CN106265500B

CN106265500B - Solution containing miboplatin, application of solution, miboplatin freeze-dried powder injection, preparation method and application

Info

Publication number: CN106265500B
Application number: CN201610858543.6A
Authority: CN
Inventors: 袁利佳
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-09-28
Filing date: 2016-09-28
Publication date: 2020-01-31
Anticipated expiration: 2036-09-28
Also published as: CN106265500A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to solutions containing miboplatin, an application of the solutions, a miboplatin freeze-dried powder injection, a preparation method of the miboplatin freeze-dried powder injection and an application of the miboplatin freeze-dried powder injection.

Description

Solution containing miboplatin, application of solution, miboplatin freeze-dried powder injection, preparation method and application

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to miboplatin-containing solution and application thereof, a miboplatin freeze-dried powder injection and a preparation method and application thereof.

Background

Chemical name: (SP-4-2) - [ (1R,2R) -1,2 cyclohexanediamino-N, N' ] bis (tetradecanoic acid-O) platinum;

the molecular formula is as follows: c₃₄H₆₈N₂O₄Pt·H₂O；

Molecular weight: 782.01, respectively;

structural formula (xvi):

the miboplatin is white to yellowish crystalline powder and a fat-soluble platinum metal complex; the product is soluble in chloroform and dichloromethane, slightly soluble in ethanol, slightly soluble in methanol, and hardly soluble in water and acetonitrile.

The miboplatin is a platinum anticancer drug developed by Nippon Sumitomo pharmaceutical company, the specification of the freeze-dried powder injection is 70 mg/ampoule, and the miboplatin has obvious effects on treating liver cancer, malignant lymphoma, non-small cell lung cancer, small cell lung cancer and overlook cancer on the surface.

The preparation method of the miriplatin freeze-dried powder injection can be seen in Chinese patent CN02818527.7, wherein the preparation technology of the miriplatin freeze-dried powder injection is to dissolve miriplatin in tert-butyl alcohol and adjust the water content of the solution. Although the prepared product is stable after being suspended in iodine addition compound of fatty acid ethyl ester of the baby chestnut oil (iodized oil injection) and is easy for clinical operation, when the product is produced, in order to prevent the solution from solidifying or partially solidifying (the melting point of the tertiary butanol is 25.5 ℃) due to low environmental temperature in the processes of preparing the miboplatin and filtering and filling, a special heat preservation device is needed in the whole filtering and filling process to ensure that the tertiary butanol cannot be solidified, the production is normally carried out, the production cost of the crude method is increased, and the operation of operators is difficult to work under the aseptic environment. Because the solubility of the miboplatin in the tert-butyl alcohol is low, the preparation concentration of the freeze-drying solution is 4mg/mL, the specification of the commercially available miboplatin freeze-drying powder is 70 mg/count, the volume of the medicine solution is about 17.5mL, the volume of the freeze-drying solution is large, the preparation process time is long, the energy consumption is high, the unit production time is long, and the production cost is increased.

The preparation method of the miriplatin freeze-dried powder injection can be seen in Chinese patent application No. 20110201119.1, wherein the preparation technology of the miriplatin freeze-dried powder injection is to dissolve miriplatin in a mixed solution of tert-butyl alcohol and ethanol to reduce the melting point of a drug solution, but the solubility of the miriplatin in the mixed solution of tert-butyl alcohol and ethanol is low, the preparation concentration of the freeze-dried solution is 3.93mg/mL, the specification of the commercially available miriplatin freeze-dried powder is 70 mg/count, the volume of the drug solution is about 17.8mL, the volume of the freeze-dried solution is large, the preparation process time is long, the energy consumption is high, the unit production time.

Disclosure of Invention

The problems of the prior art solved by the invention are as follows: the existing miboplatin freeze-dried powder injection has low solubility in a solvent, large volume of freeze-dried solution when the freeze-dried powder is used, long preparation process time, much energy consumption and high production cost.

The invention aims to overcome the defects of the prior art and provides miboplatin-containing solutions and application thereof, and a miboplatin freeze-dried powder injection and a preparation method and application thereof.

Specifically, the invention provides miboplatin-containing solutions comprising miboplatin, t-butanol and n-butanol.

In a second aspect, the invention provides application of a mixed solvent containing tert-butyl alcohol and n-butyl alcohol in the field of miriplatin freeze-dried powder injection.

