WO2005102312A1 - Solutions concentrees d'oxaliplatine - Google Patents

Solutions concentrees d'oxaliplatine Download PDF

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Publication number
WO2005102312A1
WO2005102312A1 PCT/AU2005/000587 AU2005000587W WO2005102312A1 WO 2005102312 A1 WO2005102312 A1 WO 2005102312A1 AU 2005000587 W AU2005000587 W AU 2005000587W WO 2005102312 A1 WO2005102312 A1 WO 2005102312A1
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WO
WIPO (PCT)
Prior art keywords
oxaliplatin
formulation according
add
pharmaceutically acceptable
cyclodextrin
Prior art date
Application number
PCT/AU2005/000587
Other languages
English (en)
Inventor
Darryl Vanstone Whittaker
Aikun Julie Liu
Marisa Ciampini
Allan Harvey Spencer
Original Assignee
Mayne Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2004902190A external-priority patent/AU2004902190A0/en
Application filed by Mayne Pharma Limited filed Critical Mayne Pharma Limited
Publication of WO2005102312A1 publication Critical patent/WO2005102312A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to formulations containing oxaliplatin.
  • oxaliplatin as used herein includes mdividually ci ⁇ oxalato(trans-l-l,2-dia ⁇ r ⁇ mocyclohexane) plat tum ⁇ II), its optical enantiomer cLs ⁇ xalato(trans-d-l,2-diaminc ⁇ y ohexane) plat ram(II) or any racemic mixture thereof.
  • Oxaliplatin is currently approved and marketed for second-line treatment of colorectal cancer. Hospitals generally purchase oxaliplatin in a lyopt ⁇ lised form (20 mg, 50 g or 100 mg vials). Just prior to administration, the lyophilised powdef is reconstituted using water for injection or 5% glucose injection solution to provide a solution containing 5 mg/mL oxaliplatin. The reconstituted solution is then further diluted in 250-500 mL of 5% glucose injection solution. The diluted oxaliplatin solution is then in used either by peripheral vein or central venous line over 2 to 6 hours.
  • US 5,716,988 and AU 731981 disclose a pharmaceutical formulation consisting of a 1 to 5 mg/mL solution of oxaliplatin in water having a pH range of 4.5 to 6. According to this disclosure, oxaliplatin is not stable and soluble at concentrations greater than 5 mg/mL. An oxaliplatin in water solution at a concentration of 5 mg/mL was approved by the FDA in January 2005. 2.
  • WO 99/43355 and US 6,306,902 disclose an oxaliplatin solution formulation containing 1 to 7 mg/mL oxaliplatin, a buffering agent and a pharmaceutically acceptable carrier.
  • the buffering agent is defined to be any acidic or basic agent and the preferred buffering agent (and only example) is oxalic acid or an alkali metal salt thereof.
  • the patent also reports that the presence of die anionic buffering agents citrate, acetate, and phosphate, and additionally buffers comprising glycine and TRIS result in unacceptable degradation of oxaliplatin in aqueous solutions.
  • 3. WO 01/15691 discloses solutions of at least 7 mg/mL oxaliplatin containing a solvent containing a sufficient amount of at least one hydroxylated derivative selected from 1,2-propane-diol, glycerol, maltitol, sucrose and inositol. The specification states that these are the only suitable agents to use after consideration of several options. It also teaches that alternative solubilisers such as cyclodextrins are inappropriate in oxaliplatin solutions as they cannot achieve the desired solubility.
  • US 6,476,068 discloses an oxaliplatin solution forniulation comprising 0.1 to 10 mg/mL oxaliplatin, an effective stabilising amount of lactic acid and a pharmaceutically acceptable carrier.
  • fl c preferred range of oxaliplatin is 2 to 5 mg/mL
  • US Patent Application No.20030109515 discloses an oxaliplatin solution formulation containing a stabilising amount of malonic acid. The examples are directed to formulations having an oxaliplatin concentration of 2 mg/ml.
  • Issues associated with aqueous oxaliplatin solutions include: (1) solubility of the oxaliplatin; and (2) stability of the oxaliplatin.
