Patent Abstract:
this invention describes a novel formulation containing both cis - diammine dichloro platinum and a water soluble disulfide , 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate in the same solution , wherein the presence of the disulfide and the parenteral administration of the formulation reduces the risk of cisplatin induced nephrotoxicity when treating human patients with cancer .

Detailed Description:
in its preferred embodiments , this invention involves the preparation and administration of a sterile , aqueous formulation of cis - diammine dichloro platinum with 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate in the same formulation . the following examples illustrate selected modes for carrying out the claimed invention and are not meant to be construed as limiting the specification and claims in any way . 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate is prepared by oxidizing 2 - mercapto ethane sulfonate in water with equimolar amount of iodine as previously reported by lamaire and reiger ( lemaire and reiger , j . org . chem ., 26 , 1330 - 1 , 1961 ). the stability of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate at room temperature was determined at ph ranges of 1 . 5 to 9 . 0 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate , as produced by the method described above , was found to be stable in the ph range of 1 . 5 - 9 . 0 . briefly , the following experiment was performed to determine the stability of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate in acidic and basic aqueous media . in a typical experiment , 50 mg of 2 , 2 &# 39 ; dithio - bis - ethane sulfonate ( as produced by using the above described method ) was dissolved in one ml of water and the ph was adjusted to 1 . 5 , 2 . 0 , 3 . 0 , 4 . 0 , 5 . 0 or 6 . 0 by adding 1n hydrochloric acid in water or the ph was adjusted to 8 . 0 or 9 . 0 by adding 1n sodium hydroxide in water . the reaction mixture was stirred for 24 hours at room temperature , the water was removed at reduced pressure , dissolved in spectral grade d 2 o , and the proton nmr spectrum was recorded . one peak corresponding to the starting material was observed on the nmr spectra ; no additional peaks were observed . the stability of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate at ph 1 . 5 was further studied by heating the reaction mixture to 100 degrees centigrade for 10 minutes . no change in the proton spectrum was observed after heating the 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( ph 1 . 5 ). the data indicate that 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate is stable in aqueous solutions at ph values from 1 . 5 to 9 . 0 . method # 1 to produce a sterile solution containing cisplatin and 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate this example is designed to detail one method to produce a sterile solution containing cisplatin and disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate . for the purpose of this example , cisplatin and cis - diammine dichloro platinum are used interchangeably . for the purpose of this example , &# 34 ; approximately &# 34 ; is defined to include a range of plus or minus 1 %. step 1 . u . s . p . grade of sodium chloride ( nacl ; purchased from vwr scientific ) is dissolved in sterile , injectable water to a final concentration of 0 . 9 % nacl by weight of water . a suitable amount of pure hydrochloric acid ( hcl , 99 . 999 %; purchased from aldrich chemical company ) is added to the sterile , injectable 0 . 9 % sodium chloride solution in order to obtain a final ph in the range of approximately 2 . 0 to 6 . 0 . step 2 . one part by weight of pure , cisplatin ( 99 . 999 %, purchased from aldrich chemical company ) is added to the admixture of step 1 . the cisplatin is allowed to completely dissolve by agitation ( 1500 - 2500 rpm ) at room temperature , for 60 to 90 minutes . step 3 . then , 15 parts by weight of disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( as produced above in example 1 ) is added the mixture of step 2 . this mixture is agitated until complete dissolution and the final ph is adjusted to a ph ranging between approximately ph 2 . 0 and ph 6 . 0 by adding pure hydrochloric acid ( 99 . 999 %, purchased from aldrich chemical company ). step 4 . the solution of step 3 is sterilized via filtration through a sterile 0 . 22 micron filter ( obtained from vwr scientific ). step 5 . the sterile solution of step 4 is stored in sterile injection amber vials wherein each vial contains approximately 0 . 9 mg of cisplatin and 14 . 3 mg of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate per ml of injection solution . method # 2 to produce a sterile solution containing cisplatin and 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate this example is designed to detail another method to produce a sterile solution containing cisplatin and disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate . for the purpose of this example , cisplatin and cis - diammine dichloro platinum are used interchangeably . for the purpose of this example , &# 34 ; approximately &# 34 ; is defined to include a range of plus minus 1 %. step 1 . u . s . p . grade of sodium chloride ( nacl ; purchased from vwr scientific ) is dissolved in sterile , injectable water to a final concentration of 0 . 9 % nacl by weight of water . step 2 . disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( as produced above in example 1 ; fifteen ( 15 ) parts by weight ) is added to the sterile , injectable 0 . 9 % nacl solution from step 1 . the 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate is allowed to completely dissolve by agitation ( 1500 - 2500 rpm ) at room temperature . this should take 5 - 10 minutes at room temperature . the ph of the 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate solution is adjusted to a ph ranging between approximately ph 2 . 