In a third aspect, the invention provides miriplatin freeze-dried powder injection, which is obtained by freeze-drying a miriplatin solution, wherein the miriplatin solution is dissolved in a mixed solvent containing tert-butyl alcohol and n-butyl alcohol.

Preferably, the volume ratio of n-butanol to t-butanol in the mixed solvent is (1: 99) to (10: 90).

Preferably, the volume ratio of n-butanol to t-butanol in the mixed solvent is (2:98) - (5: 95).

More preferably, the volume ratio of n-butanol to t-butanol in the mixed solvent is 3: 97.

Preferably, the concentration of the miboplatin in the mixed solvent is 3 mg/mL-50 mg/mL,

preferably, the concentration of the miboplatin in the mixed solvent is 5mg/mL to 30 mg/mL.

More preferably, the concentration of the miboplatin in the mixed solvent is 10 mg/ml.

Preferably, the purity of the miriplatin is greater than 99%.

Preferably, the particle size of the miriplatin freeze-dried powder injection is 5-25 μm.

More preferably, the particle size of the miriplatin freeze-dried powder injection is 5-15 μm.

In a fourth aspect, the invention provides a preparation method of miboplatin freeze-dried powder injection, which comprises the steps of uniformly mixing miboplatin with a mixed solvent containing tert-butyl alcohol and n-butyl alcohol, and freeze-drying to obtain the miboplatin freeze-dried powder injection.

Preferably, the concentration of the miboplatin in the mixed solvent is 3 mg/mL-50 mg/mL.

Preferably, the purity of the miriplatin is greater than 99%.

Preferably, the temperature during mixing is 40 to 70 ℃.

Preferably, the temperature range during freeze-drying is-40 ℃ to 40 ℃.

Preferably, the temperature interval during lyophilization comprises: freeze-drying at-40 ℃ to-35 ℃ for 5-15 h, freeze-drying at-30 ℃ to-20 ℃ for 20-30 h, and freeze-drying at 30-40 ℃ for 10-20 h.

In a fifth aspect, the invention provides the use of the miriplatin freeze-dried powder injection of any one of in the preparation of a medicament for treating cancer,

preferably, the miboplatin lyophilized powder injection of any above is applied to the field of preparing drugs for treating hepatocellular carcinoma.

The beneficial effects obtained by the invention are as follows: (1) in the miriplatin freeze-dried powder injection, a mixed solvent of n-butyl alcohol and tert-butyl alcohol is used in the preparation process, so that the solubility of the miriplatin can be improved, the volume of a miriplatin freeze-dried solution is reduced, and the production time and energy consumption are reduced; meanwhile, the central particle size distribution of the freeze-dried finished product is 5-25 mu m, and the sedimentation coefficient and viscosity have no obvious change within 24 hours after the freeze-dried finished product is suspended in iodized oil of poppy seeds, namely the produced sample is relatively stable in clinical use.

(2) The preparation method is simple, convenient and feasible, can be used for industrial mass production, reduces the production cost and can generate considerable economic and social benefits. The miriplatin freeze-dried powder injection prepared by the method can be used for treating tumors related to hepatocellular carcinoma, and can provide medical facilities with enough measures and local therapies for cancer chemotherapy and liver cancer cells in emergency.

Drawings

FIG. 1 is an electron micrograph of a Miripla preparation (Miripla) commercially available from Japan (Sumitomo, Japan).

FIG. 2 is an electron microscope image of the miboplatin lyophilized preparation prepared in the second embodiment of the invention.

Detailed Description

As described above, the invention provides miriplatin freeze-dried powder injections and a preparation method thereof, aiming at solving the problem of higher production cost caused by lower solubility of the existing miriplatin freeze-dried powder injection in a solvent.

Specifically, the invention provides miboplatin freeze-dried powder injection which is obtained by freeze-drying a mixed solvent containing miboplatin, tert-butyl alcohol and n-butyl alcohol.

Wherein in preferred embodiments of the invention, the volume ratio of the tertiary butanol to the n-butanol is (95-98): 2-5.