  • Oxaliplatin is moderately soluble in water.
  • the maximum solubility of the oxaliplatin in water at 37°C is reported to be 7.9 mg/mL and at 20 ⁇ C is only 6.0 mg/mL As a consequence of this, aqueous solutions are about 5mg/ml in concentration to prevent any risk of formation of precipitates or crystalline matter.
  • the required dose volume of oxaliplatin is such that the storage and handling of a large number of bottles or soft bags may be required, thus preventing the convenient use of containers such as pre-filled syringes or multi-dose bottles.
  • the recommended dose of 130 mg/m 3 for an average person of 1.7 m 2 requires the use of at least 110 L of a 2 mg/mL solution.
  • Oxaliplatin is known to produce certain degradation products in aqueous solutions when other additives are present Ionic salts such as chloride, dtrate, acetate, phosphate and the additives glycine and TRJS, have all been reported to destabilise oxaliplatin in solution. Therefore, in any attempt to improve the solubility of oxaliplatin, care must be taken to ensure that the stability of the oxaliplatin in the solution is maintained so as to oid the formation of unwanted impurities such as diaqua oxaliplatin and diaqua oxaliplatin ditner.
  • Ionic salts such as chloride, dtrate, acetate, phosphate and the additives glycine and TRJS
  • cyclodextrins may be used as solubilising agents for improving the water solubility of certain poorly water soluble drugs.
  • Cyclodextrins are water-soluble cyclic sugar oligo ers (oligosaccharides) which differ from one another in the number of glucopyranose units.
  • the most readily available cyd ⁇ dextrins are composed of six, seven or eight al ⁇ ha-D-glucose units (c , ⁇ and ⁇ respectively).
  • the solubility of a drug may be increased by virtue of the inclusion of the drug in the relatively hydrophobic cavity of the cyclodextrin.
  • US 4696918 discloses that ⁇ - cyclodextrin can be used to solubilisc l,l- ⁇ ydobutanedica ⁇ boxylatedia-- ⁇ mineplatinu (H) (carboplatin).
  • H waterplatinu
  • cyclodextrins will improve the solubility of a particular drug.
  • WO 01 /15691 teaches that cyclodextrins are inappropriate as solub ⁇ isers of oxaliplatin. It is stated that certain cyclodextrins have allowed the concentration of oxaliplatin to be increased only very slightly.
  • cyclodextrins may affect the stability of the drug.
  • destabilisation may result when the included drug is conf ormati ⁇ nally constrained or when flic included drug Ls in close prox-mity to a substituent group on the cyclodextrin itself, which may lead to accelerated chemical degradation.
  • ⁇ -lactam antibiotics it has been reported that the stability of certain ⁇ -lactam antibiotics is adversely affected by cyclodextrin, and the drugs indomethacin, chlorpromazine, acetylsalicylic acid and prostaglandin El are also destabilised by cydc ⁇ 3ex-rins.
  • the degradants so formed may be new degradants that might not ordinarily result in the absence of the cyclodextrin. For this reason, one cannot readily predict the effect dissolved cyclodextrin will have on the stability of a drug in solution.
  • oxaliplatin is prone to destabilisation in solution when additives are present, one might expect destabi-isation to occur in the presence of cyclodextrin, particularly if the cyclodextrin is in an ionic salt form.
  • cyclc ⁇ kxtrins can increase the solubility of oxaliplatin in aqueous formulations to levels significantly greater than its intrinsic aqueous solubility without a significant decrease in stability, without the formation of significant amounts of new degradants, and without a significant increase in the viscosity of the formulations.
  • a pharmaceutical liquid formulation for parenteral administration comprising:
  • a pharmaceutical formulation according to the first aspect of the invention for the treatment of a cancer.
  • a pharmaceutical f rmulation according to the first aspect of the invention in the preparation of a medicament for the treatment of a cancer.
  • a method for treating a cancer which comprises aclministerlng a therapeutic amount of a pharmaceutical formulation according to the first aspect of the invention to the patient.
