Pharmaceutical composition with anti-tumor activity based on carboplatin

 

(57) Abstract:

The invention can be used in pharmacy to obtain anticancer drugs. The claimed pharmaceutical composition which is an aqueous solution containing 1-20 mg/ml carboplatin, 1,1-cyclobutanecarbonyl acid and/or its salt in an amount of less than 0.1% by weight carboplatin directly after preparation of the composition. The invention allows to obtain stable during storage solution carboplatin. The reduction in the content of active substance in 2.5 years is 1.8 to 1.9%. table 1.

The invention relates to pharmaceutical compositions with anti-tumor activity based on carboplatin containing aqueous solution carboplatin content carboplatin from 1 to 20 mg/ml

Carboplatin (complex CIS-diamine-1,1-cyclobutanedicarboxylate (II) is an active substance, which is applicable in the treatment of tumors. This containing platinum cytotoxic agent was introduced into medical practice in 1986 in the form of lyophilized powder for injectable solution containing mannitol as a pharmaceutically acceptable triturating agent. Although freeze-dried product is time and energy. The disadvantage in the use of freeze-dried form carboplatin is time-consuming preparation of the solution carboplatin for infusion applications; in addition, there is a certain risk to staff, based on the possible interaction carboplatin with DNA, leading to chromosomal aberrations. These shortcomings motivate efforts in obtaining liquid dosage forms carboplatin that due to limited manipulation could lead to reducing the risks of environmental contamination and infection of medical personnel.

The main problem in obtaining liquid dosage forms carboplatin is based on the fact that solutions carboplatin in water or some aqueous solutions are stable and therapeutically applicable only within the time interval of a few hours or days. After this time the solution carboplatin are formed in a large number of unwanted highly toxic aquacomplex and/or other toxic substances. Thus, the problem of stability carboplatin in aqueous solutions is crucial for the commercial use of aqueous solutions carboplatin.

In EP 334551 Opera, which serve as preservatives. The disadvantage of this method of stabilization is that it does not solve the problem long-term stability of aqueous solutions carboplatin. In EP 401896 described aqueous dosage form carboplatin, which is stabilized by buffer that supports the pH value of an aqueous solution carboplatin in the range of 2-6. In the patent CZ 281349 described aqueous dosage form carboplatin, which is stabilized by the presence of from 0.01 to 0.5 mg/ml 1,1-cyclobutanedicarboxylic acid and/or its ammonium, sodium or potassium salt. In EP 642792 described aqueous dosage form carboplatin, which is stabilized by the presence of 0.25-4 mg/ml 1,1-cyclobutanedicarboxylic acid or its alkali metal salt, supporting the solution pH in the range from 4 to 7. Finally, in International patent publication WO 95-20956 described aqueous dosage form carboplatin, whose stability is ensured by the pH value of the solution carboplatin in the range from 2.5 to 7 and the presence of 1,1-cyclobutanedicarboxylic acid and/or its sodium, potassium or ammonium salt, therefore a prerequisite for this solution is that at least 110-4mg/ml of these soy is not inspired confidence among professionals in this field, the presence of 1,1-cyclobutanedicarboxylic acid and/or its above-mentioned salt is absolutely necessary to achieve a certain acceptable stability of aqueous solutions carboplatin.

After a thorough study of the kinetics of hydrolysis carboplatin in aqueous solutions is a professional bias, described above, was overcome new and unexpected discovery, which can be summed up in the statement that the presence of any acid facilitates the hydrolysis carboplatin through electrophilic destruction carboxyl ligands carboplatin. Similarly, any nucleophilic compound, which has a stronger nucleophilicity than water, can reduce the stability carboplatin due to the substitution of the carboxylate ligand carboplatin. Therefore, any presence of buffer, including 1,1-cyclobutanedicarboxylic acid and/or its conjugated base in salt form, is, contrary to expectations, reduce the stability carboplatin in aqueous solution. In contrast to the accepted still believe the most stable water form carboplatin is an aqueous solution carboplatin high purity in sterile is the slot.

Thus, the object of this invention is a pharmaceutical composition with anti-tumor activity based on carboplatin containing aqueous solution carboplatin content carboplatin from 1 to 20 mg/ml, characterized in that it contains directly after its preparation, the amount of 1,1-cyclobutanedicarboxylic acid and/or its salt, which is less than 0.1% by weight based on the weight of the present carboplatin.