In the miriplatin freeze-dried powder injection, n-butyl alcohol is used in the preparation process, so that the temperature requirement of the miriplatin powder injection on the production environment can be reduced, and the miriplatin solution is prevented from being solidified or partially solidified at room temperature in the production process; the central particle size distribution of the freeze-dried finished product of the miboplatin freeze-dried powder injection prepared by the method is 5-25 mu m, and the sedimentation coefficient and the viscosity have no obvious change within 24 hours after the miboplatin freeze-dried powder injection is suspended in the iodized oil of poppy seeds, namely the produced sample is relatively stable in clinical use.

The preparation method of the miboplatin freeze-dried powder injection comprises the steps of measuring the prescription amount of tert-butyl alcohol and n-butyl alcohol, adding the tert-butyl alcohol and n-butyl alcohol into a material preparation tank, uniformly stirring, controlling the temperature of the solution at 40-70 ℃, then weighing the prescription amount of miboplatin, uniformly dissolving the miboplatin under stirring or ultrasonic treatment at a keeping temperature, checking to be qualified, filtering the obtained solution to be clear by using an organic microporous filter membrane of 0.22 mu m under aseptic conditions, filling the obtained filling amount according to the miboplatin into a penicillin bottle, filling a half plug of a butyl rubber plug into the penicillin bottle, loading the obtained product into a tray, feeding the product into a freeze dryer, closing a box , opening the freeze dryer for freeze drying, then pressing and taking out the product, rolling the opening by using a combined aluminum-plastic cover, and packaging the.

The present invention is further described in in detail in connection with the following detailed description, which is intended to be illustrative only and is not to be construed as limiting the scope of the invention.

TABLE 1 information on reagents and raw materials used in examples of the present invention and comparative examples

TABLE 2 information on the equipment used in the examples of the present invention and the comparative examples

The raw material miboplatin for researching the miboplatin freeze-drying process can be prepared and synthesized by the raw material miboplatin per se according to the synthesis route disclosed in the prior art, and can also be obtained by purchasing high-purity miboplatin sold in the market as the raw material.

Among them, in preferred embodiments of the present invention, miboplatin was synthesized by the following process:

the synthetic process route of the miboplatin is as follows:

step, potassium tetrachloroplatinate, potassium iodide and levo- (1R,2R) -cyclohexanediamine are prepared into an intermediate (1R; 2R) - (-) -1,2 cyclohexanediamine-diiodoplatinum (II), and the second step, sodium myristate and silver nitrate are reacted to prepare another intermediate side chain, namely the reaction is carried out according to the formula (II);

and step three, butting and refining the side chains of the two intermediates to obtain a final product, namely, reacting according to the formula (III), and then repeatedly refining and crystallizing the prepared finished product to obtain the miboplatin raw material with the purity of 99.5% for later use. The process is closest to the synthetic route reported in the original research, and is also beneficial to the industrialization of the production of the product.

Example

Screening of organic solvents

Because the miboplatin is difficult to dissolve in water, and the solubility of the miboplatin in an organic solvent is different due to different solvents, if the solubility of the miboplatin in the organic solvent can be improved, the volume of the miboplatin freeze-dried solution in use can be reduced, meanwhile, the solvent content of the miboplatin freeze-dried powder injection in freeze-drying is reduced, the production time and energy consumption are reduced, and the process is simplified.

Example an organic solvent that significantly improves the solubility of miboplatin in the solvent was selected by measuring the solubility of miboplatin in different solvents at different temperatures.

The dissolution performance test comprises the steps of weighing quantitative miboplatin bulk drug, placing the miboplatin bulk drug in quantitative solvent, transferring the mixture into a constant-temperature water bath, magnetically stirring the mixture, and observing the dissolution condition every 10 minutes, wherein if no visible solute particles exist, the dissolution is complete.

1.(1) selection of organic solvent

quantitative miriplatin was dissolved in n-butanol, t-butanol solution containing 1% n-butanol (volume ratio, the same shall apply hereinafter), t-butanol solution containing 5% ethanol, t-butanol solution containing 1% acetonitrile, t-butanol solution containing 1% acetone, t-butanol solution containing 1% chloroform, and t-butanol solution containing 1% DMSO, respectively, and the solubility of miriplatin in different solvents was measured at 35 ℃.

