
., To a solution o 2.5 gms of CaC12 in 10 ml of purified water U.S.P. was added 90 ml of Polyethylene Glycol 400, and the resulting solution was stirred for ten minutes. To 50 ml of the above solution was added 750 mg of cisplatin and the mixture was stirred for 5 hours in the dark at room temperature to give a clear solution. TLC of the freshly prepared solution showed only a cisplatin zone. Dilutions of the freshly prepared solution with 1, 2, 5 and 10 volumes, respectively, of purified water U.S.P. gave clear solutions. Aliquots of the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and put on storage stability at 45C and 56C. Af~er two months' storage at 45C, TLC indicated the presence of 1.5% platinum B
and no transplatinum. After one month storage at 56C, TLC indicated the presence of 2.5-5~ platinum B and no transplatinum. The sample aged at 56C was diluted to a concentration of 2 mg/ml, and the sample aged at 45C
was diluted to concentrations of 2~5 and 5~0 mg/ml~ of cisplatin with sterile water for injection. They formed clear solutions which remained clear after standing at room temperature for 24 hours.
Example 12 Sterile, Stable, Concentrated Solution of Cisplatin in 90% Polyethylene Glycol 400 - 10% 0.5 N HCl (La~el claim .
is 15 mg/ml of cisplatin activity) NOTE: Cisplatin is a possible carcinogen. Protective clothing, gloves, masks, eyeglasse~ and head covering must be worn during the entire procedure. A11 work are~s and equipment must be thoroughly cleaned to avoid any future contamination, 9!'7~
--26 - .
FORMU~A
- Per ml Per 10~0 ml Cisplatin 0.0l5 gm(l) 0.150 gm Sodium Chloride 0.015 gm 0.150 gm 0.SN Hydrochloric Acid(2) 0.10 ml 19 0 ml Polye~hylene Gl~col 400 (SENTRY grade) qOs. to 1.0 ml q.s. to 10~0 ml (1) This weight of cisplatin assum~s a potency of 1000 mcg~mg. To determine the amount of cisplatin required use the following formula:
1000 x 0.015 ~m ~ = Grams of cisp}atin required Potency of cisplatin in mcg/mg ~2)One liter of 0.SN hydrochloric acid is prepared as follows:
1. Place 957~25 ml of Sterile Water for Injection, U.S.P. in a clean one liter Erlenmeyer flask.
2. With rapid stirring, slowly and cautiously add 42.75 ml of concentrated hydrochloric acid. Stir for 10 minutes. Stopper with a clean butyl rubber stopper.
MANUFACTURING INSTRUCTIONS FOR ONE LITER OF STERILE SOLUTION
1. Place 100 ml of 0.5 N hydrochloric acid in a clean, calibrated l-liter Erlenmeyer fla~k containing a suitable stirrer, such as a 6 cm magnetic, teflon coated stirrer bar.
2. Add, with modera~e stirring, 15.0 grams of sodium chloride. Stir until the salt is completely dissolved.
3. Add with rapid stirring 750 ml of Polyethylene ~lycol ~ ~ ' f.~. ~
400 (SENTR~ grade) and stir for 5 minu~e$.
NH4Cl K2[PtC14~ + 2NH3 ~- ~ cis-~pt(NH332cl2] ~ 2KCl [see Kauffman, G. B~ et al., in Inor~anic Svnthesist J.
_ _ .. .
Kleinberg (Ed.), pages 239-245, McGraw-Hill Book Co., Inc., New York, 1963].
Breusova-Baidala, Y. G. et al., in Akademia Nauk SSSR, No. 6, pp. 1239-1242 (June 1974), discuss the slow isomerization of cis-platinum (II) diamminedichloride in aqueous solution to the trans form.
Reishus, J. W. and Martin, D. S~, in Journal of the American Chemical Society, 83, 2457-2462 (1961), describe the acid hydrolysis of cisplatin at 25C and 35C. These studies were conductPd in aqueous solutions at concentrations of 1.5 x 10 M, 2.5 x 10 M and 5.0 x 10 3 M, which correspond to 0.45~ 0.7S and 1.5 mg/ml, respectively. The authors state that there was some ~.6~
ambiguity in locating the origin (i.e "zero point") for the hydrolysis curves because the samples required from lO to 30 minutes to dissolve completely even at those low concentrations.
Rozencweig, M. et al., in Annals of Internal __ Medicine, 86, 803-812 (1977), review the results of various preclinical and clinical investigations of the use of cisplatin in experimental tumors in animals as well as various type~ of human tumors. They point out that the investigational drug, available to qualified investigators through the Investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute, was supplied as a white lyophilized powder in vials containing 10 mg of cisplatin, 90 mg of sodium chloride, lO0 mg of mannitol (U.S~P.) and hydrochloric acid for p~ adjustment. When reconstituted with 10 ml of sterile water for injection (U~S.P.), each ml of the resulting solution would contain 1 mg of cisplatin, lO mg of mannitol and 9 mg of NaCl.
Talley, R. W. et al., in Cancer Chemotherapy Reports, 57, 465-471 (1973), describe the results of their Phase I clinical stuay of the use of cisplatin in the treatment of 65 human patients with a wide variety of neoplasms. As in the preceding publication, the drug was supplied to them by the National Cancer Institute in vials containing lO mg of cisplatin, 90 mg sodium chloride and lO0 mg of mannitol, for reconstitution with lO ml of sterile water.
Rossof, A. H. et al , in Cancer, 30, 1451-1456 (1972), describe the results o their use of cisplatin in the trea~ment of 31 human patients with a variety of tumor 7~
types. They state that the drug supplied by the Naticnal Cancer Institute was manu~actured by Ben Venue Laboratories, Inc. and contained, per vial, 10 mg of cisplatin, 10 mg ~sic) of mannitol and 9 mg (sic) of NaCl, and that the yellowish-white powder dissolved readily in 8-10 ml of sterile water.
Certain information concerning the chemistry and pharmaceutical formula~ion of cisplatin are given on pages 1-5 and 31-32 of the publication entitled "CLINICAL BROCHURE, CIS-PLATINUN ~II) DIAMMINEDICHLORIDE (NSC~119~75) ~
Haldelsman et al., Investigational Drug Branch9 Cancer Chemotherapy Evaluation Program9 Division of Cancer Traatment, National Cancer Institute (Revised Au~ust 1974).