A hypothetical mechanism for the decomposition of carboplatin, which is similar to the mechanism of hydration cisplatin (Cheung Y. W., J. C. Cradock, Vishnuvajjala centuries , Flora K. R., Am. J. Hosp. Pharm., 1987, 44, 124), is a two-step hydrolysis to the mono - and dianacamera.com platinum formulas I and II:

< / BR>
The first stage of decomposition carboplatin in aqueous solution in accordance with the equation /1-0/, which causes the instability, can be further generalized by the equation /1-1/

< / BR>
From equations /1-0/ 1-1/ it is obvious that each acid or every nucleophilic compound, which is a stronger nucleophile than water, will reduce the stability carboplatin through the mechanism of substitution of the carboxylate ligand carboplatin. Although this assumption of equation /1-1/ is the Finance to overcome the above professional biases using evidence has been collected and developed data from stability studies of liquid injection solutions carboplatin, which differed in content 1,1-cyclobutanedicarboxylic acid and/or its salts.

It was hypothesized that the rate of hydrolysis carboplatin to monovacancies formula (I) is the magnitude of the first order with respect to the concentration carboplatin and not dependent on the concentration of water:

< / BR>
,

that can be integrated with the receipt:

,

which can be represented as:

ln(1-x)=-k1t /1-3/

Depending on the concentration in accordance with the equations /1-2/ 1-3/ assessed by linear regression, and it was possible to calculate the reaction rate constant and/or the speed of the decomposition reaction carboplatin.

The rate of decomposition carboplatin depending on the concentration of 1,1-cyclobutanedicarboxylic acid.

The average initial concentration carboplatin was 10,0 mgml-1. The initial concentration of 1,1-cyclobutanedicarboxylic acid were 0,017, 0,129, and 1,189 14,804 mgml-1. Temperature and relative humidity during storage were 25oC/60% and 35oC/60%. The vials with the samples kept in a vertical position corked.

The decrease carboplatin was calculated as the difference between the content carboplatin between the reference the consequence of a good linear correlation, these indicators were assessed using linear regression.

The calculated degradation rate carboplatin (g /Malm-3with-1) are summarized in table (see the end of the description).

Following concentration dependence of the reaction rate were obtained at temperatures of storage 25 and 35oWITH:

r25=5,210-9+1,710-9cCBDCA/Malm-3with-1/ /1-4/

r35=5,410-8+1,210-9cCBDCA/Malm-3with-1/ /1-5/

(CBDCA=1,1-cyclobutanecarbonyl acid).

According to the Arrhenius equation was calculated activation energy EA:

EA=190 000 Gmol-1/1-6/

The calculated value indicates a strong dependence of the rate of decomposition carboplatin temperature. For the reference temperature 35oWith, which was the highest determination coefficient (R2=0,99), from equations /1-5/ 1-6/ can be obtained the following dependence of the rate of decomposition carboplatin concentration present 1,1-cyclobutanedicarboxylic acid and the temperature:

< / BR>
where r is expressed in Malm-3with-1and cCBDCAexpressed in Malm-3.

On the basis of Ncentrate 1,1-cyclobutanedicarboxylic acid:

a) the concentration of 1,1-cyclobutanedicarboxylic acid equal to 0.005 mg/ml (concentration in the range in accordance with the invention):

r=4,4810-9Malm-3with-1,

b) the concentration of 1,1-cyclobutanedicarboxylic acid equal 0,150 mg/ml (concentration in commercially manufactured drug form carboplatin Ribocarbol L):

r=4,5810-9Malm-3with-1(the increase in the rate of 2.2%)

c) the concentration of 1,1-cyclobutanedicarboxylic acid equal 0,250 mg/ml (the lower limit of the concentration in an aqueous dosage form carboplatin in accordance with EP 642792):

r=4,6510-9Malm-3with-1(increase speed 4%).

From the above data it is evident that the rate of decomposition carboplatin in aqueous solution varies in accordance with the equation /1-7/ negatively on the number of available 1,1-cyclobutanedicarboxylic acid and/or its salts and very negatively on the storage temperature. The rate constant k in 0.1 M phosphate buffer at a temperature of 37oWith approximately 200 times higher than 1,410-4M CBDCA-buffer at a temperature of 40oC. a temperature Increase of 10oWith causes approximately a tenfold increase in the rate of decomposition of carboplatin. From the data obtained in the long-term stability studies show that the most stable liquid dosage form carboplatin is a solution of pure carboplatin in water with a minimum content of other impurities, such as acids or nucleophiles. The content of 1,1-cyclobutanedicarboxylic acid and its salts, and possibly other bafarawa agents or nucleophilic compounds, in an aqueous dosage form carboplatin should be less than 0.1% by weight is present carboplatin, i.e., less than 0.01 mg/ml concentration carboplatin 10 mg/ml During prolonged periods of storage (up to several years) or at elevated temperatures in a liquid dosage form carboplatin appears yellow staining caused, perhaps, by the disproportionation carboplatin in Pt(IV) and Pt(0) complexes. To avoid this, the disproportionation liquid dosage form carboplatin should be stored with the exclusion of light, perhaps in vials made of amber glass suitable hydrolytic class.