TABLE 3 solubility of miboplatin in various solvents

Organic solvent	Concentration of
		N-butanol	11.88mg/mL
Tert-butyl alcohol	4.00mg/mL
		1% n-butanol in tert-butanol	4.35mg/mL
1% ethanol in tert-butanol	4.04mg/mL
		3% ethanol in tert-butanol	3.77mg/mL
5% ethanol in tert-butanol	3.62mg/mL
		1% acetonitrile in tert-butanol	4.17mg/mL
1% chloroform in tert-butanol	4.92mg/mL
		1% acetone in tert-butanol	4.12mg/mL
1% DMSO in tert-butanol	4.17mg/mL

As can be seen from Table 3, the solubility of miboplatin in n-butanol is much higher than that in t-butanol at 35 ℃. However, the melting point of the n-butyl alcohol is about-90 ℃, and the n-butyl alcohol is simply used as a solvent, so that the N-butyl alcohol can not be used for preparing the freeze-dried powder injection of the miboplatin. Therefore, the inventors continued to examine the solubility of miboplatin in t-butanol solutions of other solvents (including n-butanol, ethanol, acetonitrile, acetone, chloroform, DMSO) in various ratios. From the experimental results of table 3, it can be seen that the solubility of miboplatin in t-butanol solution of 1% n-butanol is significantly higher than that in t-butanol solution of 1% ethanol, t-butanol solution of 3% ethanol or t-butanol solution of 5% ethanol. Although the solubility in a solution of 1% acetonitrile in t-butanol and 1% chloroform in t-butanol is comparable to or even higher than that in a solution of 1% n-butanol in t-butanol, acetonitrile and chloroform are both among the second class of organic solvents, i.e., solvents that are non-genotoxic but carcinogenic to animals, and therefore are not considered to be preferred.

(2) Selection of organic solvents

In order to consider the influence of temperature on the solubility of the miriplatin in different solvents in steps, different solvents are selected, the solubility of the miriplatin in different solvents at 45 ℃ or 60 ℃ or above is examined, experiments show that the solubility of the miriplatin in different solutions is not changed greatly and the solubilization effect is not obvious under the 45 ℃ condition, the boiling points of dichloromethane and acetone are both less than 60 ℃, therefore, the solubility of the miriplatin in dichloromethane or acetone is examined under the 60 ℃ condition without considering dichloromethane or acetone as the solvent, DMSO has greater toxicity to blood vessels and liver and kidney, so that the miriplatin is not selected, when the temperature is increased to be higher than 60 ℃, is used for increasing the volatilization speed of the organic solvent and is not easy to control, and a manufacturer controls the cost to be higher than 60 ℃, therefore, finally, the experiment examines that the solubility of the miriplatin in n-butanol, tert-butanol, absolute ethyl alcohol, absolute methanol or ethyl acetate under the 60 ℃ condition, the solubility of the miriplatin in the n-butanol, the absolute ethyl acetate is respectively measured under the 60 ℃, and the solubility of the miriplatin in the 60 ℃ condition is measured, and the table of different solvents is found in 4.

TABLE 4 solubility of miboplatin in various solvents

Solvent(s)	Concentration of
		N-butanol	＞40mg/ml
Tert-butyl alcohol	＞24mg/ml＜25mg/ml
		Anhydrous ethanol	＜15mg/ml
Anhydrous methanol	＜15mg/ml
		Ethyl acetate	＜15mg/ml

As can be seen from Table 4, the solubility of miboplatin in n-butanol or t-butanol is significantly greater than that in absolute ethanol, absolute methanol or ethyl acetate at 60 ℃. Moreover, comparing the data in tables 3 and 4, it can be easily seen that the temperature is raised from 35 ℃ to 60 ℃ and the solubility of miboplatin in n-butanol is increased from 11.88mg/ml to >40 mg/ml; the solubility in the tertiary butanol is improved from 4.00mg/ml to 24-25 mg/ml. Therefore, the solubility of the miboplatin in the solvent can be improved by increasing the temperature during the dissolution.

2. Investigation of miboplatin solubility in tert-butanol solutions of n-butanol at different ratios

The solubility of miboplatin in a 1% n-butanol tert-butanol solution, a 2% n-butanol tert-butanol solution, a 3% n-butanol tert-butanol solution, a 4% n-butanol tert-butanol solution, a 5% n-butanol tert-butanol solution, and a 10% n-butanol tert-butanol solution was determined at 60 ℃ respectively. The results are shown in Table 5.

TABLE 5 solubility results for miboplatin in t-butanol solutions containing different proportions of n-butanol

As can be seen from Table 5, the solubility of n-butanol in the t-butanol solution was 19mg/mL or more regardless of whether the n-butanol content was 1% or 10%, and the 3% n-butanol solution had the best solubility and the highest solubility for miboplatin at the same temperature.