Pages 31 and 32 thereof ~oncern 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:
PHARMACEUTICAL DATA S~EET
NSC-119875 Cis-Diamminedic~loroplatinum (II) Dosa~e Formulation 10 mg./vial : The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial con-tains 10 mg. of NSC-119875; 90 mg.
of Sodium Chloride; 100 mg. o Mannitol and Hydrochloric acid for pH adjustment, 7~3 --6~
501ution Preparation 10 mg./vial : When reconstituted wikh 10 ml. of Sterile Water for Injection, USP;
each ml. of the resulting solution will contain 1 mg. of ~SC-119875, 10 mg. of Mannitol, and 9 mg. of Sodium Chloride ha~ing a pH range o 3~5-4-5D
Storage : The dry, ~ vials should be stored at refri~eration temperatures (4-8~C.).
Stability : Intact vials have a provisional stability of one year when stored at refrigeration temperature (4-8C.). Stability recommendations may be adjusted pending completion of a two-year shelf~life studyO
Reconstitution as recommended results in a pale, yellow solution which is stable for not more than one hour at room temperature t22C.) when exposed to normal room illumina-tion and not more than eight hours at room temperature (22C.) when protected from light. Reconstituted solutions may form a precipitate after one hour a~ refrigeration temperature (4-8C.).
Caution : The lyophilized dosage formulations contain no preser~atives and therefore it is advised to discard solutions eight hours after reconstitution.
August, 1974 ClLnical Drug Distribution Section Drug ~evelopment Branch ~ 7 ~
Published Unitea Kingdom Patent Application No.
2021946~ describes stab7e aqueous solutions o cisplatin having a concentration of cisplatin between about 0.1 and lo O mg/ml and a pH in the range of 2.0 to 3.0, The solution~ may also contain a nontoxic, pharmaceutically acceptable, inorganic sourc2 of chloride ions, such as sodium chloride, and an excipient such as mannitol.
_omplete Disclosure This invention relates to stable, concen~rated, solutions of cisplatin ha~ing concentration~ o fr~m about 2.5 to about ~5 mg/ml. More particularly, the invention relates to stable, concentrated solutions of ci~platin in a solvent medium comprising from about 30% to about 95~ polyethylene glycol having an average molecular weight of from about lS0 to about 9000 or a methoxy polyethylene glycol haYing an average molecular weight o~ fro~ about 300 to about 6000, or a mixture thereof, and from about 5~ to about 70% water, said solutions also containing at least one nontoxic, pharmaceutically acceptable source of chloride ion in an amount whi~h is at least about equivalent to the amount of cisplatin pxesent in the solution, and said solutions having a cisplatin concentration of from about 2.5 to about 25 mg/mlO
Stable aqueous solutions of cisplat~n have been described in published United Kingdom Patent Application No. 2021946A. Although stable solutions containing cisplatin concentrations up to about 1 mg/ml may be obtained in such aqueous media at room temperature, crystallization of the cisplatin may occur in the cold at cisplatin concen~rations substantially above about 0.5 mgtml. Redissolving such crystallized cisplatin is not readily accomplished by shaking a~ room temperature, although a solution may be re-obtained by heating to about 37C. Since shipping and storage temperatures after sale cannot be controlled, and crystallization of oisplatin in the vials would create an undesirable problem for the administering physician, the maximum practical concentration of cisplatin in such aqueous media is a~out 0.5 mg/ml.
The cisplatin solutions of the present invention may contain up to about 25 mg of cisplatin per mlf although the preferred maximum is about 15 mg/ml. Solutions of the present invention containing 15 mg of cisplatin per ml have been maintained at a temperature of 4C for 12 months without crystallization of cisplatin. Such solutions have also been frozen at -60C and then thawed at room temperature with no e~idence of cisplatin pre-cipitation~ Thus, practical solutions prepared according to the present invention may have cisplatin concentrations at least 30 times higher than practical aqueous solu~ions prepared according to the prior art.
It will be appreciated that the concentrated solutions of cisplatin provided by the present invention will require lower shipping, storage and other cos~s per unit dose when compared to the known aqueous solutions~
Although the known lyophilized solid form also has lower shipping and storage costs, that saving is more than offset by the time and expenses invol~ed in lyophiliæation.
~ 7 ~
_g_ In a preerred embodiment of the present ~nvention, the solvent medium comprises from about 80%
to about 95% (and more preferably from about 85~ to about 90~) polyethylene glycol having an average molecular weight of from about 250 to about 1600 (and more prefer-ably from about 250 to about 650) and from about 5% to about 20~ (and more preferably from about 10~ to about 15%) water. In a most preferred embodLment the sol~ent medium comprises about 90% polyethylene glycol having an average molecular weight of from about 350 to about 450 and about 10% waterO
Preferably the solution contains from about 5 to about 20 mg of cisplatin per ml and most preferably from about 10 to about lS mg/ml. The nontoxic, pharma-ceutically acceptable source of chloride ion preferably is present in a concentration of at least about two equivalents per equivalent of cisplatin in the solution.
Concentrations as high as 50 equivalents or more of chloride ion per equivalent of cisplatin may be utilized, depending on the cisplatin concentration, the percentage of water present and the particular source of chloride ion, but such high concentrations of chloride ion usually are neither necessary nor desirable. It will be appreciated by those skilled in the art that, with a high cisplatin concentration and a low water content, it would not be possible to dissolve a suficient amount of a chloride ion source such as sodium chloride to provide 50 equiva~ents of chloride ion per equivalen~ of cisplatin~
Further, a saturated, or nearly saturated solution of an inorganic chloride salt would be undesirable because of the possibility of crystallizatiDn from the solution in the cold. In the situation set forth above, 50 equi~alents - ~ . ~
, of chloride ion per equivalent of cisplatin could be obtained by the use of hydr~chloric acid as the ~ource of chloride ion, but this might give a solution having an undesirably high acidity, ~.e. low pH~ We haYe found that excessively aciaic solutions are somewhat le~s stable than more moderately acidic solution~. The p~
range of the solutions preferably is from about 1.5 to about 4.5. We prefer to u~ilize from about 2 to about 10 equivalents of chloride ion per squivalent of cisplatLn~
and most preferably from abou~ 3 to about 7 equival~nts o~ chloride ion per e~uivalent of cisplatin.
