阅读说明：本技术 卡铂的肠胃外剂型 (Parenteral dosage forms of carboplatin ) 是由 撒玛利亚·库马尔 马赫什库马尔·帕拉斯马尔·索尼 苏巴斯·巴拉姆·布霍米克 普拉尚·凯恩 于 2019-08-30 设计创作，主要内容包括：本发明提供了一种具有输注容器的肠胃外剂型,所述输注容器填充有体积在40ml至500ml范围内的水溶液,所述水溶液包含1mg/ml至2mg/ml的卡铂,其中所述溶液含有按卡铂的重量计不超过1.0％的量已知杂质1,1-环丁烷二羧酸,并且所述溶液在室温下储存时保持物理稳定。(The present invention provides a parenteral dosage form having an infusion container filled with an aqueous solution having a volume in the range of 40ml to 500ml, the aqueous solution comprising 1mg/ml to 2mg/ml of carboplatin, wherein the solution contains the known impurity 1, 1-cyclobutane dicarboxylic acid in an amount of not more than 1.0% by weight of carboplatin and the solution remains physically stable when stored at room temperature.)

1. A parenteral dosage form having an infusion container filled with an aqueous solution having a volume in the range of 40ml to 500ml, the aqueous solution comprising 1mg/ml to 2mg/ml of carboplatin, wherein the solution contains the known impurity 1, 1-cyclobutanedicarboxylic acid in an amount of no more than 1.0% by weight of carboplatin and the solution remains physically stable when stored at room temperature.

2. The parenteral dosage form of claim 1, wherein the solution comprises 1mg/ml of carboplatin, a stabilizing amount of ammonium sulfate, and optionally a dissolved oxygen content in the range of about 5ppm to 50 ppm.

3. The parenteral dosage form of claim 2 wherein the stable amount of ammonium sulfate is 0.2mg/ml to 2.0mg/ml and the dissolved oxygen content is in the range of about 5ppm to 10 ppm.

4. The parenteral dosage form of claim 2 wherein the stable amount of ammonium sulfate is 0.02mg/ml to 2.0mg/ml and the dissolved oxygen content is in the range of about 10ppm to 50 ppm.

5. The parenteral dosage form of claim 3 or 4 wherein the volume of the aqueous solution is 50 ml.

6. The parenteral dosage form of claim 2 wherein the aqueous solution is free of dextrose.

7. The parenteral dosage form of claim 1 wherein the solution comprises 2mg/ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content in the range of about 5ppm to 50 ppm.

8. The parenteral dosage form of claim 7 wherein a stable amount of ammonium sulfate is 0.02mg/ml to 2.0mg/ml and the dissolved oxygen content is in the range of about 10ppm to 50 ppm.

9. The parenteral dosage form of claim 7 wherein the stable amount of ammonium sulfate is 0.5 to 2.0mg/ml and the dissolved oxygen content is in the range of about 5 to 10 ppm.

10. The parenteral dosage form of claim 8 or 9 wherein the volume of the aqueous solution is 50 ml.

11. The parenteral dosage form of claim 7 wherein said aqueous solution is free of dextrose.

Technical Field

The present invention relates to a storage stable aqueous solution of carboplatin and parenteral dosage forms containing the same.

Background

Carboplatin is a platinum coordination compound with chemical name of [1, 1-cyclobutane dicarboxy (2-) -0, 0']Diammine. It can be obtained from Bristol-Myers Squibb under the trade name Bristol and pre-concentrated aqueous solution (10mg/ml) in the form of a lyophilized powder and a pre-concentrated aqueous solutionAre commercially available.

From numerous references and fromThe reconstituted carboplatin solution was stable for only 8 hours, as can be seen in the package insert of (a). Indeed, Cheung YW et al Am J Hosp pharm.1987 Jan; 44(1) 124-30; swell GJ et al J Clin Pharm Ther.1987 Dec; 427-32 (6); gust and B.Schnurr Monatshefte fur Chemie 1999; 130: 637-44; all of these references report that reconstituted carboplatin solutions are highly unstable. Myres et al in Journal of Oncology Practice, 2016 for 2 months; the publications on 22(1):31-6 report that, although the reconstituted solution is stored under special storage conditions (such as refrigeration in the dark or exposure to fluorescent lamps at room temperature), the reconstituted or diluted aqueous solution of carboplatin is only stable for seven days. There was a significant decrease in the measurement of carboplatin. It is further reported that carboplatin decomposes to form highly toxic compounds such as di-p-hydroxy bis (cis-diammineplatinum (II)) and tri-p-hydroxy tris (cis-diammineplatinum (II)), which appear as black silver deposits when stored in glass containers.