3. Examination of miboplatin solubility in 3% n-butanol t-butanol at different temperatures

The solubility of miboplatin in a 3% n-butanol tert-butanol solution was determined at 40 deg.C, 50 deg.C, and 60 deg.C, respectively.

TABLE 6 solubility results for miboplatin without heating temperature

Temperature of heating	Concentration of
		60℃	25mg/ml
50℃	＜15mg/ml
		40℃	＜15mg/ml

As can be seen from Table 6, the solubility of miboplatin in t-butanol solution containing 3% n-butanol at 60 deg.C was 25mg/ml, which is much greater than the solubility of miboplatin in the same solution at 40 deg.C or at 50 deg.C. Therefore, the solution of 3% n-butanol in tert-butanol has the best solubility for miboplatin at 60 ℃ and the solubility is the highest.

4. Examination of the precipitation Rate of a solution of 3% n-butanol at different concentrations at 60 deg.C in t-butanol

Respectively adding the miboplatin with different masses into a tert-butyl alcohol solution of 3% n-butyl alcohol at 60 ℃ to prepare miboplatin solutions of 10mg/mL, 12mg/mL, 14mg/mL, 16mg/mL and 20mg/mL, after the miboplatin solutions are completely dissolved, quickly transferring the miboplatin solutions into a water bath at 25 ℃, and observing and timing.

TABLE 7 precipitation time limits of miboplatin at different concentrations

The precipitation time limit can be used for the stability of the miboplatin with different concentrations in the solvent. As can be seen from Table 7, when the miboplatin solution was transferred from 60 ℃ to 25 ℃, the lower the miboplatin concentration was, the slower the precipitation rate of the solution was. When the concentration of the miriplatin is 10mg/mL, the precipitation time limit is 25 min.

From the above experiments including screening of organic solvents, examination of the solubility of miriplatin in t-butanol solutions of n-butanol at different ratios, examination of the solubility of miriplatin in t-butanol solutions of 3% n-butanol at different temperatures, examination of the precipitation rate of t-butanol solutions of 3% n-butanol at different concentrations at 60 ℃, etc., it can be seen that, overall, miriplatin has the best solubility in t-butanol solutions containing 1-10% n-butanol, and the best solubility in t-butanol solutions with 3% n-butanol. Moreover, when the concentration of miboplatin is 10mg/ml, the precipitation time is longest and the stability is the best.

Example two

Preparation of freeze dried powder for injection

Under the heating of water bath at 60 ℃, 10mg/mL of miboplatin solution is prepared, the freeze-drying solvent is (n-butyl alcohol/tert-butyl alcohol: 3/97 by volume ratio), under the aseptic condition, a 0.22 mu m organic microporous filter membrane is used for filtering the solution to be clear, the obtained filling amount is filled into a cillin bottle according to the miboplatin, a butyl rubber plug is half plugged, the solution is packaged into a tray, the tray is sent into a freeze dryer, a box is closed , the freeze-drying machine is started for freeze-drying, the initial temperature of the freeze dryer is-40 ℃, the concentration of each freeze-drying bottle sample is 10mg/mL, the water content is 0.8mg/mL, and the volume is 7mL, wherein the freeze-drying parameters are set in a table:

TABLE 8 Freeze drying parameters

And (4) after freeze-drying, performing tamponade and box discharging, and rolling a port by using an aluminum-plastic combined cover to obtain the freeze-dried powder injection.

EXAMPLE III

And respectively representing the content, the particle size, the sedimentation coefficient and the like of the freeze-dried powder injection prepared in the second embodiment. Wherein the determination method comprises the following steps:

(1) content detection method and instrument

Octadecylsilane chemically bonded silica is used as a filling agent; methanol and acetonitrile (70: 30) are taken as mobile phases; the detection wavelength was 210nm, the flow rate was 1.0ml per minute, the sample chamber temperature was 5 ℃ and the column temperature was 30 ℃. The number of theoretical plates is not less than 3000 calculated by platinum.

Taking a proper amount of the product, precisely weighing, adding absolute ethanol for dissolving, and quantitatively diluting to obtain a solution containing about 0.5mg per 1ml, wherein the solution is used as a test solution. Precisely measuring 10uL, injecting into a liquid chromatograph, and recording a chromatogram; taking a proper amount of the platinum control substance (with the purity of 99.5%), measuring by the same method, and calculating by peak area according to an external standard method to obtain the platinum control substance.

