Parenteral Formulations of Carboplatin

Abstract

The present invention provides a parenteral dosage form having an infusion container, the infusion container being filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml to 2 mg / ml of carboplatin, wherein the solution contains a known impurity 1,1-cyclobutanedicarboxylic acid in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

Description

Technical Field

[0001] The present invention relates to a storage-stable aqueous solution of carboplatin and a parenteral dosage form containing the same. Background Art

[0002] Carboplatin is a platinum coordination compound with the chemical name [1,1-cyclobutanedicarboxy(2-)-0,0']diamine. It is available from Bristol-Myers Squibb in the form of a lyophilized powder and a preconcentrated aqueous solution (10 mg / ml) under the trade name Commercially available.

[0003] From numerous references and from The package insert of the invention states that the reconstituted carboplatin solution is only stable for 8 hours. In fact, Cheung YW et al. Am J Hosp Pharm. 1987 Jan; 44(1): 124-30; Swell GJ et al. J Clin Pharm Ther. 1987 Dec; 12(6): 427-32; R. Gust and B. Schnurr: Monatshefte fu rChemie 1999;130:637-44; All of these references report that reconstituted carboplatin solutions are highly unstable. Myres et al., in a publication in Journal of Oncology Pharmacy Practice, February 2016;22(1):31-6, reported that reconstituted or diluted aqueous solutions of carboplatin were only stable for seven days despite storage of the reconstituted solution under special storage conditions (such as refrigeration in the dark or exposure to fluorescent light at room temperature). The determination of carboplatin was significantly reduced. It was further reported that carboplatin decomposes to form highly toxic compounds such as di-p-hydroxybis(cis-diammineplatinum(II)) and tri-p-hydroxytris(cis-diammineplatinum(II)), which appear as black silver deposits when stored in glass containers.

[0004] Furthermore, despite numerous attempts and suggestions in the art to prepare storage-stable solutions of carboplatin, commercial carboplatin solutions have been recalled from the market due to reports of the presence of particulate matter. For example, Novartis' marketing partner Ebewe Pharma announced in a press release on March 29, 2012, a recall of an aqueous solution of carboplatin (10 mg / ml) in Hong Kong due to the presence of precipitates in several batches. Similarly, in a press release on April 27, 2015, the Indiana State Department of Health notified local health departments of a recall of an injectable product manufactured by Mylan Pharma - Carboplatin 10 mg / ml 100 ml vial due to the presence of visible foreign particulate matter.

[0005] Therefore, there is an urgent need to provide a storage-stable carboplatin injection solution suitable for direct infusion, which does not have many stability-related problems of carboplatin.

[0006] The present invention does achieve this objective and provides a parenteral dosage form comprising a stable storage aqueous solution of carboplatin stored in an infusion container. Summary of the invention

[0007] The present invention provides a parenteral dosage form having an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml to 2 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate and optionally a dissolved oxygen content ranging from about 5 ppm to 50 ppm.

[0008] The present invention can be summarized as follows:

[0009] A. A parenteral dosage form having an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml to 2 mg / ml of carboplatin, wherein the solution contains a known impurity, 1,1-cyclobutanedicarboxylic acid, in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

[0010] B. A parenteral dosage form as described in A, wherein the solution comprises 1 mg / ml carboplatin, a stabilizing amount of ammonium sulfate, and optionally a dissolved oxygen content in the range of about 5 ppm to 50 ppm.

[0011] C. A parenteral dosage form as described in B, wherein the stabilizing amount of ammonium sulfate is 0.2 mg / ml to 2.0 mg / ml, and the dissolved oxygen content is in the range of about 5 ppm to 10 ppm.

[0012] D. A parenteral dosage form as described in B, wherein the stabilizing amount of ammonium sulfate is 0.02 mg / ml or more, and the dissolved oxygen content is in the range of about 10 ppm to 50 ppm.

[0013] E. A parenteral dosage form as described in C or D, wherein the volume of the aqueous solution is 50 ml.

[0014] F. A parenteral dosage form as described in A or B, wherein the aqueous solution does not contain dextrose.

[0015] G. A parenteral dosage form as described in A, wherein the solution comprises 2 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content in the range of about 5 ppm to 50 ppm.

[0016] H. A parenteral dosage form as described in G, wherein the stabilizing amount of ammonium sulfate is 0.02 mg / ml or more and the dissolved oxygen content is in the range of about 10 ppm to about 50 ppm.