  • a method of preparing a pharmaceutical liquid formulation of oxaliplatin according to the first aspect comprising the steps of: (i) and oxaliplatin; and
  • a phaimaccutical composition for the preparation of a liquid formulation according to the first aspect comprising:
  • Figure 1 depicts solubility isotherms obtained for oxaliplatin in sdertcd cydodcxtrin solutions.
  • cyclodextrins of the present invention are appropriate for parenteral use and it has been found that even when high concentrations of the cydodcxtrin is present in solution, the viscosity of the oxaliplatin/ cycl ⁇ dextrin formulation is suffidently low for it to be suitable for 'parenteral administration,
  • a pharmaceutical liquid formulation for parenteral administration comprising:
  • the term "effective solubilising amount of cyclodextrin” means an amount of cyclodextrin which is suffident to improve the solubility of oxaliplatin in water.
  • the concentration of cydodextrin is at least 1% w/ .
  • the cyclodextrin is selected such that the solubility of the oxaliplatin is improved.
  • the quantity of oxaliplatin in a pharmaceutical formulation according to the present invention will dictate the quantity of cyclodextrin required.
  • the amount of oxaliplatin can range up to 15 mg/mL or higher provided that sufficient c clodexftrin is added.
  • the concentration of oxaliplatin is at least 7 mg/mL, more preferably at least 10 mg/mL, even more preferably at least 14 mg/mL.
  • the amount of oxaliplatin is in the range of from 9 mg/mL to 12 mg/mL, more preferably it is about 10 mg/mL.
  • the cydodextrin used may be an ⁇ -, ⁇ , or ⁇ -cyclodextrin and may be substituted or unsubstituted. More preferably, the cydodextrin is substituted. Even more preferably, the cydodextrin is a substituted derivative of ⁇ dodextrin selected from the group consisting of hydroxypropylatcd, methylated and sulphobutyl ether derivatives of ⁇ -cyclodextrin. Yet more preferably, the cydodextrin is a sulphobutyl ether substituted derivative of ⁇ - cyclodextrin.
  • the cyclodextrin is a pharmaceutically acceptable derivative.
  • the formulation is preferably pharmaceutically stable. It has been found that the oxaliplatin in formulations according to the invention displays a level of stability that is within he limits appropriate for a pharmaceutical which is administered parenterally. The established limits are exempli ied by international guidelines issuing from International Conference on Harmonisation (ICH). A person skilled in the art will know what are the accepted limits for oxaliplatin stability at the time of preparing the pharmaceutical formulation. The relationship between oxaliplatin solubility and cydodextrin concentration in the concentration ranges studied has been found to be approximately linear (see Figure 1).
  • the concentration of cyclodextrin required to solubilise the oxaliplatin will vary depending on the type of cydodextrin used and the concentration of oxaliplatin desired.
  • the amount of the sulfobutyl substituted ⁇ -cylcodex-rin required will typically be at or above 20% w/v.
  • the pH of the pharmaceutical formulation according to the invention is preferably the pH of the resulting oxaliplatin solution obtained following complete dissolution of the drug and the cydodextrin. Typically this is a pH in the range from 3 to 7.
  • the pH of the oxaliplatin formulation may be adjusted if necessary using known pharmaceutically- acceptable adds and bases which are compatible with oxaliplatin.
  • the present invention further provides a pharmaceutical liquid formulation for parenteral administration comprising:
  • an additive selected from the group consisting of a pharmaceutically acceptable acid, a pharmaceutically acceptable salt of a pharmaceutically acceptable acid, a pharmaceutically derivative of a pharmaceutically acceptable acid, and mixtures thereof.
  • the pharmaceutically acceptable add is an organic acid. More preferably, the acid is selected rom the group consisting of dtric add, maleic add, saccharic add, succinic acid, malic acid and mixtures thereof.
  • the pharmaceutically acceptable add is a dicarboxylic acid. More preferably, the acid is selected rom the group consisting of maleic add, saccharic add, succinic add, malic acid, tartaric add and mixtures thereof.