Furthermore, despite many 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 emergence of particulate matter. For example, the marketing partner of Novartis Ebewe Pharma announced in the press release on 3.29/2012 that an aqueous solution of carboplatin (10mg/ml) was recalled in hong kong due to the appearance of precipitates in several batches. Similarly, in the press release on day 27 of month 4 of 2015, the indiana health agency notified the local health department about recalling the injected product manufactured by Mylan Pharma-carboplatin 10mg/ml 100ml vials as visible foreign particulate matter was present.

Thus, there is an urgent need to provide a carboplatin injection solution that is storage stable and suitable for direct infusion, which solution does not suffer from many of the stability-related problems of carboplatin.

The present invention does achieve this object and provides a parenteral dosage form comprising a stable storage aqueous solution of carboplatin stored in an infusion container.

Disclosure of Invention

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

The invention can be summarized as follows:

A. a parenteral dosage form having an infusion container filled with an aqueous solution having a volume in the range of 40ml to 500ml, the aqueous solution comprising 1mg/ml to 2mg/ml of carboplatin, wherein the solution contains the known impurity 1, 1-cyclobutanedicarboxylic acid in an amount of no more than 1.0% by weight of carboplatin and the solution remains physically stable when stored at room temperature.

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

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

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

E. The parenteral dosage form as claimed in C or D, wherein the volume of the aqueous solution is 50 ml.

F. The parenteral dosage form as claimed in a or B, wherein the aqueous solution is free of dextrose.

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

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

I. The parenteral dosage form as claimed in G wherein the stabilizing amount of ammonium sulfate is 0.5mg/ml to 2.0mg/ml and the dissolved oxygen content is in the range of about 5ppm to about 10 ppm.

J. The parenteral dosage form of claim H or I, wherein the volume of the aqueous solution is 50 ml.

Drawings

Figure 1 shows the physical appearance (black precipitate) of a solution according to comparative examples 1A, 1B, 1C, 1D having a concentration of 1mg/ml when subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes.

Figure 2 shows the physical appearance of the solutions according to working examples 1E, 1F, 1G, 1H with a concentration of 1mg/ml when subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes (clear solutions).

Fig. 3 shows the physical appearance (black precipitate) of solutions according to comparative examples 2A to 2G having a concentration of 2mg/ml when subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes.

Figure 4 shows the physical appearance of the solutions according to working examples 2H to 2L with a concentration of 2mg/ml when subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes (clear solutions).

Detailed Description

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

As used herein, the term "extreme stress condition" refers to subjecting the parenteral dosage form to autoclaving at 121 ℃ for 7 minutes. For testing, the parenteral dosage forms were prepared and wrapped in a second pouch of aluminum and then autoclaved at 121 ℃ for 7 minutes. The autoclaved filled infusion containers were visually observed for any discoloration, precipitation or crystal formation. The presence of any or all of them indicates instability. Parenteral dosage forms that were maintained autoclaved at 121 ℃ for 7 minutes without any precipitation were found to be stable and therefore considered stable upon storage at room temperature for two years.

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.

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 ℃ for 7 minutes. Parenteral dosage forms that were maintained autoclaved at 121 ℃ for 7 minutes without any precipitation were found to be stable and therefore considered stable upon storage at room temperature for two years.

As used herein, the term "chemically stable" refers to aqueous solutions of carboplatin that exhibit 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 1, 1-cyclobutanedicarboxylic acid, an impurity, is known to not exceed 1.0% by weight of carboplatin when stored at room temperature for two years.

According to one embodiment, the parenteral dosage form comprises a storage stable aqueous solution of carboplatin comprising carboplatin at a concentration ranging from about 1mg/ml to 2 mg/ml. According to another embodiment, the aqueous solution of carboplatin is physically stable when subjected to extreme conditions of autoclaving at 121 ℃ 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. Parenteral dosage forms that are autoclaved at 121 ℃ for 7 minutes without any precipitation or crystallization or discoloration are stable when stored at room temperature for at least two years.