0 and ph 6 . 0 by adding pure ( 99 . 999 % purity ) hydrochloric acid . step 3 . cisplatin ( 99 . 999 % purity ; purchased from aldrich chemical company ) is added ( 1 part by weight ) to the solution of step 2 . this mixture is agitated until complete dissolution and the final ph is adjusted to a ph ranging between approximately ph 2 . 0 and ph 6 . 0 by adding pure ( 99 . 999 % purity ) hydrochloric acid . step 4 . the solution of step 3 is sterilized via filtration through a sterile 0 . 22 micron filter ( obtained from vwr scientific ). step 5 . the sterile solution of step 4 is stored in sterile injection amber vials wherein each vial contains approximately 1 . 0 mg of cisplatin and 14 . 3 mg of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate per ml of injection solution . method # 3 to produce a sterile solution containing cisplatin and 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate this example is designed to detail another method to produce a sterile solution containing cisplatin and disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate . for the purpose of this example , cisplatin and cis - diammine dichloro platinum are used interchangeably . for the purpose of this example , &# 34 ; approximately &# 34 ; is defined to include a range of plus or minus 1 %. step 1 . a suitable amount of pure , disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( as produced in example 1 ) is dissolved in sterile , injectable water to a concentration of 15 . 0 mg / ml . step 2 . u . s . p . grade sodium chloride crystals ( nacl ; purchased from vwr scientific ) is added to the solution of step 1 such that the final concentration of nacl is 0 . 9 % by weight of water . step 3 . the ph of the 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate -- nacl solution of step 2 is adjusted to range between approximately ph 2 . 0 and ph 6 . 0 by the addition of pure ( 99 . 999 % purity ), hydrochloric acid ( purchased from aldrich chemical company ). step 4 . an amount of cisplatin ( 99 . 999 % purity ; purchased from aldrich chemical company ) is added to the solution of step 3 such that the final concentration is approximately 1 . 0 mg / ml cisplatin . step 5 . the solution of step 4 is sterilized via filtration through a sterile 0 . 22 micron filter . step 6 . the sterile solution of step 5 is store in sterile injection amber vials wherein each vial contains approximately 1 . 0 mg of cisplatin and 14 . 3 mg of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate per ml of injection solution . method # 4 to produce a sterile solution containing cisplatin and 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate this example is designed to detail another method to produce a sterile solution containing cisplatin and disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate . for the purpose of this example , cisplatin and cis - diammine dichloro platinum are used interchangeably . for the purpose of this example , &# 34 ; approximately &# 34 ; is defined to include a range of plus or minus 1 %. step 1 . u . s . p . grade sodium chloride ( nacl ; purchased from vwr scientific ) is dissolved in sterile , injectable water to a final concentration of 0 . 9 % nacl by weight of water . step 2 . the ph of this nacl solution is brought to approximately 2 . 0 to 6 . 0 by the addition of 99 . 999 % pure hydrochloric acid ( purchased from aldrich chemical company ). step 3 . suitable amount of cisplatin ( 99 . 999 % purity ; purchased from aldrich chemical company ) is added to the solution obtained in step 2 and allowed to dissolve completely by agitation ( 1500 - 2500 rpm ) for approximately 60 to 90 minutes at room temperature . step 4 . then , 30 parts by weight of disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( as produced in example 1 ) is added to the solution step 3 . the 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate - cisplatin mixture is allowed to completely dissolve with agitation at room temperature . step 5 . the ph of the disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate -- cisplatin solution is adjusted to a final ph ranging between approximately 2 . 0 and 6 . 0 by the addition of pure ( 99 . 999 % purity ) hydrochloric acid ( obtained from aldrich chemical company ). step 6 . the solution of step 5 is sterilized via filtration through a sterile 0 . 22 micron filter ( obtained from vwr scientific ) step 7 . the sterile solution of step 6 is stored in sterile injection amber vials wherein each vial contains 0 . 5 mg of cisplatin and 12 . 9 mg of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate per ml of injection solution . method # 5 to produce a sterile solution containing cisplatin and 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate this example is designed to detail another method to produce a sterile solution containing cisplatin and disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate . for the purpose of this example , cisplatin and cis - diammine dichloro platinum are used interchangeably . for the purpose of this example , &# 34 ; approximately &# 34 ; is defined to include a range of plus or minus 1 %. step 1 . u . s . p . grade sodium chloride ( nacl ; purchased from vwr scientific ) is dissolved in sterile , injectable water to a final concentration of 0 . 9 % nacl by weight of water . step 2 . an amount of pure ( 99 . 999 % purity ) hydrochloric acid ( obtained from aldrich chemical company ) is added to the nacl solution of step 1 in order to obtain a final ph in the range of approximately 2 . 0 to 6 . 0 . step 3 . an amount of u . s . p . grade potassium chloride crystals ( kcl ; purchased from vwr scientific ) is dissolved in the solution of step 2 ( 0 . 