[0017] I. A parenteral dosage form as described in G, wherein the stabilizing amount of ammonium sulfate is 0.5 mg / ml to 2.0 mg / ml, and the dissolved oxygen content is in the range of about 5 ppm to about 10 ppm.

[0018] J. A parenteral dosage form as described in claim H or I, wherein the volume of the aqueous solution is 50 ml. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Shown are the physical appearances (black precipitate) of solutions according to Comparative Examples 1A, 1B, 1C, 1D having a concentration of 1 mg / ml when subjected to extreme stress conditions of autoclaving at 121° C. for 7 minutes.

[0020] Figure 2 Shown is the physical appearance of solutions according to working examples IE, IF, IG, 1H having a concentration of 1 mg / ml when subjected to extreme stress conditions of autoclaving at 121°C for 7 minutes (clear solution).

[0021] Figure 3 Shown are the physical appearances (black precipitates) of solutions according to Comparative Examples 2A to 2G having a concentration of 2 mg / ml when subjected to extreme stress conditions of autoclaving at 121° C. for 7 minutes.

[0022] Figure 4 Shown is the physical appearance of solutions according to working examples 2H to 2L having a concentration of 2 mg / ml when subjected to extreme stress conditions of autoclaving at 121° C. for 7 minutes (clear solution). DETAILED DESCRIPTION

[0023] The instability of carboplatin has been a major hindrance. In order to obtain a storage stable aqueous solution of carboplatin without any instability issues such as the appearance of particulate matter during long term storage, the inventors determined to subject the test to extreme stress conditions of autoclaving. It is assumed that once the solution passes this test, the parenteral dosage form will be physically and chemically stable when stored at ambient storage conditions such as room temperature throughout the shelf life of the product.

[0024] As used herein, the term "extreme stress conditions" refers to subjecting a parenteral dosage form to autoclaving at 121°C for 7 minutes. For testing, a parenteral dosage form was prepared and wrapped in a second aluminum pouch and then autoclaved at 121°C for 7 minutes. The autoclaved filled infusion container was visually observed for any discoloration, precipitation, or crystal formation. The presence of any or all of them indicates instability. It was found that a parenteral dosage form that maintained autoclaving at 121°C for 7 minutes without any precipitation was stable and was therefore considered stable for storage at room temperature for two years.

[0025] As used herein, the term "stabilizing amount of ammonium sulfate" refers to the amount of ammonium sulfate required to stabilize an aqueous solution of carboplatin stored in a parenteral dosage form having an infusion container when subjected to extreme stress conditions.

[0026] As used herein, the term "physically stable" refers to a parenteral dosage form comprising an aqueous solution of carboplatin that shows no signs of precipitation or crystal formation or discoloration when autoclaved at 121°C for 7 minutes. A parenteral dosage form that sustains autoclaving at 121°C for 7 minutes without any precipitation is found to be stable and is therefore considered to be stable for storage at room temperature for two years.

[0027] As used herein, the term "chemically stable" means that the aqueous solution of carboplatin exhibits acceptable levels of known and unknown impurities over the shelf life of the product, particularly when stored at room temperature for at least two years. According to a preferred embodiment, the content of the known impurity 1,1-cyclobutanedicarboxylic acid does not exceed 1.0% by weight of carboplatin when stored at room temperature for two years.

[0028] According to one embodiment, the parenteral dosage form comprises a storage-stable aqueous solution of carboplatin, the aqueous solution comprising carboplatin at a concentration in the range of about 1 mg / ml to 2 mg / ml. According to another embodiment, the aqueous solution of carboplatin is physically stable when subjected to the extreme conditions of autoclaving at 121°C for 7 minutes, i.e., the aqueous solution shows no signs of precipitation or crystallization or discoloration. According to another embodiment, the aqueous solution is physically and chemically stable throughout the shelf life. The parenteral dosage form that sustains autoclaving at 121°C for 7 minutes without any precipitation or crystallization or discoloration is stable for at least two years when stored at room temperature.

[0029] The present invention provides a parenteral dosage form having an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml to 2 mg / ml of carboplatin, wherein the solution contains a known impurity 1,1-cyclobutanedicarboxylic acid in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature for a period of about two years.

