JP3296545B2 - Cisplatin fine powder and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fine cisplatin powder which can be used for treating cancer, particularly for hepatic arterial infusion.

[0002]

2. Description of the Related Art Cisplatin was reported by Rosenberg et al. In 1969 for its antitumor effect (Nature,
222, 385, 1969), which is a typical antitumor platinum complex drug that has been developed as an anticancer drug, and has a wide range of effects such as bladder cancer, testicular tumor, esophageal cancer, ovarian cancer, and lung cancer. Cisplatin is a yellow, odorless, crystalline powder,
Pharmaceuticals are mainly formulated as solutions for intravenous injection.

[0003] With the development of cancer treatment, the use of anticancer drugs has also become diversified. Although liver cancer is said to be intractable, chemotherapy such as hepatic artery embolization therapy, hepatic arterial infusion chemotherapy, and systemic chemotherapy plays a part in multidisciplinary treatment. Above all, hepatic arterial infusion chemotherapy, which can reach drugs at high concentrations to tumor tissues, is effective. Cisplatin is recognized as a highly effective anticancer drug, and is expected to be used for treatment of liver cancer. However, the solubility of cisplatin in water is about 1 mg / ml at room temperature, and the solubility is extremely low. Therefore, a commercially available injection solution (0.5 mg / ml) is a diluted solution, and the dose for hepatic arterial administration is large. It is not appropriate because it becomes. Therefore, there is a demand for a highly convenient powder formulation that can be prepared into a highly concentrated solution at the time of use and can be used for hepatic arterial infusion chemotherapy.

[0004] The fine powdering of cisplatin is disclosed in JP-B-62-1.
As disclosed in Japanese Patent Publication No. 0930 and JP-B-3-13174, cisplatin is dissolved in cisplatin-soluble tertiary amide or dialkyl sulfoxide, and a solution of cisplatin-insoluble or poorly-soluble solvent such as water and alcohol is prepared. There is known a method in which microcrystalline cisplatin is precipitated and recovered by filtration.

[0005]

However, in the cisplatin fine powder obtained by these methods, tertiary amide used as a soluble solvent remains at a relatively high concentration of 70 ppm or more even on a laboratory scale. Therefore, on an industrial scale, a residue of 100 ppm or more cannot be avoided. Therefore, it is inevitable that these solvents are mixed into the product as it is. In arterial infusion therapy, the high-concentration solution of the drug is directly introduced into the affected area. Therefore, it is necessary to consider the effects of impurities compared to conventional intravenous formulations. Tertiary amide and the like are considered to have an effect on the human body, and it is desirable to remove as much as possible.

[0006] The fine powder according to the conventional method is agglomerated in a state after drying and is in the form of a lump, and requires a lump disintegration step by pulverization or sieving. % Or more, substantially 90% or more, so that when handling the powder in the bulk disintegration step and the subsequent preparation step, fine powder is scattered, which poses a problem of contamination of the working environment. . Anticancer drugs such as cisplatin, which have mutagenic properties, require careful handling and should not be operated in a dry operation or in an open system due to the problem of powder scattering. Furthermore, the conventional fine powder has a high agglomeration property due to a small particle diameter, and the particles are aggregated into a powder having a low fluidity, so that agglomeration and adhesion to instruments and the like are likely to occur, Even if it is moved, it is difficult to handle in the formulation operation because it does not separate. The secondary aggregated particles are aggregated by a relatively strong bond, and are hardly dispersed during solution preparation,
It causes rapid dissolution.

[0007] As another method of pulverization, a method of lyophilizing cisplatin injection to obtain a powder preparation is considered. This method has an advantage that the sterilization step is easy and the obtained cisplatin powder has a short dissolution time. However, the cisplatin solution in the manufacturing process is a dilute solution as described in Japanese Patent Publication No. 3-13174, so that water to be removed must be removed in order to obtain an appropriate amount of cisplatin powder for use. Becomes large, expensive and time consuming, which is not practical. There is also a problem that hydrogen chloride removed at the same time during lyophilization corrodes the lyophilizer system. Also, freeze-dried products require that glass bottles be stored at refrigerated temperatures due to stability issues. (NCI pharmaceutical data sheet)

Accordingly, an object of the present invention is to provide a fine powdered cisplatin drug substance which has a low crystallization solvent content, has low solubility and does not form secondary aggregated particles which hinder the preparation operation, and has a high fluidity as a powder. And to provide a formulation with good stability.