The results of the measurement were as follows: the average content of the platinum lyophilized preparation per bottle is 70.1 mg.

(2) Residual solvent

The detection method comprises the following steps: precisely weighing 25mg of the product, placing in a headspace bottle, precisely adding 5ml of dimethyl sulfoxide, sealing (dissolving in headspace heating process), taking a proper amount of n-butanol/tert-butanol as a test solution, precisely weighing, quantitatively diluting with dimethyl sulfoxide to obtain a solution containing 5 μ g of n-butanol/tert-butanol per 1ml, precisely weighing 5ml, placing in a headspace bottle, sealing, and taking as a control solution. According to the determination of a residual solvent determination method (an appendix VIII P of the second part of the 2010 version of Chinese pharmacopoeia), a capillary column taking 6 percent of cyanopropylphenyl-94 percent of dimethylpolysiloxane as a stationary liquid is taken as a chromatographic column; the initial temperature is 50 ℃, the temperature is maintained for 10 minutes, the temperature is raised to 200 ℃ at the rate of 30 ℃ per minute, and the temperature is maintained for 5 minutes; the temperature of a sample inlet is 200 ℃; the temperature of the detector is 250 ℃; the flow rate is 2.0 ml/min; the headspace bottle had an equilibration temperature of 90 ℃ and an equilibration time of 30 minutes.

After detection, n-butanol and tert-butanol are not detected in the freeze-dried powder injection, which indicates that the freeze-dried powder injection prepared by the method has clean solvent removal and no residue.

(3) Particle size detection method and instrument

About 7mg of the product is taken, 1ml of isopropyl carob bean oil is added as a dispersion medium, and the mixture is dispersed by ultrasonic treatment for 1 minute to be used as a test suspension. Adding 100ml of the isopropyl myristate of the meat bean into a sample injector, adding the test suspension, setting the light shielding degree limit to be 5-12%, stirring at 2000 r/min, and detecting the particle size distribution of the sample by using a Malvern 2000 particle size analyzer according to a particle size determination method (XI E third method in the second part of the 2010 edition of Chinese pharmacopoeia).

TABLE 9 particle size determination values for miboplatin lyophilized powder for injection of the present invention

TABLE 10 particle size measurement of platinum crude drug

As can be seen from the particle size measurement data in tables 9 and 10, the particle size of the miriplatin lyophilized powder for injection prepared according to the present invention is not much different from that of the original drug (miriplatin preparation commercially available from Sumitomo corporation, Japan). The miriplatin freeze-dried powder injection prepared by the method shows good particle size performance.

(4) Sedimentation coefficient detection

Since the miboplatin is usually suspended in the poppy seed iodized oil injection to form a suspension solution during clinical medication, and exists in a suspension form in vivo, the sedimentation coefficient of the miboplatin is considered.

The detection method comprises the following steps: precisely adding 3.5m1 parts of iodized oil of semen Papaveris into 1 piece of the product, shaking, mixing, transferring into penicillin bottle, standing at room temperature for 3 hr, sucking 250 μ l of upper and lower layer solutions, placing into 10m1 volumetric bottles, dissolving in anhydrous ethanol, diluting to scale, and shaking to obtain test solution (2 parts of upper and lower layer test solutions).

Taking a proper amount of the miriplatin reference substance (with the purity of 99.5 percent), precisely weighing, adding absolute ethyl alcohol to dissolve, and quantitatively diluting to prepare a solution containing about 0.5mg of miriplatin in each 1ml, wherein the solution is used as the miriplatin positioning solution. According to the content determination method, 10 mul of each of the miboplatin positioning solution and the test solution is precisely measured, the solutions are injected into a liquid chromatograph, the chromatogram is recorded, and the running time is 60 minutes. The calculation is done according to the following disclosure:

the ratio of the platinum peak area of the upper solution to the lower solution is (A)_{Upper 1}+A_{Upper 2})/(A_{Lower 1}+A_{Lower 2})

A_{Upper 1}、A_{Upper 2}: the peak area of the platinum in the upper solution;

A_{lower 1}、A_{Lower 2}: area of the platinum peak in the lower solution.