[0030] In a preferred aspect, the present invention provides a parenteral dosage form having an infusion container filled with an aqueous solution having a volume in the range of 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate, and optionally a dissolved oxygen content in the range of about 5 ppm to 50 ppm. Preferably, in one embodiment, the stabilizing amount of ammonium sulfate is 0.02 mg / ml-2.0 mg / ml, and the dissolved oxygen content is in the range of about 10 ppm-50 ppm, and the volume of the aqueous solution is 50 ml. Preferably, in another embodiment, the stabilizing amount of ammonium sulfate is 0.5 mg / ml-2.0 mg / ml, and the dissolved oxygen content is in the range of about 5 ppm-10 ppm, and the volume of the aqueous solution is 50 ml.

[0031] In another preferred aspect, the present invention provides a parenteral dosage form having an infusion container filled with an aqueous solution having a volume in the range of 40 ml to 500 ml, the aqueous solution comprising 2 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content in the range of about 5 ppm-50 ppm. Preferably, in one embodiment, the stabilizing amount of ammonium sulfate is 0.02 mg / ml-2.0 mg / ml, and the dissolved oxygen content is in the range of about 10 ppm-50 ppm, and the volume of the aqueous solution is 50 ml. Preferably, in another embodiment, the stabilizing amount of ammonium sulfate is 0.2 mg / ml-2.0 mg / ml, and the dissolved oxygen content is in the range of about 5 ppm-10 ppm, and the volume of the aqueous solution is 50 ml.

[0032] The parenteral dosage form of carboplatin according to the present invention is "ready for infusion" or "ready for administration", meaning that an aqueous solution of carboplatin is contained in an infusion container at a concentration of 1 mg / ml to 2 mg / ml, and meaning that the solution is directly infused or directly administered to a patient without the need for any reconstitution, dilution, manipulation, transfer, treatment or formulation prior to intravenous parenteral administration of the drug solution.

[0033] It can be noted that the aqueous solution of carboplatin with a stable amount of ammonium sulfate is required to be free of dextrose and chloride salts such as sodium chloride, potassium chloride or any other chloride. It is important that the solution does not contain dextrose or sodium chloride, otherwise the solution is found to produce a black precipitate and very high levels of impurities 1,1-cyclobutanedicarboxylic acid and total impurities. In addition, the inventors have found that the stable amount of ammonium sulfate depends not only on the concentration of carboplatin, but also on the content of dissolved oxygen in the solution and the percentage of oxygen in the head space of the filling container. For example, when the concentration of carboplatin is 1 mg / ml, it is found that 0.02 mg / ml or more of ammonium sulfate stabilizes the solution, but in a lower range, the dissolved oxygen content in the aqueous solution is required to be about 10 ppm to 50 ppm, and when a higher concentration such as 0.2 mg / ml to 2 mg / ml of ammonium sulfate is used, the dissolved oxygen content is not required to be in the range of about 10 ppm to 50 ppm, and the dissolved oxygen content can be as low as 5 ppm to about 10 ppm. The oxygen level present in the solution is in the range of about 5 ppm to 10 ppm. On the other hand, when the concentration of carboplatin was 2 mg / ml, it was found that 0.02 mg / ml or more of ammonium sulfate stabilized the solution, however, a dissolved oxygen content of 10 ppm to 50 ppm was required in the aqueous solution. When the solution was not purged with oxygen, i.e., the amount of oxygen in the solution was about 5 ppm to about 10 ppm, it was found that 0.5 mg / ml to 2 mg / ml of ammonium sulfate was required for stabilization.