[0009]

Means for Solving the Problems The inventors of the present invention dissolve a cisplatin drug substance in a solvent such as dimethylformamide containing hydrogen chloride and water, and then precipitate the cisplatin crystals by the method of the present invention. It has been found that a fine cisplatin powder having a high fluidity that satisfies the above conditions and is less likely to adhere and aggregate can be obtained. Further, the obtained cisplatin fine powder is stirred in a solvent hardly soluble in cisplatin such as dilute hydrochloric acid for a certain period of time or more, and the solvent such as DMF can be sufficiently removed by eluting the residual solvent. The present inventors have found that the obtained cisplatin fine powder has high fluidity and maintains the property of hardly causing adhesion and aggregation, thereby completing the present invention.

The fine cisplatin powder according to the present invention has a residual solvent amount smaller than that of the conventional method, and when DMF is used, it is analyzed by gas chromatography at 60 pp.
m or less. It was easily dispersed in water or physiological saline, and was rapidly dissolved at room temperature by gentle shaking two to three times per second. The drug substance obtained after drying is in the form of a free flowing powder that does not form secondary aggregated particles, so there is no need for operations such as pulverization, there is no problem of powder scattering and adhesion, It is easy to handle in the conversion operation. Also, by manufacturing using aseptic technology, it can be made into a sterile drug substance, and it is possible to shift to the formulation operation as it is,
Application to actual industrialization was made possible. Those aseptically manufactured and formulated can be used as anticancer agents for arterial infusion therapy. In addition, the preparation of the present invention having a fine powder has good storage stability, and can be used as a preparation for hepatic artery embolization therapy by dispersing in distilled water for injection, physiological saline or the like at the time of use. Was.

That is, the present invention provides the following 1 to 6
It is about. 1. A fine powder composed of fine particles of cisplatin substantially passing through a 40-mesh sieve and placed on a 40-mesh sieve is subjected to a sieve passing test (vibration frequency 50 times / sec, vibration at 4.6 G for 5 minutes at a vibration intensity of 4.6 G). ), Wherein the fine particles of cisplatin are characterized in that the residual ratio of the secondary aggregated particles on the sieve is 10% or less, and the crystalline form has the following characteristic peaks in the X-ray powder diffraction diagram. 2θ plane spacing (Å) 13.98 6.329 15.1 5.862 16.42 5.394 26.92 3.309

2. Powder compression degree derived from tapping test is 45 to 54%, and bulkiness is 0.45 to 0.55
2. The fine cisplatin powder according to the above 1, wherein the tertiary amide content is 60 ppm or less. 3. 3. The fine cisplatin powder according to the above 1 or 2, wherein the fine powder of cisplatin is dissolved within 10 minutes by light shaking (2 to 3 times per second) with light shaking to obtain an aqueous solution of cisplatin at a concentration of 1 mg / ml. 4. The above 3 for arterial infusion therapy or embolization therapy for cancer treatment
The described cisplatin fine powder.

5. The following continuous process, ie, (1) third
Hydrogen chloride was added in an amount of 0.1 wt.
3% (weight) to 3% (weight), water 4% (weight) to 15% (weight) and cisplatin 20 to 40 g /
Preparing a cisplatin solution containing at a concentration of L;
(2) 10 to 3 volumes 1 to 4 times the volume of the cisplatin solution.
The cisplatin solution is dropped into 0.1 to 2N hydrochloric acid at 0 ° C. with stirring at a flow rate of dropping the cisplatin solution in 20 to 40 minutes to precipitate fine cisplatin powder, (3)
A method for producing fine cisplatin powder, comprising collecting the precipitated fine cisplatin powder by filtration. 6. The organic solvent-containing cisplatin fine powder was used in an amount of 0.02 to 1
A method for producing fine cisplatin powder having a reduced organic solvent content, comprising suspending and stirring in normal hydrochloric acid at room temperature for 1 to 5 hours, and filtering and collecting the suspension.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The preferred conditions relating to the method for producing fine cisplatin powder having high fluidity and dissolving quickly according to the present invention will be described below. Cisplatin used as a raw material in the present invention is not particularly limited, for example, Indian Journal of Chemistry,
According to a production method represented by Vol. 8, p. 193 (1970), those having a purity that can be used as a drug substance are desirable. First, the raw material cisplatin is dissolved in a tertiary amide solution containing hydrogen chloride and water, and hydrogen chloride is added to the entire tertiary amide solution in an amount of 0.3% (weight) to 3% by weight.
A cisplatin solution is prepared comprising a tertiary amide solution containing 4% (wt) water, 4% (wt) to 15% (wt), and cisplatin at a concentration of 20-40 g / L.
This cisplatin solution may be prepared in any manner, but is usually obtained by first uniformly mixing hydrochloric acid with a tertiary amide and then dissolving cisplatin in the tertiary hydrochloric acid solution.