  • the pharmaceutically acceptable acid is selected from a dicarboxylic add of the formula H02CtC(Rl)(R2)InC02H wherein n « 2 to 6; and Rl and R2 are each independently selected from the group consisting of hydrogen, hydroxy, halo and methyl.
  • the pharmaceutically acceptable add is selected from the group consisting of dtric add, maleic add, saccharic acid, sucdnic acid, malic acid and mixtures thereof.
  • the add is selected from, the group consisting of tartaric add, succinic acid and malic acid. Most preferably, the add is tartaric add.
  • the total concentration of the additive is from 0.01 mM to 2mM, more preferably from 0-lmM to ImM, even more preferably from O.l M to 0.6mM, and most preferably from 0.2mMto 0.6mM.
  • the additive is a salt it is preferably a sodium salt :
  • Pharmaceutically acceptable derivatives of carboxylic acids indiide but are not limited to such derivatives as esters, amides, carbonates and carbamates of the acid.
  • the pH of the formulation may be buffered by the use of a mixture of an add and its conjugate base which is typ aily, in the case of an organic acid, the salt of the add, Accordingly, the present invention further provides a pharmaceutical liquid formulation for parenteral administration comprising
  • the attainment of concentrated solutions of oxaliplatin makes it possible to produce low volume oxaliplatin parenteral products which are more convenient and safer to handle than the conventional products.
  • the reduced product volume further improves safety in handling since the volumes to be transferred from container to infusion bag become smaller. Syringing is easier and more convenient and this, in turn, reduces the likelihood of accidental spillage or dilution error.
  • the pharmaceutical formulation of the invention is provided in a sterile, sealed container.
  • a neutral glass of type 1 and a stopper examples include those made of an elastomer based on halogenated butyls, possibly coated with a fluorinatcd polymer.
  • a pharmaceutical formulation according to the first aspect of the invention for the treatment of a cancer.
  • a pharmaceutical formulation according to the first aspect of the invention in the preparation of a medicament for the treatment of a cancer.
  • a method for treating a cancer which comprises administering a therapeutic amount of a pharmaceutical rmulation according to the first aspect of the invention to a patient in need thereof.
  • treating as used herein, unless otherwise indicated r means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • the therapeutic amount of the pharmaceutical formulation to be administered to a patient will typically provide an effective dosage of oxaliplatin which ranges from about 10 mg/m 2 to about 250 mg/m 2 , more preferably from about 30 mg/m 2 to about 180 mg/m 2 and most preferably is about 85 mg/m 1 .
  • the therapeutic dosage administered will be determined by the physi ⁇ an in the light of the relevant ci-xurnstances including the severity of the condition to be treated and the chosen route of administration. Therefore, the above dosage ranges are not intended to limit the scope of the invention in any way.
  • Administration of oxaliplatin will typically be according to best practice known to those skilled in the art at the time of administration.
  • a method of preparing a pharmaceutical liquid formulation of oxaliplatin comprising the steps of. (i) preparing an aqueous solution of a cydodextrin and oxaliplatin; and
  • step (i) optionally, adjusting the pH of the solution.
  • step (i) comprises the steps of:
  • the oxaliplatin is added as a solid and dissolved in the aqueous solution.
  • the solution is made up to a desired final volume or weight with the addition of water for injection.
  • composition for the preparation of liquid formulation according to the first aspect, the composition comprising;
  • the pharmaceutical composition is in a lyc ⁇ hilised form.
  • lyophilised compositions are well known to those skilled in the art. This will enable the composition to be re-constituted by the addition of a suitable diluent and may confer added stability benefits. It is well known In the art that a lyophilised form will often need a bulking agent. Tn order that the nature of the present invention may be more clearly understood, preferred forms thereof will now be described with reference to the following non-limiting examples.
  • SBECD sulphobutyl ether substituted cyclodextrin
  • Captisol® A 40% w/v solution of Captisol® was prepared and then serially diluted to 20% w/v, 10% w/v, 5% w/v and 23% w/v.