[0034] It has been found that aqueous solutions having a dissolved oxygen content of about 10 ppm to 50 ppm, preferably 11 ppm to 50 ppm, are useful in concentrations of 0.02 mg / ml or more, preferably 0.02 mg / ml to 2.0 mg / ml, such as, for example, 0.02 mg / ml, 0.04 mg / ml, 0.06 mg / ml, 0.08 mg / ml, 0.10 mg / ml, 0.15 mg / ml, 0.20 mg / ml, 0.25 mg / ml, 0.30 mg / ml, 0.35 mg / ml, 0.40 mg / ml, 0.45 mg / ml, 0.50 mg / ml, 0.55 mg / ml, 0.60 mg / ml, 0.65 mg / ml, 0.70 mg / ml, 0.76 mg / ml, 0.80 mg / ml, 0.81 mg / ml, 0.82 mg / ml, 0.83 mg / ml, 0.84 mg / ml, 0.86 mg / ml, 0.87 mg / ml, 0.88 mg / ml, 0.89 mg / ml, 0.90 mg / ml, 0.91 mg / ml, 0.92 mg / ml, 0.93 mg / ml, 0.94 mg / ml, 0.95 mg / ml, 0.96 mg / ml, 0.97 mg / ml, 0.98 mg / ml, 0.99 mg / ml, The invention can be stabilized with ammonium sulfate of 5mg / ml, 0.80mg / ml, 0.85mg / ml, 0.90mg / ml, 0.95mg / ml, 1.0mg / ml, 1.05mg / ml, 1.10mg / ml, 1.15mg / ml, 1.20mg / ml, 1.25mg / ml, 1.30mg / ml, 1.35mg / ml, 1.40mg / ml, 1.45mg / ml, 1.50mg / ml, 1.55mg / ml, 1.60mg / ml, 1.65mg / ml, 1.70mg / ml, 1.75mg / ml, 1.80mg / ml, 1.85mg / ml, 1.90mg / ml, 1.95mg / ml or 2.0mg / ml. For a solution having a dissolved oxygen content of about 5 ppm to about 10 ppm and 1 mg / ml of carboplatin, a stable amount of ammonium sulfate is 0.2 mg / ml to 2.0 mg / ml, such as, for example, 0.20 mg / ml, 0.25 mg / ml, 0.30 mg / ml, 0.35 mg / ml, 0.40 mg / ml, 0.45 mg / ml, 0.50 mg / ml, 0.55 mg / ml, 0.60 mg / ml, 0.65 mg / ml, 0.70 mg / ml, 0.75 mg / ml, 0.80 mg / ml, 0.85 mg / ml, 0.90 mg / ml, 0.91 mg / ml, 0.92 mg / ml, 0.93 mg / ml, 0.94 mg / ml, 0.95 mg / ml, 0.96 mg / ml, 0.97 mg / ml, 0.98 mg / ml, 0.99 mg / ml, 0.100 mg / ml, 0.110 mg / ml, 0.120 mg / ml, 0.130 mg / ml, 0.140 mg / ml, 0.150 mg / ml, 0.160 mg / ml, 0.170 mg / ml, 0.180 mg / ml, 0.190 mg / ml, 0.200 mg / ml .95mg / ml, 1.0mg / ml, 1.05mg / ml, 1.10mg / ml, 1.15mg / ml, 1.20mg / ml, 1.25mg / ml, 1.30mg / ml, 1.35mg / ml, 1.40mg / ml, 1.45mg / ml, 1.50mg / ml, 1.55mg / ml, 1.60mg / ml, 1.65mg / ml, 1.70mg / ml, 1.75mg / ml, 1.80mg / ml, 1.85mg / ml, 1.90mg / ml, 1.95mg / ml or 2.0mg / ml.For a solution having a dissolved oxygen content of about 5 ppm to about 10 ppm and 2 mg / ml of carboplatin, a stable amount of ammonium sulfate is 0.5 mg / ml to 2.0 mg / ml, such as, for example, 0.50 mg / ml, 0.55 mg / ml, 0.60 mg / ml, 0.65 mg / ml, 0.70 mg / ml, 0.75 mg / ml, 0.80 mg / ml, 0.85 mg / ml, 0.90 mg / ml, 0.95 mg / ml, 1.0 mg / ml, 1.05 mg / ml, 1.06 mg / ml, 1.10 mg / ml, 1.20 mg / ml, 1.30 mg / ml, 1.40 mg / ml, 1.50 mg / ml, 1.60 mg / ml, 1.70 mg / ml, 1.80 mg / ml, 1.90 mg / ml, 1.11 mg / ml, 1. 10mg / ml, 1.15mg / ml, 1.20mg / ml, 1.25mg / ml, 1.30mg / ml, 1.35mg / ml, 1.40mg / ml, 1.45mg / ml, 1.50mg / ml, 1.55m g / ml, 1.60mg / ml, 1.65mg / ml, 1.70mg / ml, 1.75mg / ml, 1.80mg / ml, 1.85mg / ml, 1.90mg / ml, 1.95mg / ml or 2.0mg / ml.

[0035] The pH of the aqueous solution of carboplatin is in the range of about 4.0 to 6.0, preferably 4.5 to 5.5, such as, for example, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5. In a most preferred embodiment, the aqueous solution of carboplatin does not contain a pH adjuster or buffer.

[0036] The aqueous parenteral dosage forms of the present invention are clear solutions rather than formulations that are substantially particulate in nature such as novel drug delivery systems such as liposomes, niosomes, lipid vesicles, other lipid-based drug delivery systems, microparticles, microcapsules, nanoparticles, and the like.