That is, based on the entire tertiary amide solution, hydrogen chloride is converted to about 0.3% (weight) by weight, more preferably about 0.4% (weight) to about 4% (weight). Is a tertiary hydrochloride amide solution containing about 3% (by weight) and about 4% (by weight) water, preferably about 7% (by weight) to about 15% (by weight), more preferably about 12% (by weight), Cisplatin is dissolved at a concentration of about 20 to about 40 g / L.
The above-mentioned tertiary hydrochloric acid solution for dissolving cisplatin may be prepared in any manner, but usually, 2 to 6N, preferably 2.5 to 4N hydrochloric acid is added to a tertiary amide solution such as dimethylformamide (DMF). It can be obtained by adding and mixing with a tertiary amide. The compounding amount of the hydrochloric acid is 5 to 15% (weight), preferably 8 to the whole obtained solution.
Preferably, it is contained in an amount of up to 12% (by weight).

The present inventors have found that when the cisplatin solution obtained as described above is dropped into dilute hydrochloric acid to precipitate crystals, the time of dropping greatly affects the quality. That is, for example, when 1 liter to 6 liters of the cisplatin solution is dropped into hydrochloric acid of 1 to 4 times the volume of the cisplatin solution with stirring, if the dropping time is within 20 minutes, the flowability is low and the secondary aggregated particles are low. When the cisplatin solution was added dropwise over 40 minutes or more, a powder having high fluidity but extremely poor solubility was obtained. That is, the dropping time is 20 to 40.
Minutes, preferably 22 to 35 minutes.

The temperature of the solution for precipitating the crystals is 10-30.
It is desirable to keep the temperature at 12 ° C, preferably 12-25 ° C. Crystallization at higher temperatures resulted in reduced yields. For crystallization, as described above, a method of adding a cisplatin solution to dilute hydrochloric acid is usually preferable. In some cases, the reverse method may be used, but the method of adding a cisplatin solution to dilute hydrochloric acid as described above is generally more advantageous in terms of easy temperature control. The reaction system is preferably stirred uniformly, but the stirring speed and the shape of the stirring blade have little effect on the quality of the product.

That is, in order to produce the fine cisplatin powder of the present invention, (1) 2 to 6 normalization, preferably 2.5 to 4
A cisplatin solution is prepared by dissolving cisplatin at a concentration of 20 to 40 g / L, preferably 22 to 30 g / L, in a tertiary amide solution containing 5 to 15%, preferably 8 to 12% of normal hydrochloric acid, and (2) 0.1 to 2N, preferably 0.2 to 0.6N hydrochloric acid maintained at 10 to 30 ° C, preferably 12 to 25 ° C, 1 to 4 times the volume of the cisplatin solution, preferably 1.5 to 3 times the volume. Under stirring, the cisplatin solution is dropped at a constant flow rate at a constant flow rate for 20 to 40 minutes, preferably at a flow rate at which the dropping takes place over 22 to 35 minutes,
Precipitating fine cisplatin powder,

(3) A method of recovering the precipitated cisplatin fine powder by filtration is preferred. In the present invention, examples of the tertiary amide include N, N-dialkylformamide and N, N-dialkylacetamide. Specific examples of these include N, N-dimethylformamide, N, N-diethylformamide,
N-dimethylacetamide, N, N-diethylacetamide and the like can be mentioned. Particularly, in the present application, N, N-dimethylformamide is preferable. A crystallization solvent, for example, fine cisplatin powder from which tertiary amide has been removed as much as possible can be obtained by the following steps.