  • Excess oxaliplatin was added to a series of 2 mL clear glass vials and about 1 mL of the respective Captisol solutions were added to each vial.
  • the vials ere capped and sealed.
  • the sealed vials were placed on a tumbling roller mixer. Solutions were continuously mixed at room temperature for 48 hours.
  • the resulting suspensions were filtered through 0-45 ⁇ m nylon syringe filters.
  • the filtrates were diluted and analysed for oxaliplatin content by HFLC.
  • the solubility of oxaliplatin in water at room temperature was determined to be 6.45 mg/mL.
  • the solubility of oxaliplatin exceeded 10 mg/mL when the sulfobutyl derivative (Captisol®) concentration was 20 % w/v.
  • the solubility of oxaliplatin was increased with addition of the sulfobutyl substituted cyclcdextrin Captisol to the solution.
  • An oxaliplatin solubility of approximately 15 mg/mL was achieved using a cydodextrin concentration of 40% w/v.
  • Aqueous solutions containing different concentrations of Cavitron solutions were prepared by dissolving known quantities of Cavitron 82003 or 82004 in 1 mL of WFI in 2 mL dear glass vials. Oxaliplatin in excess was added to each vial The vials were capped and sealed, and placed on a tumbling roller mixer. Solutions were mixed at room temperature for 24. hours. . The resulting suspensions were filtered through 0.45 ⁇ m nylo syringe filters. The filtrates were diluted and analysed for oxaliplatin content by TTPLC. The solubility results are shown in Tables 2 and 3. The solubility data obtained with these two grades of hydroxypropyl- ⁇ -cyclodextrin are shown in Figure 1.
  • Cavitron 82003 proved to be more effective in increasing the solubility of oxaliplatin than Cavitron 82004.
  • the oxaliplatin solubility increased to values above 10 mg/mL with 20% (w/v) concentrations of Cavitron 82003 (Table 2), whereas the solubility was 9.30 mg/mL for the same concentration of Cavitron 82004 (Table 3).
  • Table 2 :
  • the oxaliplatin solubility was increased from 6.0 mg/mL to 12.0 mg/mL with the use of Cavitron 82003 at a concentration of 40% (w/v).
  • the solubility isotherms obtained for oxaliplatin for the Cavitron 82003 and Cavitron 82004 solutions are shown in Figure 1.
  • Cavasol W7 M Pharma® is a statistically methylated ⁇ -cyclodextrin derivative variably substituted on the 2-, 3- and 6- positions with a degree of substitution ranging from 11.2 to 133.
  • Known degradation products of oxaliplatin include:
  • This degradation product has been designated as Impurity B in this study (SP ⁇ 2)-di- ⁇ -oxobis[(lR ⁇ )-cycl ⁇ hexane-l,2 ' dia ⁇ nine- N,]d ⁇ , ]platinum, or diaqua DACH platinum dimer. This is a degradation produd resulting from further reaction of Impurity B. This degradation product has been designated as Dimer in this study.
  • Table 6 shows the 10 mg/ml oxaliplatin solutions formulated using two different cyclodextrins, (1) Captisol, a sulfobutyl ether ⁇ cyclodextrin (SBECD), and (2) Cavitron 82003, a hydroxypropyl - -cyclodextrin (HPBCD) with an average degree of substitution of 4 .
  • Captisol a sulfobutyl ether ⁇ cyclodextrin
  • HPBCD hydroxypropyl - -cyclodextrin
  • the oxaliplatin solutions were placed under accelerated conditions for six months.
  • the following parameters were tested or the oxaliplatin formulation to determine the stability of oxahplatin fo ⁇ nulations: pH Potency Platinum (TV) complex (impurity C) Dimer; and Diaqua (DACH) platinum (II) complex (impurity B)
  • the test results for oxaliplatin formulations that contain cyclodextrins at temperatures of 8°C, 25 C and 40 C at the six month time point are shown in Table 7, 8 and 9-
  • the formulations are compared with a control formulation containing 5mg/ml of oxaliplatin in Water for injection (WFI).