[0037] The aqueous solution of the parenteral dosage form according to the present invention does not contain surfactants, such as polyoxyethylene sorbitan fatty acid esters, such as Tween 20, Tween 80. In a preferred embodiment, the aqueous solution of the parenteral dosage form according to the present invention does not contain organic cosolvents, such as ethanol, propylene glycol. In a preferred embodiment, the aqueous solution of the parenteral dosage form according to the present invention does not contain antioxidants, such as sodium pyrosulfite, sodium sulfite, methionine, etc. In a preferred embodiment, the aqueous solution of the parenteral dosage form according to the present invention does not contain chelating agents, such as disodium edetate, citric acid, etc.

[0038] It has been found that when attempts are made to use the following excipients, such as, for example, antioxidants, such as sodium metabisulfite, sodium sulfite, methionine; chelating agents, such as disodium edetate, citric acid; preservatives, such as boric acid, m-cresol, phenol, chlorobutanol; buffers or pH adjusters, such as trisodium citrate dehydrate, tromethamine, ammonia solution, sodium hydroxide, sodium acetate, sulfuric acid, sodium sulfate, potassium sulfate, sodium bicarbonate, phosphoric acid, tartaric acid, meglumine, arginine; solvents or solubilizers, such as propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyvinyl pyrrolidone, N,N-dimethylethylamine, cyclodextrin; osmotic agents, such as dextrose, sorbitol and glycerol; surfactants, such as polyoxyethylene sorbitan monooleate; chlorides, such as sodium chloride, potassium chloride, calcium chloride, ammonium chloride, etc., in place of ammonium sulfate, then the aqueous solution shows black precipitate formation or discoloration or produces a high content of 1,1-cyclobutanedicarboxylic acid impurities, which is a problem. In particular, when a salt having chloride ions such as sodium chloride, potassium chloride, calcium chloride, ammonium chloride, etc. is used, the aqueous solution shows the formation of a black precipitate.

[0039] According to a preferred embodiment, the aqueous solution consists essentially of or consists of 1 mg / ml to 2 mg / ml of carboplatin and a stabilizing amount of ammonium sulfate, wherein the solution contains no more than 1.0% of a known impurity, 1,1-cyclobutanedicarboxylic acid, based on the weight of carboplatin, and the solution remains physically stable when stored at room temperature. The term consisting essentially of means "the aqueous solution does not contain excipients, such as antioxidants, e.g., sodium metabisulfite, sodium sulfite, methionine; chelating agents, e.g., disodium edetate, citric acid; preservatives, e.g., boric acid, m-cresol, phenol, chlorobutanol; buffers or pH adjusters, e.g., trisodium citrate dehydrate, tromethamine, ammonia solution, sodium hydroxide, sodium acetate, sulfuric acid, sodium sulfate, potassium sulfate, sodium bicarbonate, phosphoric acid, tartaric acid, meglumine, arginine; solvents or solubilizers, e.g., propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyvinyl pyrrolidone, N,N-dimethylacetamide, cyclodextrin; osmotic agents, e.g., dextrose, sorbitol, glycerol; surfactants, e.g., polyoxyethylene sorbitan monooleate; chlorides, e.g., sodium chloride, potassium chloride, calcium chloride, ammonium chloride".

[0040] According to the present invention, carboplatin solution is filled in a container made of non-glass, plastic or polymer material. In a preferred embodiment, the container is a flexible infusion container made of plastic or polymer material. In a preferred embodiment, the container is selected from a perfusion bag, an infusion bag, a flexible bag, etc. The flexible infusion container can be single-layer or multi-layer. The container is filled with a drug solution and is hermetically sealed such as by means of a stopper. In some embodiments, the infusion container can be made of glass, such as a glass vial, a glass ampoule, etc. In a preferred embodiment, the container has a single outlet for extracting an aqueous solution when administered intravenously. The volume of each infusion container is in the range of about 40ml to 500ml, for example 40ml, 50ml, 75ml, 100ml, 150ml, 165ml, 180ml, 195ml, 200ml, 215ml, 235ml, 260ml, 285ml, 300ml, 310ml, 340ml, 380ml, 400ml, 420ml, 460ml or 500ml. In one embodiment, a kit with two or more infusion containers is provided. According to another embodiment, the dosage provided in each infusion container is listed in the table below.

[0041]

[0042]

[0043] According to yet another embodiment, the dosages provided in each infusion flexible container are listed in the following table.