That is, the precipitated cisplatin fine powder is collected by filtration, recovered, suspended in dilute hydrochloric acid of 0.02 to 1 normal, preferably 0.05 to 0.2 normal, and preferably suspended at room temperature for 10 to 30 normal. After stirring at 1 ° C. for 1 hour or more, more preferably 3 hours or more, and within 5 hours, preferably within 4.5 hours, the mixture is filtered and the residual solvent is removed. By this solvent removal step, the solvent content in the fine cisplatin powder of the present invention can be reduced to 60 ppm or less, more preferably 55 ppm or less, further preferably 40 ppm or less, particularly preferably 30 ppm or less. The fine cisplatin powder of the present invention thus obtained has a remarkably low residual organic solvent content (for example, 10 to 60).
ppm, more preferably 10 to 55 ppm,
More preferred is 10 to 40 ppm, particularly preferably 10 to 30 ppm), which is characterized by good storage stability and good flowability since it is difficult to form large secondary aggregated particles.

The more detailed properties of the fine cisplatin powder of the present invention are described below. That is, the individual particles of the cisplatin fine powder of the present invention all have a columnar or plate-like appearance of 30 μm or less when viewed with an electron microscope of about 1,000 to 4,000 times, and the formation of large secondary aggregated particles is Few. On the other hand, in the case of the example of Japanese Patent Publication No. Hei 3-13174 (comparative example) described below, each of the fine particles is as small as 5 μm or less, but these are primary aggregates in the form of scales (about 10 μm)
In addition, the primary aggregated particles secondary aggregate and form an aggregate. For reference, crystal images of the fine powder of the present invention and the comparative example by an electron microscope are shown in FIGS. 1 and 2, respectively.

Further, in the cisplatin fine powder of the present invention, for example, large secondary aggregated particles having a mesh size of 40 mesh or more have a residual ratio on a sieve of 10% or less, preferably 1 to 1, as determined by a 40 mesh sieve passing test shown in Test Example 2. 10%, more preferably 1
~ 5%. Further, the powder compression degree derived from the tapping test shown in Test Example 3 is 45 to 54%, preferably 4 to 54%.
6 to 50%, and the bulkiness is 0.45 to 0.55;
It preferably has properties (physical properties) of 0.48 to 0.53. In addition, 100 mg of this and 100 ml of physiological saline or distilled water were gently placed in a test tube (2 times a second).
~ 3 times) When shaken, complete dissolution occurs within 10 minutes, preferably within 6 minutes, more preferably within 5 minutes, and usually within 2 to 5 minutes. Due to this property, it is easy to handle in the preparation operation, and the obtained fine powder preparation can be dissolved for use in hepatic arterial infusion and used for hepatic embolization therapy because of its good dispersibility. Table 1 below shows data on the crystal structure of the fine cisplatin powder of the present invention obtained from X-ray powder diffraction (filtered CuKα1 radiation, 1.5406 °).

[0023]

Table 1 Table 1 Main peak values of the X-ray powder diffraction pattern of Example 1 of the present invention 2θ Relative intensity Plane spacing (Å) 13.98 100 6.329 15.1 22 5.862 16.42 24 5. 394 24.2 8 3.674 26.92 24 3.309 28.51 12 3.128

As is clear from the above table, the fine cisplatin powder of the present invention has a 13.theta.
It is characterized by having strong peaks at 1, 16.42 and 26.92. On the other hand, for example, the freeze-dried product does not show a clear characteristic peak at the 2θ value corresponding to the above in the X-ray powder diffraction diagram measured under the same conditions, and the crystal structure is clearly different. Was. Hereinafter, the effects of the present invention will be specifically described with appropriate comparison with conventional techniques. First, the tertiary amide of the crystallization solvent, for example, N, N-dimethylformamide (DMF) is compared with respect to the residual degree. The residual amount was 70 ppm or more, whereas the fine cisplatin powder of the present invention was 30 ppm or less (see Test Example 1).

When the solvent removal step of the present invention is carried out to reduce the residual amount of DMF from the fine cisplatin powder having a large residual DMF obtained by the prior art, although the solvent content is reduced, the fluidity is significantly deteriorated. As in the case of the cisplatin fine powder according to the present invention, it was not possible to obtain a cisplatin fine powder having a small residual amount of DMF and excellent in fluidity and the like (see Reference Example).