The chloride ion may be provided by the addition of hydrochloric acîd, a nontoxic pharmaceutically metallic halide such as sodium chloride, potassium chloridet calcium chloride or magnesium chloride, or the hydxochloric acid addition salt of a nontoxic pharma-ceutically acceptable ~er~iary amine suGh as trie~hylamine, or by mixtures theraof~ The preferred source of chloride ~on is hydrochloric acid, sodium Ghloride or a mixture thereofO
Polyethylene glycols and me~hoxy polyethylene glycols have the general formulae H (OC~I2CEI;! ) ",OH and CH3 (CH2cH2 ) nC~3 respectively, and are commercially available as C~RBO~
Polyethylene Glycols and C~æX Methoxy Polyethylene GlycolsO We preer to utilize the SE~ Grades of CAR~OW~X Polyethylene Glycols, which are produced to meet U.S.P~, N. F. and F.C.C. specification5 ~or ~ood and dr~ applications. Typical molecular weight ranges ~or a vari~ty of C~RBOWAX Polyethylene Glycols and CAR~OWAX
, Trademark Methoxy Polyethylene Glycols are given in Tables 1 and 2 ~able 1 ~ ~ _ .
CARBOWAX Typical Polyethylene Molecular Glycols . Weight Range _ _ ___ .
200 190 ~o 210 300 285 t~ 315 400 380 to ~20 , 600 570 to 630 1000 950 to 1050 15~0 1300 to 1600 4000 3000 to 37~0 6000 7000 to 9000 _ _ . ..
Table 2 _ ~, CARBOWAX Typical Methoxy Molecular Polyethylene Weight Glycols Range _ __ ~ . .
350 335 to 365 .
SS0 525 ~o 575 75~ 715 t~ 785 2000 . 1850 to 2150 _ __ _. . ,.
Polyethylene glycols are known to ~orm complexes with certai~ inorganic salts. Thus, the reaction of polyethylene glycols with ammonium cobalt thiocyanate ko form a blue complex is the basi~ o~ one color1metric method of determining the concentration o~ ~olyethylene glycols ~ ~6 ~ ~7 ~
in various mixtures. We believe that the unique stability of cisplatin in the solutions o~ the present invention may be due to a complex formed bet~een the cisplatin and the polyethylene glycol, but this is only theory and does not form a part of the invention. Evidence of complex formation has been noted in our TLC procedure. Using techniques described below, aqueous cisplatin produces a spot at about Rf 0.65~ However, a solution of cisplatin in 90~ Polyethylene Glycol 400 - 10% H20 (or 10% 0.5 N
HCl) gives a spot at about Rf 0.3 which streaks to about Rf 0.65. Dilution with ~ubstantial quantities of water appears to immediately break the complex, since dilution of the above PEG-H20 (or HCl) solution with five volumes of water then shows only a cisplatin spot at about R~ 0.65.
Thin Layer Chromato~raphy Apparatus and Rea~ents (a) TLC plates - EM Laboratories silica gel 60 plates, Catalog No. 57~3, or equivalent.
(b) Eluent - Acetone:l N HNO3 (9:1). Prepare fresh daily.
(c) Developer - Dissolve 5.6 gm of stannous chloride in 10 ml concentrated HC1. Add 90 ml of distilled water and 0.2 gm of KI. Mix well. Prepare fresh daily.
(d) Laboratory oven set to 100C.
Procedure (a) Dilute the sample with 5 volumes of dimethylformamide .
(DMFl ~Burdick and Jackson, distilled in glass].
(b) Spo~ ~ TLC plate with 5 rnicrolit~rs of the sample and 5 microliters of a standard solution containing cisplatin (and transplatinum and platinum B, if appropriate) at a concentration approximately th~
same as that expected in the sample being analyzed.
Develop a height of 10 cm in a TLC tank pre-equilibrated with the eluent. Spray the dried plate with freshly prepared developer solution and place it in a 100C oven fox 10 minutes. O~serve the yellow/
purple zones.
(c) Approximate Rf values:
0.65 - cisplatin 0~7~ - transplatinum O.9 - platinum Bo HPLC assays of the solutions of this invention for cisplatin content may ~e conducted according to the procedure described in our colleagues' published United Kingdom Patent Application No. ~021946A. The preferred mobile phase is ethyl acetate/methanol/dimethylformamide/
distilled water (~5/16/5/5). The standard preferably is cisplatin dissolved in dimethylformamide at a concentration of 1 mg/ml. Samples for analysis are diluted with dimethylformamide to an approximate cisplatin concentration of 1 mg/ml.
Although no particular advantage is obtained by their presence, tbe solutions of this invention may, i~
desired, contain a customary, physiologically acceptable excipient such as mannitol.
Based on stability studies to date, the pre dicted stability of the solutions of this invention (defined as a 10% loss of potency) i5 in excess of two years at room temperature.
In a preferred embodiment of this invention~
the solutions are sterile and pyrogen-free, and are packaged in sterile, pyrogen-free containers. Such ~olutions may then be diluted with, for example, Sterile Water for Injection~ U.g.P., or Sterile Normal Saline Solution, U.S.P., and administered by the intramuscular or intravenous route. Means for sterilizing these solutions are well known in the art. W8 prefer to pass the solutions through a ~teril~, pyrogen-free 0.22 micron Millipore filter, using aseptic techniques, under sterile nitrogen pressure. Millipore is a registered trademark of the Millipore Corporation for membrane filters~ The sterile iltrate is collected in sterile, pyrogen-free containers and is ultimately filled, in the desired amount, into suitable sterile, pyrogen-free vials, stoppered with sterile, pyrogen-free stoppers (preferably teflon coated) and sealed with sterile aluminum seals.