EXAMPLE 1

Under GMP (see below) sterile aqueous solution carboplatin concentration carboplatin there is a 10.03 mg/ml was prepared from substances carboplatin, within the pH value of 6.3, was subjected to ultrafiltration under aseptic conditions through a filter with a porosity of 0.2 μm and then again placed in portions of 5 ml vials made of glass of the first hydrolytic class, which covered covered with Teflon rubber stoppers and aluminium caps. Atmospheric air is formed gaseous environment above the solution. The obtained composition was subjected to stability studies at 25oC and 60% relative humidity when excluding the effects of light. The vials were kept in a vertical position with the tubes. Content carboplatin and 1,1-cyclobutanedicarboxylic acid was subjected to monitoring using liquid chromatography and high resolution has been evaluated in comparison with an external reference standard. After 36 months, this pharmaceutical composition showed the content carboplatin 9.85 mg/ml, i.e., the decrease of the active ingredient content was 1.8%.

EXAMPLE 2

Under GMP sterile aqueous solution carboplatin concentration carboplatin 9,99 mg/ml was prepared from substances carboplatin having a purity 99,82% and containing 0,08% by weight 1,1-cyclobutanedicarboxylic acid and 0.07% by weight of water. The obtained pharmaceutical composizione of example 1. After 36 months, this pharmaceutical composition showed the content carboplatin 9,80 mg/ml, i.e., the decrease of the active ingredient content was 1.9%.

EXAMPLE 3

Under GMP sterile aqueous solution carboplatin concentration carboplatin 10,02 mg/ml was prepared from substances carboplatin having a purity 99,86% and containing 0.03% by weight 1,1-cyclobutanedicarboxylic acid and 0.10% by weight of water. The obtained pharmaceutical composition having a pH of 6.3, were placed in the form of portions 45 ml vials. The subsequent procedure was identical to the procedure of example 1. After 36 months, this pharmaceutical composition showed the content carboplatin 9,84 mg/ml, i.e., the decrease of the active ingredient content was 1.8%.

EXAMPLE 4 (comparative example)

Under GMP sterile aqueous solution carboplatin concentration carboplatin there is a 10.03 mg/ml and a concentration of 1,1-cyclobutanedicarboxylic acid 0.25 mg/ml (i.e., the minimum stabilizing concentration according to EP 642792) was prepared from substances carboplatin having a purity of 99.85% and containing 0.05% by weight 1,1-cyclobutanedicarboxylic acid and 0.05% by weight water, and from a substance 1,1-cyclobutanedicarboxylic acid having a purity of 99.7% and the example 1. After 36 months, this pharmaceutical composition showed the content carboplatin 9,83 mg/ml, i.e., the decrease of the active ingredient content was 2.0%.

EXAMPLE 5 (comparative example)

Under GMP sterile aqueous solution carboplatin concentration carboplatin 9,95 mg/ml and a concentration of 1,1-cyclobutanedicarboxylic acid 1,19 mg/ml (i.e., equal to the median of the sample from the interval stabilizing concentrations according to EP 642792) was prepared from substances carboplatin having a purity of 99.85% and containing 0.05% by weight 1,1-cyclobutanedicarboxylic acid and 0.05% by weight water, and from a substance 1,1-cyclobutanedicarboxylic acid having a purity of 99.7% and containing 0.12% water. The pH of this solution was to 5.7. The subsequent procedure was identical to the procedure of example 1. After 36 months, this pharmaceutical composition showed the content carboplatin 9,73 mg/ml, i.e., the decrease of the active ingredient content was 2.2%.

EXAMPLE 6 (comparative example)

Under GMP sterile aqueous solution carboplatin concentration carboplatin 9,73 mg/ml and a concentration of 1,1-cyclobutanedicarboxylic acid 14,80 mg/ml was prepared from substances carboplatin having a purity of 99.85% and codenamespace, having a purity of 99.7% and containing 0.12% water. The pH of this solution was 5,5. The subsequent procedure was identical to the procedure of example 1. After 36 months, this pharmaceutical composition showed the content carboplatin to 8.94 mg/ml, i.e., the decrease of the active ingredient content was 8.1%.

Abbreviation GMP used in the examples is a reduced expression of commonly used technical term "Good Manufacturing Practice" (Techniques of good cooking), which differ in that preparation meets a number of specific terms and conditions required in the pharmaceutical practice.

Pharmaceutical composition with anti-tumor activity, which is an aqueous solution containing from 1 to 20 mg/ml carboplatin, 1,1-cyclobutanecarbonyl acid and/or its salt in an amount of less than 0.1% by weight carboplatin directly after preparation of the composition.

 

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