The present invention provides a parenteral dosage form having an infusion container filled with an aqueous solution having a volume in the range of 40ml to 500ml, the aqueous solution comprising 1mg/ml to 2mg/ml of carboplatin, wherein the solution contains the known impurity 1, 1-cyclobutane dicarboxylic acid in an amount of no more than 1.0% by weight of carboplatin and the solution remains physically stable upon storage at room temperature for a period of about two years.

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

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

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 1mg/ml to 2mg/ml, and that the solution is meant to be directly infused or administered directly to a patient without the need for any reconstitution, dilution, manipulation, transfer, treatment or formulation prior to intravenous parenteral administration of the drug solution.

It may 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. Importantly, the solution contained no dextrose or sodium chloride, otherwise the solution was found to produce a black precipitate and very high levels of the impurity 1, 1-cyclobutanedicarboxylic acid and total impurities. Furthermore, the inventors have found that the amount of ammonium sulfate that stabilizes depends not only on the concentration of carboplatin, but also on the amount of dissolved oxygen in the solution and the percentage of oxygen in the headspace of the filled container. For example, ammonium sulfate of 0.02mg/ml or higher was found to stabilize the solution when the concentration of carboplatin was 1mg/ml, but in the lower range, dissolved oxygen levels in aqueous solutions of about 10ppm to 50ppm were required, whereas when higher concentrations such as 0.2mg/ml to 2mg/ml were used, dissolved oxygen levels in the range of about 10ppm to 50ppm were not required and dissolved oxygen levels could be as low as 5ppm to about 10 ppm. The oxygen level present in the solution is in the range of about 5ppm to 10 ppm. On the other hand, when the concentration of carboplatin is 2mg/ml, ammonium sulfate of 0.02mg/ml or more is found to stabilize the solution, however, the presence of dissolved oxygen content of 10ppm to 50ppm in the aqueous solution is required. While when the solution is not purged with oxygen, i.e., the amount of oxygen in the solution is about 5ppm to about 10ppm, it is found that 0.5mg/ml to 2mg/ml of ammonium sulfate is required for stabilization.

It was found that an aqueous solution having a dissolved oxygen content of about 10ppm to 50ppm, preferably 11ppm to 50ppm, was used at a concentration of 0.02mg/ml or more, preferably 0.02mg/ml to 2.0mg/ml such as, for example, 0.02mg/ml, 0.04mg/ml, 0.06mg/ml, 0.08mg/ml, 0.10mg/ml, 0.15mg/ml, 0.20mg/ml, 0.25mg/ml, 0.30mg/ml, 0.35mg/ml, 0.40mg/ml, 0.45mg/ml, 0.50mg/ml, 0.55mg/ml, 0.60mg/ml, 0.65mg/ml, 0.70mg/ml, 0.75mg/ml, 0.80mg/ml, 0.85mg/ml, 0.90mg/ml, 0.95mg/ml, 1.0mg/ml, 1.05mg/ml, 1.10mg/ml, 1.25mg/ml, 1, Ammonium sulfate of 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 2.0 mg/ml. For solutions having a dissolved oxygen content of about 5ppm to about 10ppm and 1mg/ml of carboplatin, a stable amount of ammonium sulfate is 0.2mg/ml to 2.0mg/ml, such as, for example, 0.20mg/ml, 0.25mg/ml, 0.30mg/ml, 0.35mg/ml, 0.40mg/ml, 0.45mg/ml, 0.50mg/ml, 0.55mg/ml, 0.60mg/ml, 0.65mg/ml, 0.70mg/ml, 0.75mg/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, 1.55mg/ml, 1.80mg/ml, 1.20mg/ml, 1.25mg/ml, 1.50mg/ml, 1., 1.65mg/ml, 1.70mg/ml, 1.75mg/ml, 1.80mg/ml, 1.85mg/ml, 1.90mg/ml, 1.95mg/ml or 2.0 mg/ml. For solutions having a dissolved oxygen content of about 5ppm to about 10ppm and carboplatin at 2mg/ml, a stable amount of ammonium sulfate is 0.5mg/ml to 2.0mg/ml, such as, for example, 0.50mg/ml, 0.55mg/ml, 0.60mg/ml, 0.65mg/ml, 0.70mg/ml, 0.75mg/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, 1.80mg/ml, 1.90mg/ml, 1.45mg/ml, 1.50mg/ml, 1.55mg/ml, 1.85mg/ml, 1.10mg/ml, 1.15mg/ml, 1.20mg, 1.95mg/ml or 2.0 mg/ml.