For u~e in the treatment of cancer, the concen-trated solutions are diluted to the desired concentration ~typically 1 mg ci~platin per ml) with, for example, Sterile Water for Injection, U.S~P~, 5terile Normal Saline Solution, U.S.P., or Sterile Glucose Solution and used by intramuscular or LntraVenOUs injection, or intravenous ,.
infusion as known for prior art cispla~in preparationsO
Currently used dosages with mild to moderately acceptable toxicity are in the range of 60-100 mg/M2 intravenously as a single dose or divided over 3-5 days, to be repeated at 4-week intervals. A dosage of 60 mg/M2 is roughly equal to 1.5 mg/kg which in turn is roughly equal ~o 105 mg~patient weighing 70 ky. Frequently, use is made of concurrent therapy with other chemothera-peutic agents for best results.
As used herein and in the claims, references to "equivalents" of chloride ion per "equivalent" of cisplatin means molar equivalents. Thus, for example, when utilizing the preferred range of f~om about 3 to about 7 equivalents of chloride ion per equivalent of cisplatin, one would utilize from about 3 to about 7 moles of NaCl per mole of cisplatin but from about 1. 5 to about 3 . 5 moles of CaC12 per mole of cisplatin, etc.
Platinum B is an arbitrary designation used herein for an a~id reaction product of cisplatin which is one-half of the known Magnus red complex and has been tentatively assigned the following structure:
rH4 ~ Cl C1~3 \ Pt /
H3N / \ Cl This invention is illustrated by, but i~ in no way l~mited to, the following Examples.
Example 1 Stable Concentrated Solution of Ci~platin ~lO mg/ml~ in 90% Polyethylene Glycol 400 - 10% lN HCl Cisplatin (500 mg) was slurried in a solution o~
5 ml of lN HCl and 45 ml of Polyethylene Glycol 400.
After 2.5 days of stirring at room temperature (with the container protected from light with aluminum foil) a clear yellow solution was obtained. Aliquots of the solution were placed in 17 ml amber vials, stoppered with teflon coated stoppers, sealed with aluminum caps and placed on storage stability tests at various temperatures. After two weeks' storage at 45~C, thin layer chromatography (TLC) indicated the presence of a txace of transplatinum and approximately 1~ platinum B. Aftsr two weeks' storage at 56C, TLC indicated the presence of <1% transplatinum and approximately 3% platinum B. Samples stored for two weeks at 56C were diluted with 4, 9 and 19 volumes of water to give clear solutions containing 2, 1 and 0. 5 mg/ml, respectively, of cisplatinl A slight cloudiness developed in each of the diluted samples after standing approximately 18 hours at room temperature.
~ 7 Example 2 Stable Concentrated Solution of Cis~latin (10 m~/ml3 in 90% Pol~ethylene Glycol 400 - 10~ 0.5N HCl Five ml of purified water U~S.P. and 5.0 ml of lN Hcl were mixed and 90.0 ml of Polyethylene Gly~ol 400 was added. To 50 ml of the above solution was added 500 mg of cisplatin and the mixture was protected from light with aluminum foil and stirred at room temperature for 24 hours to produce a clear solu~ion. TLC of the freshly prepared solution showed only a cisplatin zone with a possible trace of transplatinum. ~o ml aliquots o~ the solution were placed in 17 ml amber vials~ stoppered with teflon coated stoppers, sealed with aluminum caps and placed on storage stability tests at various temperatures.
One sample vial was frozen in a dry ice-acetone bath for one hour and then allowed to come to room temperature. A
clear solution was obta~ned, with no evidence o a pre-cipitate. After three months' storage at both 37C and 45C, TLC indicated the presence of 1-2% platinum B and a possible trace of transplatinum. After one month storage at 56~C, TLC indicated the presence of more than 5~ but less than 10% of platinum B and a trace of trans-platinum. Samples stored at 37C and 45C for three months and at 56C for one month were diluted with four volumes of purified water U.S~P. to give clear solutions containing 2 mg/ml of cisplatin. The diluted solutions remained clear after standing 24 hours at room temperature.
.
Stable Concentrated Solution of Cisplatin (lO m~/ml) Plus CaCl2 (20 mg/ml) in 90% Polyethylene Glycol 400 - 10% 0.5N
HCl ~ wo gms of reagen~ grade anhydrous CaCl~ wa~
dissolved in a mixture o~ 5 ml purified water U.S.P. and 5 ml lN HCl. Polyethylene Glycol 400 (89 ml) was added to bring the volume to lO0 ml, To 50 ml of this solution was added 550 mg of cisplatin, and the mixture was protected from light with aluminum foil and stirred at room temper ature for 24 hours to give a clear solution. T~C o t~e freshly prepared solution indicated only a cisplatin zone with a possible trace of transplatinum. Two ml aliquots of the solution were placed in 17 ml amber vials, stoppered with teflon coated stoppers, sealed with aluminum caps and placed on storage stability tests at various t~mperatures~
One sample vial was placed in a dry ice-acetone bath for 0.5 hour and froze to a clear gel. It was then allowed to come to room temperature and a clear solution was ob tained. After three months' storage at 37C, TLC indi-cated the presence of 1~2% platinum B and a possible trace of transplatinum. After three months' storage at 45C, TLC indicated the presence of approximately 5~ platinum B
and a possible trace of transplatinum. After Qne month storage at 56C, TLC indicated the presence of 8-10%
platinum B and a trace of transplatinum. Samples stored at 37C and 45C for three months and at 56C for one month were diluted with four volumes of purified water U.S.P. to give clear solutions containing 2 mg/ml of cisplatinO The diluted solutions remained clear after standing 24 hours at room temperature.
.. . . .
.
t~
Example 4 Stable oncentrated Solution of Cisplatin (A~roxLmatel~
22 mg/ml) Plus CaCl~ (25 mg/ml) in 90% Polyethylene Glycol -10% 0.5N ~Cl To three ml of a solution of 90~ Polyethylene Glycol 400 and 10~ 0.5N HCl was added 45 mg of cisplatin, and the mixture was stirred for about one hour at room temperature to o~tain a clear solution. An additional 30 mg of cisplatin was added (to~al of 25 mg/ml) and the mixture was stirred at about 45C for one hour and then at room temperature for 18 hours to produce a nearly complete solution. The small amount of insolubl~ material was removed by filtration. TLC of the filtrate showed only a cisplatin zone with a possible trace of trans-platinum. The remainder Gf the filtrate was placed in a 17 ml am~er vial, stoppered with a teflon coated stopper, se~led with an aluminum cap and held at 45C for three months~ After aging three months at 45C, TLC indicated the presence of 1-2~ platinum B and no transplatinumO
Dilution of the aged solution with purified wate~ U.S.P.
to a concentration of 2 mg/ml of cisplatin gave clear solutions, which remained ~lear after standing at room temperature for 24 hours.