[0044]

[0045] The parenteral dosage form of the present invention is prepared by a process comprising the following steps:

[0046] a. Add the required amount of osmotic agent to water for injection and dissolve it until completely dissolved;

[0047] b. Add the required amount of stabilizer ammonium sulfate under continuous stirring;

[0048] c. adding the required amount of carboplatin to the solution in step (b) under continuous stirring and making up to volume with water for injection;

[0049] d. filtering the solution of step (c) through a 0.2μ filter; and

[0050] e. filling the filtered solution of step (d) into a suitable infusion container in a volume ranging from about 40 ml to about 500 ml and hermetically sealing the infusion container; wherein, optionally, during steps (a), (b) and before filling into the infusion container, oxygen is purged in the water for injection so that the dissolved oxygen content in the solution is in the range of about 10 ppm to 50 ppm, and optionally the head space is filled with oxygen before sealing the container;

[0051] Therein, the parenteral dosage form is wrapped outside with a second aluminum bag, and the space between the infusion container and the second aluminum bag is filled with oxygen and hermetically sealed.

[0052] According to a specific embodiment, the parenteral dosage form of the present invention comprises an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml to 2 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content ranging from about 5 ppm to 50 ppm, wherein the solution contains a known impurity 1,1-cyclobutanedicarboxylic acid in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

[0053] According to a specific embodiment, the parenteral dosage form of the present invention comprises an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate and a dissolved oxygen content ranging from 10 ppm to 50 ppm. The aqueous solution does not contain dextrose. Preferably, the stabilizing amount of ammonium sulfate is from 0.02 mg / ml to 2.0 mg / ml. The solution contains a known impurity 1,1-cyclobutanedicarboxylic acid in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

[0054] According to another specific embodiment, the parenteral dosage form of the present invention comprises an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 2 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate and a dissolved oxygen content ranging from 10 ppm to 50 ppm. The aqueous solution does not contain dextrose. Preferably, the stabilizing amount of ammonium sulfate is from 0.02 mg / ml to 2.0 mg / ml. The solution contains 1,1-cyclobutanedicarboxylic acid, a known impurity, in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

[0055] According to another specific embodiment, the parenteral dosage form of the present invention comprises an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 1 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate and a dissolved oxygen content ranging from 5 ppm to 10 ppm. The aqueous solution does not contain dextrose. Preferably, the stabilizing amount of ammonium sulfate is from 0.2 mg / ml to 2.0 mg / ml. The solution contains 1,1-cyclobutanedicarboxylic acid, a known impurity, in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

[0056] According to another specific embodiment, the parenteral dosage form of the present invention comprises an infusion container filled with an aqueous solution having a volume ranging from 40 ml to 500 ml, the aqueous solution comprising 2 mg / ml of carboplatin, a stabilizing amount of ammonium sulfate and a dissolved oxygen content ranging from 5 ppm to 10 ppm. The aqueous solution does not contain dextrose. Preferably, the stabilizing amount of ammonium sulfate is from 0.5 mg / ml to 2.0 mg / ml. The solution contains 1,1-cyclobutanedicarboxylic acid, a known impurity, in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

[0057] The invention will now be further described by the following examples, which are intended to be illustrative rather than limiting.

[0058] Example

[0059] Comparative Examples 1A to 1D and Examples 1E to 1H.

[0060] Table 1. Effect of various parameters on the physical stability of carboplatin solutions after being subjected to extreme stress conditions of autoclaving at 121°C for 7 minutes.

[0061]

[0062]

[0063] The parenteral dosage forms of Examples 1A, 1C, 1D, 1E, 1G, and 1H are prepared as follows:Water for injection is taken into a stainless steel container. The required amount of mannitol is added to the water and stirred until it is completely dissolved. Ammonium sulfate reserve (0.5mg / ml to 50mg / ml) solution is added under continuous stirring. Ammonium sulfate is not added in sample 1A. The required amount of carboplatin is added under continuous stirring until it is dissolved. Make up the volume with water for injection. Stir the solution and filter through a 0.2μ filter. The resulting solution is filled into a flexible infusion container with a filling volume of 50ml. The flexible infusion container is then wrapped with a second aluminum bag. The space between the flexible infusion container and the second aluminum bag is filled with atmosphere. The wrapped flexible infusion container is then subjected to stress conditions of autoclaving for 7 minutes at 121°C. The solution in the flexible infusion container shows black precipitation or solution discoloration after autoclaving, indicating the physical instability of the aqueous solution.