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 is free of a pH adjusting agent or buffer.

The aqueous solutions of the parenteral dosages of the present invention are clear solutions, rather than essentially particulate formulations such as novel drug delivery systems such as liposomes, niosomes, lipid vesicles, other lipid-based drug delivery systems, microparticles, microcapsules, nanoparticles, and the like.

The aqueous solution of the parenteral dosage form according to the invention is free of surfactants such as polyoxyethylene sorbitan fatty acid esters, e.g. tween 20, tween 80. In a preferred embodiment, the aqueous solution of the parenteral dosage form according to the invention is free of organic cosolvents, such as ethanol, propylene glycol. In a preferred embodiment, the aqueous solution of the parenteral dosage form according to the invention is free of antioxidants such as sodium metabisulfite, sodium sulfite, methionine and the like. In a preferred embodiment, the aqueous solution of the parenteral dosage form according to the invention is free of chelating agents, such as edetate disodium, citric acid and the like.

It has been found that, instead of ammonium sulphate, when it is attempted to use excipients such as, for example, antioxidants, such as sodium metabisulphite, sodium sulphite, methionine; chelating agents, such as edetate disodium, 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, polyvinylpyrrolidone, N dimethylethylamine, cyclodextrins; 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, and the like; the aqueous solution shows black precipitate formation or discoloration or produces a high content of 1, 1-cyclobutane dicarboxylic acid impurities, which is a problem. In particular, when a salt having a chloride ion such as sodium chloride, potassium chloride, calcium chloride, ammonium chloride, or the like is used, the aqueous solution shows the formation of a black precipitate.

According to a preferred embodiment, the aqueous solution substantially comprises or includes 1mg/ml to 2mg/ml of carboplatin and a stabilizing amount of ammonium sulfate, wherein the solution contains no more than 1.0% by weight of carboplatin of the known impurity 1, 1-cyclobutanedicarboxylic acid and the solution remains physically stable when stored at room temperature. The term includes substantially the following meanings: "the aqueous solution is free of excipients such as antioxidants like sodium metabisulfite, sodium sulfite, methionine; chelating agents, such as edetate disodium, 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, polyvinylpyrrolidone, N dimethylacetamide, cyclodextrin; osmotic agents, such as dextrose, sorbitol, glycerol; surfactants, such as polyoxyethylene sorbitan monooleate; chlorides such as sodium chloride, potassium chloride, calcium chloride, ammonium chloride ".

According to the invention, the carboplatin solution is filled in a container made of a non-glass, plastic or polymeric material. In a preferred embodiment, the container is a flexible infusion container made of a plastic or polymer material. In a preferred embodiment, the container is selected from the group consisting of a perfusion bag, an infusion bag, a flexible bag, and the like. The flexible infusion container may be single-layered or multi-layered. The container is filled with a drug solution and hermetically sealed, such as by means of a stopper. In some embodiments, the infusion container may be made of glass, such as a glass vial, glass ampoule, or the like. In a preferred embodiment, the container has a single outlet for withdrawing the aqueous solution upon intravenous administration. The volume of each infusion container is in the range of about 40ml to 500ml, such as 40ml, 50ml, 75ml, 100ml, 150ml, 165ml, 180ml, 195ml, 200ml, 215ml, 235ml, 260ml, 285ml, 300ml, 310ml, 340ml, 380ml, 400ml, 420ml, 460ml or 500 ml. In one embodiment, a kit having two or more infusion containers is provided. According to another embodiment, the doses provided in each infusion container are listed in the table below.

According to yet another embodiment, the doses provided in each infusion flexible container are listed in the table below.

The parenteral dosage form of the invention is prepared by a process comprising the steps of:

a. adding a required amount of penetrant into water for injection and dissolving the penetrant until the penetrant is completely dissolved;

b. adding a required amount of stabilizer ammonium sulfate under continuous stirring;

c. adding a desired amount of carboplatin to the solution of step (b) with continuous stirring and metering volume with water for injection;

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

e. filling the filtered solution of step (d) into a suitable infusion container in a volume in the range of about 40ml to about 500ml and hermetically sealing the infusion container; wherein, optionally, during steps (a), (b) and prior to filling the infusion container, oxygen is purged in the water for injection to bring the dissolved oxygen content in the solution in the range of about 10ppm to 50ppm, and optionally the headspace is filled with oxygen prior to sealing the container;

wherein the parenteral dosage form is externally wrapped with a second aluminum bag, and a space between the infusion container and the second aluminum bag is filled with oxygen and hermetically sealed.