Example S
Stable Concentrated Solution of Cis latin (12 mq/ml) Plus _ P ~
NaCl (10 m~/ml) in 9o~ Polyethylene Glycol 400 - 10~ 0.5N.
H
Sodium chloride (100 m~) was dissolved in a solution of 5 ml purified water U~S~P~ and 5 ml lN
~.3.~7~3;
HCl. To this solution was added 90 ml of Polyethylene Glycol 400 and the mixture was stirred for 15 minutes.
To 50 ml of the latter solution was added 500 mg of cisplatin, and the mixture was stirred in the ~ark at room ~emperature for 3 days to produce a clear solution.
T~C o the freshly prepared solution showed only a cisplatin spot. High performance liquid chromatography (HPLC) assay of the freshly prepared solution showed it to contain 12 mg of cisplatin per ml~ Aliquots were sealed in 17 ml amber vials as described in Example 3 and put on storage stability tests at various ~emperatures.
After storage at 37~C for three months, TLC indicated the presence of less than 1% platinum B and no trans-platinum. After storage at 56C for one month, TLC
indicated the presence of 1~2% platinum B an~ no transplatinum. Dilution of the aged samples with purified water U.S.P. to a concentration of 2 mg/ml of cisplatin gave clear solutions, whic~ remained clear after standing at room temperature for 24 hours.
HPLC assays of samples stored 3 months at 45C, 6 months at 37C and 8 months at room temperature showed potency losses of 6.6%, 6.1~ and 2. 3%, respecti~ely.
. .. . .. . . .
Example 6 Stable Concentrated Solution of Clsplatin (11.4 mg/ml Plus NaCl (10 mg/ml) n 90% Polyethylene Glycol 400 - 10% Water To a solution of 50 mg NaCl in 5 ml of purified water U.S.P. and 45 ml Polyethylene Glycol ~09 was added 500 mg of cisplatin; and the mixture was stirred in the dark at room temperature ~or 6 hours to give a elear solution. TLC of the freshly prepared solution showed . .
r7 91 ~ 2:L ~
only a cisplatin spot; HPLC assay showed it to contain 11.4 mg of cisplatin per ml. Aliquots were sealed in 17 ml amber vials as described in Example 3 and put on storage stability tests at various temperatures. After storage at 37C and 45C for 3 monthst TLC indicated the presence of 1% platinum B and no transplatinum. After storage at 56C for one month, TLC indicated the presence of 2-3% platinum B and no transplatinum~ Dilution of the aged samples with purified water U.S.P. to a concentration of 2 mg~ml of cisplatin gave clear solutions, which remained clear after standing at room temperature for 24 hours.
HPLC assays of samples stored 3 months at 45C, 6 months at 37C and 7 months at room temperature showed potency losses of 6.1%, 7.8% and 0O9%~ respectively.
. . .
ExamEIle 7 Stable Concentrated Solution of Cis~latin (lO mg/ml) in 90% Polyethylene Glycol 600 - 10% 0.5N HCl To a solution of 2.5 ml of purified water U7SoP~
2.5 ml of lN HCl and 45 ml of Polyethylene Glycol 600 was added 500 mg of cisplatin, and the mixture was stirred in the dark at room temperatuxe for S hours to obtaLn a clear solution. TLC of the freshly prepared solution showed only a cisplatin spot. Samples of the freshly prepared solution were diluted with 1, 2, 3, 4, 5 and 9 volumes o puriied~.~ater U.5.P.; these diluted solutions showed no crystallization after standing for 16 hours at room tèmperature or 4C. Aliquots of the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and were put on storage stability tests at various temperatures. After storage at 37C and 45C for 3 months, TLC indicated the presence of 1% platinum B
and no transplatinum. After storage at 56C for one ~ ~ ~ ?4,~?9 month, TLC indicated the presence of 3.4% platinum B
and no transplatinum. Dilution of the aged samples with purified water U~S.P. to ~ concentra~ion of 2 mg/ml of cisplatin gave clear solutions, which remained clear after standing at ro~m temperature for 24 hours.
Example 8 .
Stable Concentrated Solution of Cisplatin (10 m~ml) Plus NaCl (lO ma/ml) in 90% PolvethYlene G1YCO1 k00 - 10%
.~ , _ 0.2N HCl To a solution of O.S gm NaCl in 4 ml of purified water U.SOP., l ml of lN ~Cl and 45 ml of Polyethylene Glycol 400 was added 250 mg of cisplatin, and the mixture was stirred in the dark at room temperature for 4 hours to give a clear yellow solution. TLC of the freshly prepared solution showed ~nly a cisplatin spot. Dilutions of the freshly prepared solution with 1, 2, 3, 4, 5 and 9 volumes of purified water gave clear solutions which remained clear after standing at room temperature for 24 hours. The 1, 2, 3, 4 and 5 volume dilutions showed no crystallization when held at ~C for 24 hours. Aliquots of the freshly , , ...................... _ . . . . .
