Platinum (II) complexes have found wide acceptance for treatment of variety of tumors, especially Lung cancer, Lymphoma, Ovarian cancer, Testicular cancer, Bladder cancer, Urothelial cancer and Head/neck cancer in both humans and animals. Of these platinum analogues, oxaliplatin (U.S. Pat. No. 4,169,846), also known as L-OHP, a third generation platinum complex containing diamino cyclohexane carrier ligand, is approved for the treatment of advanced carcinoma of the colon or rectum in combination with infusional 5-FU/LV.
Currently, the marketed formulations of oxaliplatin are available as a lyophilized or freeze dried powder, which just prior to administration are reconstituted using an aqueous solvent, preferably water for injection, and administration of the solution thus obtained subsequent to dilution with dextrose solutions.
However, the lyophilized oxaliplatin formulation is associated with several disadvantages such as:                a) Double handling: To administer a lyophilized preparation, double handling of the drug is required. The lyophilized cake has to be first reconstituted and then administered;        b) Dissolution time of the cake: In some cases, the complete dissolution of the powder may require prolonged shaking because of solubilisation problems;        c) Health Hazard: Improper reconstitution of a lyophilized powder sometimes result in the formation of air-borne droplets (“blow-back”), which, in the case of a potent antitumor agent such as platinum complexes may be a health hazard to the personnel making up the solution for injection;        d) Improper dose: There is always a problem in reconstituting a lyophilized powder in that an inappropriate quantity of diluents may be used because of a different vial size. This could result in an improper dose being administered to a patient; and        e) Cost of manufacture: The manufacture of a lyophilized formulation is quite costly, since it not only requires capital investment for installation of a lyophilizer, but also its maintenance.        
Generally, the stability of the reconstituted solution is not a major issue, since such solutions need to be administered immediately or within a prescribed time, generally not exceeding 8 hrs. However, Oxaliplatin is an exception since, following reconstitutions, oxaliplatin is prone to instability, particularly in solutions containing certain nucleophilic agents. For example, some reconstitution solutions containing chloride ions, such as 0.9% sodium chloride solutions, also known as normal saline solutions, which is very commonly used in hospitals, if used for such a reconstitution of oxaliplatin lyophilized powder, has the serious consequence of rapidly decomposing the oxaliplatin metal complex, forming a precipitate (dichloro-diaminocyclohexane-platinum complex).
As a consequence of the abovementioned limitations, several ready-to-use, aqueous pharmaceutical compositions of oxaliplatin have been proposed:                a) In U.S. Pat. No. 5,716,988, Ibrahim et al disclose a pharmaceutically stable oxaliplatin preparation for parenteral administration comprising an aqueous solution of oxaliplatin, in a concentration of 1 to 5 mg/ml, and with a pH in the range of 4.5 to 6. The specification states that this preparation is free of any other components and should, in principle, not contain more than about 2% of impurities. However, subsequently, U.S. Pat. No. 6,306,902 and U.S. Pat. No. 6,476,068 report that the simple aqueous solutions of oxaliplatin prepared according the teachings of this particular patent are insufficiently stable.        b) In U.S. Pat. No. 6,306,902, Anderson et al disclose a stable oxaliplatin solution formulation comprising therapeutically effective amount of oxaliplatin, an effective stabilizing amount of a buffering agent and a pharmaceutically acceptable carrier wherein the buffering agent is oxalic acid or an alkali metal salt thereof.        c) In U.S. Pat. No. 6,476,068, Lauria et al disclose a stable oxaliplatin solution formulation comprising oxaliplatin, and effective stabilizing amount of lactic acid and/or a pharmaceutically acceptable salt of lactic acid and a pharmaceutically acceptable carrier.        d) In WO 01/15691, Ibrahim et al disclose pharmaceutically stable solutions of at least 7-mg/ml oxaliplatin containing a sufficient amount of a solvent having at least a hydroxylated derivative selected from 1,2-propane-diol, glycerol, maltitol, saccharose and inositol. The specification states that these are the only suitable agents and the limited choice of hydroxylated derivatives to use has been done following a very large number of experiments and after consideration of several options.        e) In U.S. Ser. No. 03/0,109,515, Lauria et al disclose a stable oxaliplatin solution formulation comprising oxaliplatin, and effective stabilizing amount of malonic acid and/or a pharmaceutically acceptable salt of malonic acid and a pharmaceutically acceptable carrier.        f) In EP 1466599, Schridde et al disclose a infusion-concentrate containing oxaliplatin and a physiologically compatible carbohydrate as solubility enhancer.        