9 % nacl ) such that the final concentration of potassium chloride is 0 . 1 % by weight . step 4 . one part by weight of cisplatin ( 99 . 999 % purity ; purchased from aldrich chemical company ) is added to the solution of step 3 and is completely dissolved by agitation ( 1500 to 2500 rpm ) for approximately 60 to 90 minutes at room temperature . step 5 . thirty ( 30 ) parts by weight of disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( as produced by example 1 ) is added to the solution of step 4 . this mixture is agitated until complete dissolution and the final ph ranging between approximately ph 2 . 0 and ph 6 . 0 by adding pure ( 99 . 999 % purity ) hydrochloric acid ( purchased from aldrich chemical company ). step 6 . the solution of step 5 is sterilized via filtration through a sterile 0 . 22 micron filter ( obtained from vwr scientific ) step 7 . the sterile solution of step 6 is stored in sterile injection amber vials wherein each vial contains approximately 1 . 0 mg of cisplatin and 28 . 7 mg of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate per ml of injection solution . method # 6 to produce a sterile solution containing cisplatin and 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate this example is designed to detail another method to produce a sterile solution containing cisplatin and disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate . for the purpose of this example , cisplatin and cis - diammine dichloro platinum are used interchangeably . for the purpose of this example , &# 34 ; approximately &# 34 ; is defined to include a range of plus or minus 1 %. step 1 . u . s . p . grade sodium chloride ( nacl ; purchased from vwr scientific ) is dissolved in sterile , injectable water to a final concentration of 0 . 9 % nacl by weight of water . a suitable amount of pure ( 99 . 999 % purity ) hydrochloric acid is added to the sterile , injectable 0 . 9 % sodium chloride solution in order to obtain a final ph in the range of approximately 2 . 0 to 6 . 0 . step 2 . pure mannitol ( 99 +% purity , purchased from aldrich chemical company ) is dissolved in the solution of step 1 so that the concentration of mannitol is 1 . 0 % by weight . step 3 . one part by weight cisplatin ( purchased from aldrich chemical company , 99 . 999 % purity ) is added to the admixture of step 2 . the cisplatin is allowed to completely dissolve by agitation ( 1500 - 2500 rpm ) at room temperature ( approximately 60 to 90 minutes ). step 4 . then , 30 parts by weight of disodium 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate ( as produced in example 1 ) is added to the mixture of step 3 . this mixture is agitated until complete dissolution and the final ph is adjusted to a ph ranging between approximately ph 2 . 0 and ph 6 . 0 by adding pure ( 99 . 999 % purity ) hydrochloric acid ( purchased from aldrich chemical company ). step 5 . the solution of step 4 is sterilized via filtration through a 0 . 22 micron filter ( obtained from vwr scientific ). step 6 . the sterile solution of step 5 is stored in sterile injection amber vials wherein each vial contains approximately 0 . 5 mg of cisplatin and 12 . 9 mg of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate per ml of injection solution . this example is designed to study the stability of 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate and cisplatin formulations . 1 . first , 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate -- cisplatin formulations will be prepared according to examples 3 through 8 . 2 . the final ph of each formulation will be adjusted to a range of 2 . 0 to 6 . 0 . 3 . each ph adjusted 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate -- cisplatin formulation will be stored in a sealed glass vial protected from fluorescent light at room temperature ( approximately 27 + or - 2 degrees celsius .). 4 . the stability of each ph adjusted 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate -- cisplatin formulation will be analyzed on a weekly basis for at least 6 ( six ) months by nuclear magnetic resonance ( nmr ) analysis . the nmr spectra will be compared to a freshly prepared and ph adjusted 2 , 2 &# 39 ;- dithio - bis - ethane sulfonate -- cisplatin formulation . observing one peak corresponding to the freshly prepared formulation will denote stability of the ph adjusted formulation over time , as a function of ph . arrick , b . a ., et al ., glutathione metabolism as a determinant of therapeutic efficacy : a review . cancer res . 44 : 4224 , 1984 . andrews , p . a ., et al ., metallothionein - mediated cisplatin resistance in human ovarian carcinoma cells . cancer chemother . pharmacol ., 19 : 149 , 1987 . bajorin , d . f ., et al ., pharmacokinetics of cis - 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mercaptoethane sulfonate by high performance liquid chromatography using post - column reaction calorimetry or electrochemical detection , journal of chromatography , 311 , 234 - 238 , 1984 . symposium : cisplatin : contemporary treatment approaches . semin . oncol . 16 ( suppl . 6 ): 1 - 128 , 1989 . thompson , a . j ., the interactions of platinum compounds with biological molecules . rec . res . cancer res . 48 : 38 , 1974 . the foregoing description has been directed to particular embodiments of the invention in accordance with the requirements of the patent statues for the purposes of illustration and explanation . it will be apparent , however , to those skilled in this art , that many modifications , changes , and variations in the claimed solutions and methods set forth will be possible without departing from the scope and spirit of the claimed invention . it is intended that the following claims be interpreted to embrace all such modifications , variations , and changes .