prepared solution were sealed in 17 ml ambPr vials as described in Example 3 and were puk on storage stability tests at various temperatures. After storage at 37C
for three months, TLC indicated the presence of 1%
platin~n B with a possible trace of transplatinum. After storage at 45C for three months, TLC indicated the presence of 5% platinum B with a possible trace o trans-pla~inum. After storage at 56C for one month, TLC
indicated the presence of Z-3% platinum B and no trans-platinum. Dilution of the aged samples with purified water U.S.P. to a concentration o~ 2 mg/ml of cisplatin gave clear solutions which remained clear after standing ~23 for 24 hours at room temperature, Example 9 Stable Concentrated Solution of CisE~atin (2.5 m~ml), NaCl ~9 m~/ml) and Mannitol (12.5 mg/ml) in Acidified 31% (w/v) A~ueous Polyeth~lene Gl~ol 6000 - Sodium chloride (0.9 gm), mannitol (1.25 gm~
and Polyethylene Glycol 6000 (31.3 ~m5~ were dissolved in sufficient purified water U~S.P. to make 100 ml of solution, and the solution was then acidified to pH 2.2 with 1 N HCl (0O7 ml~. Cisplatin (255 mg) was added and the mixture was stirred in the dar~ for 3 days at room temperature to obtain a clear solution. TLC of the freshly prepared solution showed only a cisplatin zone. Aliquots o~ the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and were put on storage stability tests at 45C and 56C. After storage for two months at 45C and 56C, TLC showed less than 1%
platinum B and no transplatinum. Dilutivn of the aged samples with an equal volume of purified water U.S.P.
gave c1ear solutions which remained clear after standing at room temperature for 24 hours.
Stable Concentrated Solution of Cisplatin (15.8 mq/ml) Plus NaCl (10 mg~ml) in 90% A~ueous Polyethylene_Glycol 400 Polyethylene Glycol 400 ~90 ml) was dissolved in a solution of 1.0 gm NaCl in 10 ml purified water U.S.P.
To 60 ml of the resulting solutio~ wa5 added 900 mg of cisplatin, and the mixture was stirred in the dark for five hours at room temperature to obtain a clear solutio~.
TLC of the freshly prepared solution showed only a cisplatin zone; ~P~C assay showed it to contain 15 . ~ mg of cisplatin per ml~ ~lu~ion of the ~reshly prepared solution with four volumes of purified water U.S.P. gave a clear solution which remained clear after standing at room temperature for 24 hours. ~liquots of the freshly prepared solution wRre sealed in 17 ml am~er vials as described in Example 3 and put on storage stability tests at various temperatures. A~ter two months' storage at 45C, TLC indicated 1.5% platinum B and no transplatinum.
Ater one month storage at 56C, TLC indicated 2~
platinum B and no transplatinum. The sample aged at 56C was diluted to a concentration of 2 mg/ml with sterile water for injection and the sample aged at ~45C was diluted to concentrations of 2.5 and 5.0 mg/ml of cisplatin with sterile water for injection. They each formed clear solutions which remained clear after standing at room . .
~ temperatuxe for 24 hours.
~ PLC assays of samples stored 3 months at 45C, 6 months at 37C and 8 months at room temperature showed potency losses o 7.6%, 7.6~ and %t resp~ctively.
Example_ll Stable Concentrated Solution of Cisplatin (15 m /ml) Plus _... . _g_ CaC12 (25 mg/ml) in 90% A~ueous Polyethylene Glycol 400 .
., To a solution o 2.5 gms of CaC12 in 10 ml of purified water U.S.P. was added 90 ml of Polyethylene Glycol 400, and the resulting solution was stirred for ten minutes. To 50 ml of the above solution was added 750 mg of cisplatin and the mixture was stirred for 5 hours in the dark at room temperature to give a clear solution. TLC of the freshly prepared solution showed only a cisplatin zone. Dilutions of the freshly prepared solution with 1, 2, 5 and 10 volumes, respectively, of purified water U.S.P. gave clear solutions. Aliquots of the freshly prepared solution were sealed in 17 ml amber vials as described in Example 3 and put on storage stability at 45C and 56C. Af~er two months' storage at 45C, TLC indicated the presence of 1.5% platinum B
and no transplatinum. After one month storage at 56C, TLC indicated the presence of 2.5-5~ platinum B and no transplatinum. The sample aged at 56C was diluted to a concentration of 2 mg/ml, and the sample aged at 45C
was diluted to concentrations of 2~5 and 5~0 mg/ml~ of cisplatin with sterile water for injection. They formed clear solutions which remained clear after standing at room temperature for 24 hours.
Example 12 Sterile, Stable, Concentrated Solution of Cisplatin in 90% Polyethylene Glycol 400 - 10% 0.5 N HCl (La~el claim .
is 15 mg/ml of cisplatin activity) NOTE: Cisplatin is a possible carcinogen. Protective clothing, gloves, masks, eyeglasse~ and head covering must be worn during the entire procedure. A11 work are~s and equipment must be thoroughly cleaned to avoid any future contamination, 9!'7~
--26 - .
FORMU~A
- Per ml Per 10~0 ml Cisplatin 0.0l5 gm(l) 0.150 gm Sodium Chloride 0.015 gm 0.150 gm 0.SN Hydrochloric Acid(2) 0.10 ml 19 0 ml Polye~hylene Gl~col 400 (SENTRY grade) qOs. to 1.0 ml q.s. to 10~0 ml (1) This weight of cisplatin assum~s a potency of 1000 mcg~mg. To determine the amount of cisplatin required use the following formula:
1000 x 0.015 ~m ~ = Grams of cisp}atin required Potency of cisplatin in mcg/mg ~2)One liter of 0.SN hydrochloric acid is prepared as follows:
1. Place 957~25 ml of Sterile Water for Injection, U.S.P. in a clean one liter Erlenmeyer flask.
2. With rapid stirring, slowly and cautiously add 42.75 ml of concentrated hydrochloric acid. Stir for 10 minutes. Stopper with a clean butyl rubber stopper.
MANUFACTURING INSTRUCTIONS FOR ONE LITER OF STERILE SOLUTION
1. Place 100 ml of 0.5 N hydrochloric acid in a clean, calibrated l-liter Erlenmeyer fla~k containing a suitable stirrer, such as a 6 cm magnetic, teflon coated stirrer bar.
2. Add, with modera~e stirring, 15.0 grams of sodium chloride. Stir until the salt is completely dissolved.
3. Add with rapid stirring 750 ml of Polyethylene ~lycol ~ ~ ' f.~. ~
400 (SENTR~ grade) and stir for 5 minu~e$.
4. Remove the magnetic stirrer bar and drain excess fluid back into the f la~k.
5. Cautiously add 15.0 grams of ~isplati~ activity.
6. Add Polyethylene Glycol 400 (SENTRY grade) to the 1 liter mark (a total of 880 ml of Polyethylene Glycol 400 required).