Next, regarding the cohesiveness of the powder related to the easiness of the formulation operation, a sieve of 40 mesh was used,
After vibrating for about 1 minute and comparing the residual ratios on the sieve, those of the present invention hardly agglomerated and hardly adhered to a sieve or the like. On the other hand, both those obtained by the conventional method (Comparative Example) and those obtained by reducing the solvent content (Reference Example) formed aggregated particles having a particle size larger than the mesh size of the sieve, and most remained on the sieve (test See Example 2). In the formulation operation, the filling property of the powder is also one of the important criteria, and this is an index for checking the fluidity.
Then, fine cisplatin powder was deposited in a graduated cylinder, and this was tapped, and the compressibility and bulkiness derived from its apparent bulk density and volume were determined to compare the filling properties. The degree of bulkiness is shown in Materials, Vol. 14, pp. 574 (197
0), specifically, the method described in Test Example 3. The fine powder of the present invention was small in both the degree of compression and the degree of bulkiness and had good filling properties.

Next, regarding the solubility, 100 mg of the cisplatin fine powder according to the present invention and 100 ml of physiological saline were added.
were mixed and shaken gently to dissolve within 5 minutes. On the other hand, in the samples of the comparative example and the reference example, undispersed secondary particles remained, and did not actually dissolve sufficiently even after 10 minutes. In addition, the storage stability of the fine cisplatin powder of the present invention is extremely excellent, and when sealed in a glass vial, no decomposition is observed even after storage for 39 months under natural indoor conditions. .

The fine cisplatin powder provided by the present invention can be converted into a sterile drug substance by sterilization treatment. The fine powder of cisplatin is aseptically filled in a sterilized sealed container, for example, an ampoule or a glass bottle. It is prepared into a powder formulation. In order to clarify the advantageous effects of the cisplatin fine powder of the present invention, the comparative example was obtained by comparing Example 4 of JP-B-3-13174 (Comparative Example) with that obtained by the conventional method. A solvent (dimethylformamide) removal treatment (the solvent removal treatment of the present invention) was used (Reference Example).

[0029]

The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Example 1 N, N-dimethylformamide (1080 ml) and 3N hydrochloric acid (120 ml) were mixed. To this cisplatin 30.0
g was added and stirred at room temperature for 1 hour to dissolve. This solution was passed through a 0.2 μm filter to remove insoluble components.
0.3N hydrochloric acid 2400m previously cooled to 15 ° C
1 was added dropwise with stirring and cooling at a constant flow rate over a period of 33 minutes. A fine cisplatin powder was precipitated to obtain a suspension. After the addition was completed, the mixture was stirred at room temperature for 1 hour. The precipitated fine cisplatin powder was collected by filtration and washed twice with 50 ml of 0.1 N hydrochloric acid. The wet cake was suspended in 360 ml of 0.1 N hydrochloric acid and stirred at room temperature for 4 hours. The suspension was filtered to obtain fine cisplatin powder. The plate was washed twice with 50 ml of 0.1 N hydrochloric acid and then twice with 50 ml of ethanol. After drying under reduced pressure for 3 hours, 22.55 g of fine cisplatin powder was obtained. 100 mg of the obtained fine powder of cisplatin and 100 ml of physiological saline were placed in a test tube, mixed, and gently shaken to visually confirm that the solution was completely dissolved in 4 minutes.

Example 2 Preparation of fine cisplatin powder sterile drug substance The equipment used, the filter, and the like used were those previously sterilized by an appropriate sterilization method. 3.6 L of N, N-dimethylformamide and 0.4 L of 3N hydrochloric acid were mixed. 100 g of cisplatin was added thereto, and the mixture was stirred at room temperature for 1 hour to dissolve. This solution was passed through a sterilized 0.2 μm membrane filter. The cisplatin solution was dropped into 8.0 L of 0.3 N hydrochloric acid kept at 15 ° C with stirring and cooling at a constant flow rate over 25 minutes through a sterilized 0.2 μm membrane filter. A fine cisplatin powder was precipitated to obtain a suspension. After the addition was completed, the mixture was stirred at room temperature for 1 hour. The precipitated cisplatin fine powder was collected by filtration, and this was filtered with 180 ml of 0.1N hydrochloric acid sterilized by filtration.
Washed twice. The wet cake was suspended in 1.2 L of 0.1 N hydrochloric acid sterilized by filtration and stirred at room temperature for 4 hours. The suspension was filtered to obtain fine cisplatin powder. The membrane was washed twice with 180 ml of 0.1N hydrochloric acid sterilized by filtration, and then twice with 180 ml of ethanol sterilized by filtration. After drying under reduced pressure for 3 hours, 65.1 g of fine cisplatin powder was obtained. Filled into sterile glass bottles and sealed. 100 mg of the obtained cisplatin fine powder and 100 ml of physiological saline were placed in a test tube, mixed, and gently shaken to visually confirm that they were completely dissolved in 5 minutes.