  • the formulations were prepared by dissolving Captisol in water for injection (WFI) at 45- 50°C, then dissolving the oxaliplatin in the solution. Tartaric acid was then added and, where necessary, the pH of the solution was adjusted to the desired level by the addition of NaOH. The solution was adjusted to the final volume or weight by the addition of WFI.
  • WFI water for injection

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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne une composition pharmaceutique liquide, destinée à l'administration parentale, qui comprend (a) plus de 5 mg/mL d'oxaliplatine; (b) de l'eau; et (c) au moins une quantité de solubilisation de cyclodextrine. L'invention concerne également l'utilisation d'une formulation pharmaceutique dans le traitement du cancer et un procédé pour traiter le cancer chez un patient qui consiste à administrer une quantité thérapeutique d'une formulation pharmaceutique. L'invention concerne également un procédé de préparation d'une formulation pharmaceutique liquide à base d'oxaliplatine.
PCT/AU2005/000587 2004-04-27 2005-04-27 Solutions concentrees d'oxaliplatine WO2005102312A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AU2004902190 2004-04-27
AU2004902190A AU2004902190A0 (en) 2004-04-27 Pharmaceutical Formulation
AU2004904892 2004-08-27
AU2004904892A AU2004904892A0 (en) 2004-08-27 Concentrated oxaliplatin solutions

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WO2005102312A1 true WO2005102312A1 (fr) 2005-11-03

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ300120B6 (cs) * 2006-06-20 2009-02-11 Pliva - Lachema A. S. Farmaceutická kompozice pro injekcní podání
WO2009033204A1 (fr) * 2007-09-12 2009-03-19 University Of Wollongong Compositions à multiples composants et procédés d'administration d'agents anticancereux
WO2009153704A1 (fr) * 2008-06-16 2009-12-23 Debiopharm S.A. Solution concentrée d'oxaliplatine et son procédé de préparation
CN104922688A (zh) * 2015-02-10 2015-09-23 昆明贵研药业有限公司 奥沙利铂的环糊精复合物及制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4696918A (en) * 1984-11-02 1987-09-29 Johnson Matthey Public Limited Company Solubilized platinum compound
WO1999043355A2 (fr) * 1998-02-25 1999-09-02 Sanofi-Synthelabo Formulations
WO1999061450A1 (fr) * 1998-05-27 1999-12-02 Pliva-Lachema A.S. Complexe de platine, sa preparation et sa mise en application therapeutique
US20030224037A1 (en) * 2002-06-03 2003-12-04 Mebiopharm Co., Ltd. Liposome preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4696918A (en) * 1984-11-02 1987-09-29 Johnson Matthey Public Limited Company Solubilized platinum compound
WO1999043355A2 (fr) * 1998-02-25 1999-09-02 Sanofi-Synthelabo Formulations
WO1999061450A1 (fr) * 1998-05-27 1999-12-02 Pliva-Lachema A.S. Complexe de platine, sa preparation et sa mise en application therapeutique
US20030224037A1 (en) * 2002-06-03 2003-12-04 Mebiopharm Co., Ltd. Liposome preparation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ300120B6 (cs) * 2006-06-20 2009-02-11 Pliva - Lachema A. S. Farmaceutická kompozice pro injekcní podání
WO2009033204A1 (fr) * 2007-09-12 2009-03-19 University Of Wollongong Compositions à multiples composants et procédés d'administration d'agents anticancereux
WO2009153704A1 (fr) * 2008-06-16 2009-12-23 Debiopharm S.A. Solution concentrée d'oxaliplatine et son procédé de préparation
US20110144202A1 (en) * 2008-06-16 2011-06-16 Uwe Marx Concentrated oxaliplatin solution and its method of preparation
JP2011524414A (ja) * 2008-06-16 2011-09-01 デビオファーム ソシエテ アノニム 濃縮オキサリプラチン溶液及びその調製方法
CN104922688A (zh) * 2015-02-10 2015-09-23 昆明贵研药业有限公司 奥沙利铂的环糊精复合物及制备方法

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