[0064] The parenteral dosage forms of Examples 1B and 1F are prepared as follows: Water for injection is taken into a stainless steel container and purged with oxygen therein for about 15-30 minutes. The required amount of mannitol is added to the water and stirred until it is completely dissolved. Ammonium sulfate stock solution (0.5mg / ml to 50mg / ml) is added under continuous stirring. Ammonium sulfate is not added in sample 1B. Oxygen purging is stopped, and the required amount of carboplatin is added under continuous stirring until it is dissolved. The volume is supplemented by water for injection purged with oxygen. The solution is stirred and filtered through a 0.2μ filter. Finally, the resulting solution is purged with oxygen and filled into a flexible infusion container with a filling volume of 50ml. By allowing oxygen to flow continuously on the head space of the flexible infusion container for about 30 seconds to 120 seconds, the head space is replaced by oxygen and sealed under an oxygen atmosphere. The flexible infusion container is then wrapped with a second aluminum bag. The space between the flexible infusion container and the second aluminum bag is filled with oxygen.

[0065] The parenteral dosage forms of Examples 1A to 1H were subjected to extreme stress conditions of autoclaving at 121°C for 7 minutes and observed for any physical instability of the solutions. Table 1 gives the observations.

[0066] From Table 1, it can be concluded that for a 1 mg / ml carboplatin solution, a stable amount of ammonium sulfate is 0.02 mg / ml or higher, but an oxygen purge is required to keep the dissolved oxygen content in the range of 10 ppm-50 ppm and the oxygen level in the headspace controlled. However, when at least 0.2 mg / ml or higher ammonium sulfate is used, it is found that no oxygen purge and control of the oxygen level in the headspace are required (see Example 1E). Ammonium sulfate acts as a stabilizer in an amount of 0.2 mg / ml or higher, such as 0.2 mg / ml to 2.0 mg / ml.

[0067] Comparative Examples 2A to 2G.

[0068] Table 2: Effect of various parameters on physical stability after being subjected to extreme stress conditions of autoclaving at 121°C for 7 minutes.

[0069]

[0070]

[0071] Examples 2H to 2L

[0072] Table 3: Effect of various parameters on physical stability after being subjected to extreme stress conditions of autoclaving at 121°C for 7 minutes.

[0073]

[0074] The parenteral dosage forms of Examples 2A, 2C, 2D, 2F, 2G, 2I, 2J and 2L are prepared as follows: Water for injection is taken into a stainless steel container. The required amount of mannitol is added to the water and stirred until it is completely dissolved. Mannitol is not added to sample 2D. In the case of Examples 2C, 2D, 2G, 2I, 2J and 2L, ammonium sulfate stock solution is added under continuous stirring. In the case of Example 2F, ammonia is added instead of ammonium sulfate under continuous stirring. In Example 2A, neither ammonium sulfate nor ammonia is added to the water. The required amount of carboplatin is added to the resulting solution under continuous stirring until it is dissolved. Make up the volume with water for injection. Stir the solution and filter through a 0.2μ filter. The resulting solution is filled into a flexible infusion container with a filling volume of 50ml. The flexible infusion container is then wrapped with a second aluminum bag. The space between the flexible infusion container and the second aluminum bag is filled with atmosphere. The wrapped flexible infusion container is then subjected to stress conditions of autoclaving for 7 minutes at 121°C.

[0075] The parenteral dosage forms of Examples 2B, 2E, 2H and 2K are prepared as follows: The water for injection is taken into a stainless steel container and purged with oxygen therein for about 15-30 minutes. The required amount of mannitol is added to the water and stirred until it is completely dissolved. In batch 2E, dextrose is added instead of mannitol, and in 2K, neither mannitol nor dextrose is added. The ammonium sulfate stock solution is added under continuous stirring. In Example 2B, neither ammonium sulfate nor ammonia is added to the water. Stop the oxygen purge and add the required amount of carboplatin under continuous stirring until it is dissolved. The volume is made up by water for injection purged with oxygen. The solution is stirred and filtered through a 0.2μ filter. Finally, the resulting solution is purged with oxygen and filled into a flexible infusion container with a filling volume of 50ml. The head space is replaced with oxygen by allowing oxygen to flow continuously on the head space of the flexible infusion container for 30 seconds to 120 seconds, and sealed under an oxygen atmosphere. The flexible infusion container is then wrapped with a second aluminum bag. The space between the flexible infusion container and the second aluminum bag is filled with oxygen.