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

According to a particular embodiment, the parenteral dosage form of the invention comprises an infusion container filled with a volume of aqueous solution ranging from 40ml to 500ml comprising 1mg/ml of carboplatin, a stabilizing amount of ammonium sulfate and a dissolved oxygen content ranging from 10ppm to 50 ppm. The aqueous solution was free of dextrose. Preferably, the stabilizing amount of ammonium sulfate is 0.02mg/ml to 2.0 mg/ml. The solution contains the known impurity 1, 1-cyclobutanedicarboxylic acid in an amount of no more than 1.0% by weight of the carboplatin and the solution remains physically stable when stored at room temperature.

According to another specific embodiment, the parenteral dosage form of the invention comprises an infusion container filled with a volume of aqueous solution ranging from 40ml to 500ml comprising 2mg/ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content ranging from 10ppm to 50 ppm. The aqueous solution was free of dextrose. Preferably, the stabilizing amount of ammonium sulfate is 0.02mg/ml to 2.0 mg/ml. The solution contains the known impurity 1, 1-cyclobutanedicarboxylic acid in an amount of no more than 1.0% by weight of the carboplatin and the solution remains physically stable when stored at room temperature.

According to another specific embodiment, the parenteral dosage form of the invention comprises an infusion container filled with a volume of aqueous solution ranging from 40ml to 500ml comprising 1mg/ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content ranging from 5ppm to 10 ppm. The aqueous solution was free of dextrose. Preferably, the stabilizing amount of ammonium sulfate is 0.2mg/ml to 2.0 mg/ml. The solution contains the known impurity 1, 1-cyclobutanedicarboxylic acid in an amount of no more than 1.0% by weight of the carboplatin and the solution remains physically stable when stored at room temperature.

According to another specific embodiment, the parenteral dosage form of the invention comprises an infusion container filled with a volume of aqueous solution ranging from 40ml to 500ml comprising 2mg/ml of carboplatin, a stabilizing amount of ammonium sulfate, and a dissolved oxygen content ranging from 5ppm to 10 ppm. The aqueous solution was free of dextrose. Preferably, the stable amount of ammonium sulfate is 0.5mg/ml to 2.0 mg/ml. The solution contains the known impurity 1, 1-cyclobutanedicarboxylic acid in an amount of no more than 1.0% by weight of the carboplatin and the solution remains physically stable when stored at room temperature.

The invention will now be further described by the following examples, which are intended to be illustrative and not limiting.

Examples

Comparative examples 1A to 1D and examples 1E to 1H.

Table 1. effect of various parameters on the physical stability of carboplatin solutions after being subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes.

The parenteral dosage forms of examples 1A, 1C, 1D, 1E, 1G, 1H were prepared as follows:water for injection was taken into a stainless steel container. The required amount of mannitol was added to water and stirred until it was completely dissolved. A stock solution of ammonium sulfate (0.5mg/ml to 50mg/ml) was added with continuous stirring. No ammonium sulfate was added to sample 1A. The desired amount of carboplatin was added with continuous stirring until it dissolved. Make up the volume with water for injection. The solution was stirred and filtered through a 0.2 μ filter. The resulting solution was filled into a flexible infusion container with a fill volume of 50 ml. 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 at 121 ℃ for 7 minutes. The solution in the flexible infusion container showed a black precipitate or discoloration of the solution after autoclaving indicating physical instability of the aqueous solution.

The parenteral dosage forms of examples 1B and 1F were prepared as follows:water for injection was taken into a stainless steel container and purged with oxygen therein for about 15-30 minutes. Adding the required amount of mannitol to water andstir until it is completely dissolved. Ammonium sulfate stock solution (0.5mg/ml to 50mg/ml) was added with continuous stirring. No ammonium sulfate was added to sample 1B. The oxygen purge was stopped and the desired amount of carboplatin was added with continuous stirring until it dissolved. This volume was made up with water for injection purged with oxygen. The solution was stirred and filtered through a 0.2 μ filter. Finally, the resulting solution was purged with oxygen and filled into a flexible infusion container with a fill volume of 50 ml. The headspace was replaced with oxygen by flowing oxygen continuously over the headspace of the flexible infusion container for about 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.