Comparative Example 20 g of cisplatin were dissolved in 500 ml of a solution of DMF-concentrated HCI (9: 1). This solution was stirred for 1 hour, and 0.1N-HCI (1000 ml) was added thereto. The resulting suspension was stirred for 15 minutes, then the solid was collected by filtration. This was washed twice with 40 ml of 0.1 N hydrochloric acid and twice with 80 ml of acetone, and dried under reduced pressure at room temperature for 3 hours to obtain. Reference Example According to Example 1 of the present application, the fine cisplatin powder obtained in Comparative Example 1 was stirred in 0.1 N HCl at room temperature for 4 hours to remove DMF.

Test Example 1 Analysis of Residual DMF Amount of fine cisplatin powder produced by each method was dissolved in dimethyl sulfoxide, and the solution was analyzed by gas chromatography to determine the amount of residual DMF contained in the product. Residual DMF of cisplatin fine powder according to Example 1 of the present invention; 18 ppm Residual DMF of cisplatin fine powder according to comparative example; 72 ppm Residual DMF of cisplatin fine powder according to reference example; 27 ppm

Analysis conditions for gas chromatography Column: Gas clopack 55 (GL Science) Column temperature: 180 ° C. Carrier gas: nitrogen, 50 ml / min. Detector: Flame ionization detector Sample: 0.2 g of the sample is made into a solution of 1 ml of dimethyl sulfoxide, and 5.0 μl is introduced.

Test Example 2 Sieving test Cisplatin 2.00, which was previously passed through a 40-mesh sieve having an outer diameter of 7.5 cm and passed through a 40-mesh sieve to form a powder, was obtained.
g was gently placed and vibrated (vertical direction) at a vibration frequency of 50 G / sec and a vibration intensity of 4.6 G for 5 minutes using a sieve vibrator. The vibration intensity was measured with a “strain gage type acceleration transducer”. The amount passed through the sieve and the amount remaining on the sieve were weighed to derive the residual ratio. Fig. 2 is a fine powder of cisplatin according to Example 1 of the present invention. Residual rate
2.0% Cisplatin fine powder according to Comparative Example, residual ratio 63.5% Cisplatin fine powder according to Reference Example. Residual rate 70.0%

The residue on the sieve in the sieving test is derived from the following formula described in General Tests, Japanese Pharmacopoeia. A = B / S × 100 A: Residual rate (%) B: Sample (g) remaining on the sieve S: Sample (g)

Test Example 3 Filling test by tapping Fine cisplatin powder which had been passed through a sieve of 40 mesh in advance was gently put into a 25 ml measuring cylinder through a powder funnel, and deposited in a volume of about 20 to 25 ml. The apparent volume in the loosely packed state was measured. This was tapped at a tap height of 2 cm. The apparent volume was measured every 20 taps. When the apparent volume became constant, tapping was terminated. Weigh the filled cisplatin,
The bulk density for each tap was derived. The degree of compression was derived from the bulk density. The bulkiness was determined by the method reported in Materials, Vol. 14, p. 574 (1970). Fig. 2 is a fine powder of cisplatin according to Example 1 of the present invention. Powder filling compression degree
48.8%. The degree of bulkiness is 0.51. Cisplatin fine powder according to Reference Example. Powder filling compression degree 58.6%. The bulkiness is 0.65.

The degree of compression derived from the tapping test is determined by the following equation. c = (ρf−ρ0) / ρf × 100 c: degree of compression (%) ρf: bulk density (g / ml) ρ0: loose bulk density (g / ml)

The degree of bulkiness is derived by the following method. When plotting the relationship between n / C and n from the data obtained from the tapping filling, n: number of taps (times) C = 1−v / v0 (v0: apparent volume in a loosely packed state,
v: Apparent volume for each tap) n / C and n have a linear relationship, and a linear equation: n / C = 1 /
ab + n / a (a, b: constants), and the degree of bulkiness: a is derived from the slope of the graph.