7. Place the teflon s~irrer har ~ack into the mixture and stopper with a clean butyl rubber stoppe~
8. Wrap the flask in ~luminum foil to exclude all light.
9~ Rapidly stir ~or 24-48 hours at amhient room temperatur~.
A clear solution should be obtained. If a clear solution is not obtained i~ 48 hours, the mixture may be wanmed to 37-40C for 2-6 hours in the absence of aîr and light ~o `facilitate rapid solution of th~ remaining cisplatin~
Cool ~o 23-~7C.
A clear solution should be obtained. If a clear solution is not obtained i~ 48 hours, the mixture may be wanmed to 37-40C for 2-6 hours in the absence of aîr and light ~o `facilitate rapid solution of th~ remaining cisplatin~
Cool ~o 23-~7C.
10. Using aseptic te~hniquet pass the dark yellow solution under proper sterile nitrogen pressure, through a suitabl~
;` sterile, pyrogen-free 0.22 micron Millipore filter~ Collect the sterile filtrate in a sterile, pyxogen-free Erlenmey~r flask. Stopper with a sterile, pyrogen-free butyl ruh~er stopper. The solution may be stored in the dark.
;` sterile, pyrogen-free 0.22 micron Millipore filter~ Collect the sterile filtrate in a sterile, pyxogen-free Erlenmey~r flask. Stopper with a sterile, pyrogen-free butyl ruh~er stopper. The solution may be stored in the dark.
11. Fill the required amount of sterile solution into sterile, pyrogen-free amber ~ial~. Stopper with sterile, pyrogen-free teflon stopper~ Seal with sterile aluminum seals.
*
f~, Trademark ~ 2~
*
f~, Trademark ~ 2~
12. The vials should contain the following precautionary label:
NOT FOR DIRECT INTRAMUSCULAR OR INTRAVENOUS USE*
The PEG-400 solution may be diluted with 14 parts of Sterile Water for Injection, U.S.P.
or Sterile Normal Saline Solution, U.S.P. to give a 1 mg/ml solution of cisplatin. If higher concentrations are required, proportionally less Sterile Water or Saline Solution may be used. The diluted solu~ions may be used intra-venously and are stable at room ambient temper-akure (22-26C) for at least 48 hours. Do not refrigerate diluted solu~ions as crystals may form.
NOT FOR DIRECT INTRAMUSCULAR OR INTRAVENOUS USE*
The PEG-400 solution may be diluted with 14 parts of Sterile Water for Injection, U.S.P.
or Sterile Normal Saline Solution, U.S.P. to give a 1 mg/ml solution of cisplatin. If higher concentrations are required, proportionally less Sterile Water or Saline Solution may be used. The diluted solu~ions may be used intra-venously and are stable at room ambient temper-akure (22-26C) for at least 48 hours. Do not refrigerate diluted solu~ions as crystals may form.
13. Store the vials in the dark~
Example 13 Stable Concentrated Solution of Cisplatin (2. 5 mg/ml), NaCl (9 ms/ml), CaC12 (15 mg~ml~ and Mannitol (10 mg/ml) in Acldified 31% Aqueous Polyethylene Glycol 400 Sodium chloride (0.9 gm), CaC12 (1.5 gm) and mannitol (1.0 gm) were dissolved in a mixture of 31. 25 ml Polyethylene Glycol 400 and 40 ml purified water U.S.P~
The solution was acidified to p~ 2.2 with lN HCl (0.4 ml), 255 mg of cisplatin was added, the volume was brought to 100 ml with purified water U~S.P., and the mixture was stirred,in the darX for 5 hours at room temperature to obtain a clear solution. TLC o the ~reshly prepared solution showed only A clsplatin zone.
~ 79 _~9 _ Example 14 The general pro~edure of Example 5 is repeated except that the sodium chloride utilized therein i5 re-placed by an equivalent amount of magnesium chloride, and a stable concentrated solu~ion of cisplatin is thereby produced.
Example 15 The general procedure of Example 5 i5 repeated except that the sodium chloride utilized therei~ is re-placed by an equivalent amount of triethylamine hydro-chloride, and a stable concentratea solution of cisplatin is produced.
Example 16 Th~ general procedure of Example 5 is repeated except that the Polyethylene Glycol 400 utilized therein is replaced ~y an equal volume of Polyethylene Glycols 200 and 300, respectiveIy, and stable concentrated solutions o~ cisplatin are produced.
Example 17 The general procedure of Ex~mple 9 is repeated except that ~he Polyethylene Glycol 6000 utilized therein is replaced by an equal weight of Polyethylene Glycols 1000 and 4000, respectively, and stable concentrated solutions of cisplatin are produced.
Example 13 Stable Concentrated Solution of Cisplatin (2. 5 mg/ml), NaCl (9 ms/ml), CaC12 (15 mg~ml~ and Mannitol (10 mg/ml) in Acldified 31% Aqueous Polyethylene Glycol 400 Sodium chloride (0.9 gm), CaC12 (1.5 gm) and mannitol (1.0 gm) were dissolved in a mixture of 31. 25 ml Polyethylene Glycol 400 and 40 ml purified water U.S.P~
The solution was acidified to p~ 2.2 with lN HCl (0.4 ml), 255 mg of cisplatin was added, the volume was brought to 100 ml with purified water U~S.P., and the mixture was stirred,in the darX for 5 hours at room temperature to obtain a clear solution. TLC o the ~reshly prepared solution showed only A clsplatin zone.
~ 79 _~9 _ Example 14 The general pro~edure of Example 5 is repeated except that the sodium chloride utilized therein i5 re-placed by an equivalent amount of magnesium chloride, and a stable concentrated solu~ion of cisplatin is thereby produced.
Example 15 The general procedure of Example 5 i5 repeated except that the sodium chloride utilized therei~ is re-placed by an equivalent amount of triethylamine hydro-chloride, and a stable concentratea solution of cisplatin is produced.
Example 16 Th~ general procedure of Example 5 is repeated except that the Polyethylene Glycol 400 utilized therein is replaced ~y an equal volume of Polyethylene Glycols 200 and 300, respectiveIy, and stable concentrated solutions o~ cisplatin are produced.