The specification states that, with higher concentrations of carbohydrates, the formation of the degradation or the reaction products of oxaliplatin caused by the presence of hydroxide anions is drastically reduced or suppressed. Further, since these solutions containing carbohydrates are suitable for solublising the oxaliplatin, the concentration of carbohydrates, preferably glucose, should be at least 50 mg/ml.                g) In EP 1466600, Schridde et al disclose an oxaliplatin solution, which preferably in addition contain sulfuric acid, phosphoric acid, ethane sulfonic acid, or paratoluosofonic acid.        h) In U.S. Ser. No. 05/0,090,544, Whittaker et al disclose a pharmaceutical liquid formulation of oxaliplatin for parenteral administration comprising oxaliplatin, water and an additive selected from the group consisting of tartaric acid, a salt of tartaric acid, a pharmaceutically acceptable derivative of tartaric acid and mixtures thereof.        
From the abovementioned disclosures, it would be apparent that most, if not all the methods for stabilization of oxaliplatin solutions involve utilization of buffering agents to adjust the pH of the formulation and to maintain the formulation within a desired pH range. As mentioned above, several dicarboxylic acids such as oxalic acid, lactic acid, malonic acid, tartaric acid, several monocarboxylic acid such as sulfuric acid, phosphoric acid, ethane sulfonic acid, or para-toluenesulfonic acid and their pharmaceutically acceptable salts have been proposed as a buffering and stabilizing agent for oxaliplatin. However, most of these auxiliary substances have several disadvantages, which limits their use in pharmaceutical products. For example utilization of oxalic acid or its salt, which because of Le Chatelier's principle reduces the formation of oxalate ion, generated by hydrolysis of oxaliplatin in aqueous solution, has notable nephrotoxicity. Further, in the intravenous therapy, higher concentrations of oxaliplatin or oxalate ion pose the risk of local and systemic side effects such as local pain, aggregation of thrombocytes, thrombosis, kidney stones etc. making, in general, the addition of oxalate ions in injection non-desirable, a plausible reason why oxalic acid or for that matter malonic acid utilized as additives in U.S. Pat. No. 6,306,902 and U.S. Ser. No. 03/0,109,515 are not approved by the USFDA for inclusion into a parenteral composition.
Moreover, for selection of an appropriate auxiliary substance to achieve stabilization, there is neither any general guideline nor can an inference be drawn from the teachings of the abovementioned specification. For e.g. U.S. Pat. No. 6,306,902 discloses that, except oxalic acid, utilization of other buffering agents such as acetate, citrate, phosphate, glycine or tris buffer does not stabilize the aqueous solution of oxaliplatin. U.S. Pat. No. 6,476,068 also supports and suggests that acetate and citrate buffers are not suitable for oxaliplatin solutions. However, exactly opposite is the teaching of EP 1,466,600, which states that phosphoric, sulfuric and other acids could be utilized for preparing a stable oxaliplatin solution.
Another approach utilized in stabilizing the oxaliplatin solution is through enhancing the solubility of oxaliplatin as disclosed in WO 01/15691, by adding 1,2-propane diol, glycerin, maltitol, saccharose, or inositol or as disclosed in EP 1,466,599 by adding a physiologically compatible carbohydrate in at least 50 mg/ml concentrations. However, all these additives have immense disadvantages when used at the specified concentrations for preparation of injectable medicinal solutions. All of these carbohydrates are most easily available sources of energy, which can lead unbalancing of metabolism, especially owing to widely spread diabetes mellitus in the therapy of oxaliplatin caused by age. Moreover, inositol and glucose are physiologically important intracellular sugars and their salts are essential components of signal transduction cascade. Inositol is also administered orally and intravenously in experimental therapy as maturing promoter in pre-mature babies. Further it also has unwanted potential of neurological side effects.
Further, it might be mentioned that other hydroxylated derivatives as disclosed in WO 01/15691 do not belong to the standard auxiliary substances with known side effects, which are used for preparing the parenteral solutions. These compounds are normally used only in pharmaceutical preparations as auxiliary substances for external or oral use and are not recommended by Health Authorities worldwide or the parenteral use.
It might be further mentioned that Health Authorities all over the world are very concerned about the level of degradation products and impurities present in a drug substance or a drug product. As a consequence, regulatory approval norms today are very stringent about the level of impurities present in a drug substance or a drug product. In view of this, it is rather intriguing how an oxaliplatin solution containing more often than not amounts of additives in such a higher percentage as suggested by the prior teachings could comply with pharmacopoeial specifications, even though such solutions may be stable.
From the foregoing, it would be apparent that there is no universal method or system for stabilization of an oxaliplatin solution, which is simple, convenient, economical and is not dependent on the vagaries of critical parameters like pH, amount and nature of additives, specially requisite mono carboxylic acid or dicarboxylic acid, or nature of hydroxylated solvents etc.
A need, therefore, exists for a pharmaceutical composition of oxaliplatin which is universal, simple, convenient, and is not dependent on the vagaries of critical parameters like pH, nature and amount of additives specially requisite monocarboxylic acid or dicarboxylic acid, nature of hydroxylated solvents etc.
The present invention is a step forward in this direction and overcomes most, if not all the limitations of the prior art methods in providing a novel and simple method for stabilization of oxaliplatin solutions.
USPTO Backgrounds
USPTO Backgrounds