Test Example 4 Storage stability test 15 g of the cisplatin fine powder of the present invention was sealed in a transparent glass vial and stored in a room under natural conditions for 39 months. Thereafter, the degree of degradation was measured by HPLC, and as a result, no cisplatin-related substance produced by the degradation was recognized, and the content of the drug substance cisplatin was 100.1%.

Comparison with the conventional method in the formulation operation The fine cisplatin powder of the present invention (Example 1) has almost no secondary cohesiveness, has a good free flowing property, and has no adhesion to a container. It is. Due to this property, the process proceeded smoothly in various operation points (storage, mixing, dispensing and packaging, evaluation) for formulation. On the other hand, the fine cisplatin powder according to the comparative example and the reference example is a lump after drying, which requires mill pulverization, and furthermore, the fine powder is scattered and the problem of chemical hazard is inevitable. is there. And even after milling, these fine powders are secondary agglomerated, have low fluidity, adhere to equipment, etc., and hinder the operation of mixing, dispensing, packaging and evaluation in formulation. And lacked accurate weighing.

[0042]

Industrial Applicability The present invention relates to a fine cisplatin powder formulation provided as an anticancer drug for arterial infusion therapy for treating cancer, which has a high powder flowability, is easy to handle in a formulation operation, has good dispersibility, and has excellent water dispersibility. It dissolves promptly, making it possible to provide a highly convenient powder formulation. Furthermore,
It was possible to provide a fine cisplatin powder which has a small content of N, N-dimethylformamide and can be safely applied to clinical applications.

[Brief description of the drawings]

1 is a fine powder of cisplatin according to the present invention (Example 1)
3 shows a crystal image of the sample taken by an electron microscope (× 4000).

FIG. 2 shows a crystal image of a cisplatin fine powder (comparative example) obtained by a conventional method under an electron microscope (4000 times).

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-58-32029 (JP, A) JP-A-7-101724 (JP, A) JP-A-6-183733 (JP, A) (58) Field (Int. Cl. ⁷ , DB name) C01G 55/00 CA (STN)

Claims (6)

(57) [Claims] 1. A fine powder consisting of fine particles of cisplatin substantially passing through a 40-mesh sieve, and comprising the fine particles,
Place on a 40-mesh sieve and pass through sieve test (frequency 50 times /
(Second vibration for 4.5 minutes at a vibration intensity of 4.6 G), the secondary aggregated particles have a residual rate on the sieve of 10% or less, and have a crystal form having the following characteristic peaks in the X-ray powder diffraction diagram. Cisplatin fine powder characterized by the above-mentioned. 2. The powder compression degree derived from a tapping test is 45 to 54%, the bulkiness is 0.45 to 0.55, and the tertiary amide content is 60 ppm or less. The cisplatin fine powder according to the above item. 3. The cisplatin according to claim 1, wherein the dissolution time is within 10 minutes by light shaking (2 to 3 times per second) to obtain a cisplatin aqueous solution having a concentration of 1 mg / ml. Fine powder. 4. The fine cisplatin powder according to claim 3, which is used for arterial infusion therapy or embolization therapy for cancer treatment. 5. The following continuous steps: (1) Hydrogen chloride is added in an amount of 0.3% (weight) to 3% (weight) and water is added in an amount of 4% with respect to the entire tertiary amide solution.
(Weight) to 15% (weight) and 20% cisplatin
A cisplatin solution containing a concentration of で 40 g / L was prepared.
The cisplatin solution is dropped into 0.2 to 2N hydrochloric acid cooled to 0 ° C. with stirring at a flow rate of 20 to 40 minutes while dropping the cisplatin solution to precipitate fine cisplatin powder. A method for producing fine cisplatin powder, comprising collecting the fine cisplatin powder by filtration. 6. The cisplatin fine powder obtained by the production method according to claim 5 , further comprising:
A method for producing a fine cisplatin powder in which the content of an organic solvent is reduced by suspending and stirring at room temperature for 1 to 5 hours, and filtering and collecting the suspension.