Example 17 The general procedure of Ex~mple 9 is repeated except that ~he Polyethylene Glycol 6000 utilized therein is replaced by an equal weight of Polyethylene Glycols 1000 and 4000, respectively, and stable concentrated solutions of cisplatin are produced.
Claims (7)
1. A stable concentrated solution of cisplatin in a solvent medium comprising from about 30% to about 95% polyethylene glycol having an average molecular weight of from about 150 to about 9000 or a methoxy polyethylene glycol having an average molecular weight of from about 300 to about 6000 or a mixture thereof, and from about 5% to about 70% water, said solution also containing at least one nontoxic pharmaceutically acceptable source of chloride ion in an amount which is at least about equivalent to the amount of cisplatin present in the solution, and said solution having a cisplatin concentration of from about 2.5 to about 25 mg/ml.
2. A stable concentrated solution of cisplatin in a solvent medium comprising from about 80% to about 95% of a polyethylene glycol having an average molecular weight of from about 250 to about 1600 or a methoxy polyethylene glycol having an average molecular weight of from about 300 to 800, or a mix-ture thereof, and from about 5% to about 2096 water, said solution also containing at least one nontoxic pharmaceutically acceptable source of chloride ion in an amount which is in the range of from about two equivalents to about ten equivalents per equivalent of cisplatin in the solution, and said solution containing from about 5 to about 20 mg of cisplatin per ml.
3. A solution of cisplatin as claimed in Claim 2 wherein the nontoxic pharmaceutically accept-able source of chloride ion is hydrochloric acid, sodium chloride, calcium chloride, magnesium chloride or triethylamine hydrochloride, or a mixture thereof.
4. A stable, concentrated solution of cisplatin in a solvent medium comprising from about 85% to about 90%
polyethylene glycol having an average molecular weight of from about 250 to about 650 and from about 10% to about 15% water, said solution also containing a source of chloride ion selected from hydrochloric acid, sodium chloride and mixtures thereof, in an amount which is in the range of from about three to about seven equivalents per equivalent of cisplatin in the solution, and said solution having a cisplatin concentration of from about 10 to about 15 mg/ml.
polyethylene glycol having an average molecular weight of from about 250 to about 650 and from about 10% to about 15% water, said solution also containing a source of chloride ion selected from hydrochloric acid, sodium chloride and mixtures thereof, in an amount which is in the range of from about three to about seven equivalents per equivalent of cisplatin in the solution, and said solution having a cisplatin concentration of from about 10 to about 15 mg/ml.
5. A solution of cisplatin as claimed in Claim 4 wherein said solution is sterile and is in a sealed container such as a vial.
6. A sterile, stable, concentrated solution of cis-platin in a sealed container, said solution containing from about 10 to about 15 mg of cisplatin per ml and from about 10 to about 15 mg of NaCl per ml in a solvent medium con-sisting of about 90% of a polyethylene glycol having an average molecular weight of from about 350 to about 450 and about 10% water.
7. A sterile, stable, concentrated solution of cis-platin in a sealed container, said solution containing from about 10 to about 15 mg of cisplatin per ml and from about 10 to about 15 mg of NaCl per ml in a solvent medium con-sisting of about 90% of a polyethylene glycol having an average molecular weight of from about 350 to about 450 and about 10% dilute hydrochloric acid having a concentration up to about 0.5 N.
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US13537380A | 1980-03-31 | 1980-03-31 | |
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KR (1) | KR860000841B1 (en) |
AR (1) | AR225500A1 (en) |
AT (1) | AT370996B (en) |
AU (1) | AU541056B2 (en) |
BE (1) | BE888209A (en) |
CA (1) | CA1162479A (en) |
CH (1) | CH647481A5 (en) |
CS (1) | CS246051B2 (en) |
DD (1) | DD157762A5 (en) |
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ES (1) | ES8206545A1 (en) |
FI (1) | FI70670C (en) |
FR (1) | FR2480605A1 (en) |
GB (1) | GB2074028B (en) |
GR (1) | GR72769B (en) |
HU (1) | HU183379B (en) |
IE (1) | IE51070B1 (en) |
IL (1) | IL62517A (en) |
IT (1) | IT1170838B (en) |
LU (1) | LU83270A1 (en) |
NL (1) | NL8101531A (en) |
NO (1) | NO156675C (en) |
NZ (1) | NZ196519A (en) |
PH (1) | PH17152A (en) |
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IT1153974B (en) * | 1982-09-23 | 1987-01-21 | Erba Farmitalia | PHARMACOLOGICAL COMPOSITIONS BASED ON CISPLATIN AND METHOD FOR THEIR OBTAINMENT |
NL8303657A (en) * | 1983-10-24 | 1985-05-17 | Pharmachemie Bv | SOLUTION, STABLE, AQUEOUS, AQUEOUS, CONTAINING SOLUTION OF CISPLATINE, AND METHOD OF PREPARING THEREOF. |
FI895340A0 (en) * | 1988-11-14 | 1989-11-09 | Bristol Myers Squibb Co | HYPERTONISK CISPLATIN-LOESNING. |
WO1998007409A1 (en) * | 1996-08-23 | 1998-02-26 | Sequus Pharmaceuticals, Inc. | Liposomes containing a cisplatin compound |
AUPQ641100A0 (en) | 2000-03-23 | 2000-04-15 | Australia Nuclear Science & Technology Organisation | Methods of synthesis and use of radiolabelled platinum chemotherapeutic ag ents |
JP4445304B2 (en) | 2004-03-26 | 2010-04-07 | オンキヨー株式会社 | Switching amplifier |
US8852566B2 (en) * | 2009-03-26 | 2014-10-07 | Warsaw Orthopedic, Inc. | Compositions and methods for preferential distribution of active agents to injury sites |
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CA1119954A (en) * | 1978-05-30 | 1982-03-16 | Edmund S. Granatek | Aqueous solution of cisplatin |
-
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- 1981-03-27 DE DE19813112272 patent/DE3112272A1/en active Granted
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- 1981-03-28 KR KR1019810001029A patent/KR860000841B1/en active
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