[0076] The parenteral dosage forms of Examples 2A to 2L were subjected to extreme stress conditions of autoclaving at 121° C. for 7 minutes, and any physical instability of the solutions was observed. When subjected to extreme stress conditions of autoclaving at 121° C. for 7 minutes, the parenteral dosage forms of all Examples except Examples 2H, 2I, 2J, 2K, and 2L showed black precipitate or discoloration.

[0077] From Table 3, it can be concluded that for 2 mg / ml carboplatin solution, the stable amount of ammonium sulfate is 0.02 mg / ml, but 10 ppm-50 ppm of oxygen is required to maintain the oxygen level in the headspace. However, when at least 0.5 mg / ml or higher amount of ammonium sulfate is used, it is found that oxygen purging and controlling the oxygen level in the headspace is not required. It was further observed that when a batch similar to batch 2H was charged with a solution containing 2 mg / ml carboplatin, 0.02 mg / ml ammonium sulfate, 50 mg / ml mannitol and a dissolved oxygen content in the range of 10 ppm to 50 ppm for stability testing at room temperature (25°C / 40% relative humidity), the solution was found to be stable with no precipitation, crystallization or discoloration of the solution after storage for about 24 months. The content of known impurities and total impurities was also kept to a minimum, for example, the content of the known impurity 1,1-cyclobutanedicarboxylic acid was found to be 0.60%, which is less than 1.0% by weight of carboplatin. Similarly, another batch of solutions with varying ammonium sulfate content of 0.2 mg / ml was found to be physically and chemically stable when stored at room temperature (25° C. / 40% relative humidity) for 27 months.

Claims

1. A parenteral dosage form ready for infusion with an infusion container filled with an aqueous solution having a volume in the range of 40 ml to 500 ml, the aqueous solution consisting essentially of 1 mg / ml to 2 mg / ml of carboplatin, 0.02 mg / ml to 2.0 mg / ml of ammonium sulfate and a dissolved oxygen content in the range of 5 ppm to 50 ppm, wherein The aqueous solution does not contain dextrose and sodium chloride; and The solution contains 1,1-cyclobutanedicarboxylic acid, a known impurity, in an amount not exceeding 1.0% by weight of carboplatin, and the solution remains physically stable when stored at room temperature.

2. The infusion-ready parenteral dosage form according to claim 1, wherein the aqueous solution has 1 mg / ml of carboplatin.

3. The infusion-ready parenteral dosage form according to claim 2, wherein the aqueous solution has 0.2 mg / ml to 2.0 mg / ml of ammonium sulfate, and the dissolved oxygen content is in the range of 5 ppm to 10 ppm.

4. The infusion-ready parenteral dosage form according to claim 2, wherein the dissolved oxygen content is in the range of 10 ppm to 50 ppm.

5. The infusion-ready parenteral dosage form according to claim 3 or 4, wherein the volume of the aqueous solution is 50 ml.

6. The infusion-ready parenteral dosage form of claim 1, wherein the aqueous solution has 2 mg / ml of carboplatin.

7. The infusion-ready parenteral dosage form according to claim 6, wherein the dissolved oxygen content is in the range of 10 ppm to 50 ppm.

8. The infusion-ready parenteral dosage form according to claim 6, wherein the aqueous solution has 0.5 mg / ml to 2.0 mg / ml of ammonium sulfate, and the dissolved oxygen content is in the range of 5 ppm to 10 ppm.

9. The infusion-ready parenteral dosage form according to claim 7 or 8, wherein the volume of the aqueous solution is 50 ml.

10. The infusion-ready parenteral dosage form according to claim 1, wherein the infusion container is an infusion bag, an infusion bag, or a flexible bag.

11. The infusion-ready parenteral dosage form of claim 1, wherein the parenteral dosage form is overwrapped with a second aluminum bag.

12. The infusion-ready parenteral dosage form according to claim 11, wherein the parenteral dosage form is autoclaved at 121°C for 7 minutes before storage.

13. The infusion-ready parenteral dosage form according to claim 1, wherein the aqueous solution has a pH in the range of 4.0 to 6.

0.

14. The infusion-ready parenteral dosage form according to claim 1, wherein the aqueous solution has a pH in the range of 4.5 to 5.

5.

15. The infusion-ready parenteral dosage form according to claim 1, wherein the aqueous solution is autoclaved at 121°C for 7 minutes before storage.

16. The infusion-ready parenteral dosage form of claim 1, wherein the aqueous solution does not contain chloride salts.

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