The parenteral dosage forms of examples 1A to 1H were subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes and any physical instability of the solution was observed. Table 1 gives the observations.

From table 1 it can be concluded that for a 1mg/ml carboplatin solution, the stable amount of ammonium sulfate is 0.02mg/ml or higher, but an oxygen purge is required to bring the dissolved oxygen content in the range of 10ppm to 50ppm, and that the oxygen level in the headspace is controlled. However, when using ammonium sulfate in amounts of at least 0.2mg/ml or higher, it was found that no oxygen purging and control of the oxygen level in the headspace was required (see example 1E). Ammonium sulfate acts as a stabilizer in an amount of 0.2mg/ml or more, such as 0.2mg/ml to 2.0 mg/ml.

Comparative examples 2A to 2G.

Table 2: effect of various parameters on physical stability after being subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes.

Examples 2H to 2L

Table 3: effect of various parameters on physical stability after being subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes.

Parenteral dosage forms of examples 2A, 2C, 2D, 2F, 2G, 2I, 2J and 2L were prepared as follows:water for injection was taken into a stainless steel container. The required amount of mannitol was added to water and stirred until it was completely dissolved. Mannitol was not added to sample 2D. In the case of examples 2C, 2D, 2G, 2I, 2J and 2L, the ammonium sulfate stock solution was added with continuous stirring. In the case of example 2F, ammonia was added instead of ammonium sulfate with continuous stirring. In example 2A, neither ammonium sulfate nor ammonia was added to the water. The desired amount of carboplatin was added to the resulting solution with continuous stirring until it dissolved. Make up the volume with water for injection. The solution was stirred and filtered through a 0.2 μ filter. The resulting solution was filled into a flexible infusion container with a fill volume of 50 ml. 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 at 121 ℃ for 7 minutes.

The parenteral dosage forms of examples 2B, 2E, 2H and 2K were prepared as follows:water for injection was taken into a stainless steel container and purged with oxygen therein for about 15-30 minutes. The required amount of mannitol was added to water and stirred until it was completely dissolved. In batch 2E, dextrose was added instead of mannitol, and in 2K, neither mannitol nor dextrose was added. The ammonium sulfate stock solution was added with continuous stirring. In example 2B, neither ammonium sulfate nor ammonia was added to the water. The oxygen purge was stopped and the desired amount of carboplatin was added with continuous stirring until it dissolved. This volume was made up with water for injection purged with oxygen. The solution was stirred and filtered through a 0.2 μ filter. Finally, the resulting solution was purged with oxygen and filled into a flexible infusion container with a fill volume of 50 ml. By making oxygen softThe headspace of the container was continuously flowed over for 30 seconds to 120 seconds, the headspace was replaced with 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.

The parenteral dosage forms of examples 2A to 2L were subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes and any physical instability of the solution was observed. The parenteral dosage forms of all examples, except examples 2H, 2I, 2J, 2K, 2L, exhibited black precipitates or discoloration when subjected to extreme stress conditions of autoclaving at 121 ℃ for 7 minutes.

From Table 3, it can be concluded that for a 2mg/ml carboplatin solution, the stable amount of ammonium sulfate is 0.02mg/ml, but 10ppm to 50ppm oxygen is required to maintain the oxygen level in the headspace. However, when using ammonium sulphate in an amount of at least 0.5mg/ml or more, it was found that no oxygen purging and control of the oxygen level in the headspace was required. It was further observed that when a batch similar to batch 2H, having a solution containing 2mg/ml carboplatin, 0.02mg/ml ammonium sulfate, 50mg/ml mannitol, and a dissolved oxygen content in the range of 10ppm to 50ppm, was charged for stability testing at room temperature (25 ℃/40% relative humidity), the solution was found to be stable without precipitation, crystallization, or discoloration of the solution after about 24 months of storage. The content of known impurities and of all impurities is also kept to a minimum, for example the content of 1, 1-cyclobutanedicarboxylic acid as known impurity is found to be 0.60%, less than 1.0% by weight of carboplatin. Similarly, another batch of a solution with an ammonium sulfate content of 0.2mg/ml was found to be physically and chemically stable upon storage at room temperature (25 ℃/40% relative humidity) for 27 months.