The average value of the measured sedimentation coefficients was 9.83. The determination result shows that the sedimentation coefficient of the miriplatin freeze-dried powder injection prepared by the invention is far greater than 0.90, and the prepared suspension has good stability. (5) Electron microscope assay

The particle size distribution of the solution of the miboplatin freeze-dried powder injection prepared in the second embodiment and the miboplatin preparation sold in Japan is measured by a Scanning Electron Microscope (SEM), the measurement results are shown in attached figures 1 and 2, and as can be seen from the attached figures 1 and 2, compared with the miboplatin preparation sold in Japan, the particle size distribution of the miboplatin freeze-dried powder prepared in the invention is more , the miboplatin freeze-dried powder prepared in the invention has loose and porous surfaces and 5-25 μm of central particle size distribution, and most of the miboplatin freeze-dried powder is 5-15 μm.

As can be seen from the above examples, the assay effect of the miriplatin freeze-dried powder injection is best when the temperature of the freeze-dried powder injection is controlled to be 60 ℃ and the volume ratio of the tert-butyl alcohol to the n-butyl alcohol is 3: 97.

In conclusion, the miboplatin freeze-dried powder injection prepared by the miboplatin in a solvent of tert-butyl alcohol of 1-10% of n-butyl alcohol, at the concentration of 10-15mg/ml and the temperature of 40-70 ℃ has good indexes.

According to the solvent screened by the invention and various indexes to be inspected, in the production practice, the tert-butyl alcohol and the n-butyl alcohol with the prescription amount are weighed and added into a material preparing tank, the solution temperature is controlled to be 40-70 ℃ after being uniformly stirred, then the platinum with the prescription amount is weighed and uniformly dissolved by stirring or ultrasonic treatment at the keeping temperature, after the inspection is qualified, the solution is filtered to be clear by using an organic microporous filter membrane with the diameter of 0.22 mu m under the aseptic condition, the obtained filling amount is filled into a penicillin bottle according to the calculation of the platinum, a butyl rubber plug is arranged on a half plug, the filling is carried out, the solution is sent into a freeze dryer, a box is closed, a freeze-drying machine is started for freeze-drying, then the plug is pressed and taken out, a mouth is sealed by using a combined aluminum-plastic cover, and the freeze-dried.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and all such modifications, equivalents and improvements that come within the spirit and scope of the invention are desired to be protected.

Claims

The method is characterized in that the miboplatin freeze-dried powder injection is prepared by uniformly mixing miboplatin with a mixed solvent containing tert-butyl alcohol and n-butyl alcohol, and freeze-drying, wherein the volume ratio of the n-butyl alcohol to the tert-butyl alcohol in the mixed solvent is (1: 99) - (10: 90), the mixing temperature is 40-70 ℃, and the freeze-drying temperature range comprises freeze-drying at-40 ℃ to-35 ℃ for 5-15 h, freeze-drying at-30 ℃ to-20 ℃ for 20-30 h, and freeze-drying at 30-40 ℃ for 10-20 h;

wherein the concentration of the miboplatin in the mixed solvent is 3 mg/mL-50 mg/mL.
2. The miboplatin freeze-dried powder injection as claimed in claim 1, wherein the volume ratio of n-butanol to tert-butanol in the mixed solvent is (2:98) - (5: 95).
3. The miboplatin freeze-dried powder injection as claimed in claim 1, wherein the volume ratio of n-butanol to tert-butanol in the mixed solvent is 3: 97.
4. The miboplatin lyophilized powder injection of any one of claims 1-3- , wherein the concentration of the miboplatin in the mixed solvent is 5 mg/mL-30 mg/mL.
5. The miboplatin lyophilized powder injection of any one of claims 1-3- , wherein the concentration of the miboplatin in the mixed solvent is 10mg/ml, and the purity of the miboplatin is greater than 99%.
6. The miriplatin freeze-dried powder injection according to any one of claims 1-3 to , wherein the particle size of the miriplatin freeze-dried powder injection is 5-25 μm.
7. The miriplatin freeze-dried powder injection according to any one of claims 1-3 to , wherein the particle size of the miriplatin freeze-dried powder injection is 5-15 μm.
8, A preparation method of the miboplatin freeze-dried powder injection, which is characterized in that the miboplatin is uniformly mixed with a mixed solvent containing tert-butyl alcohol and n-butyl alcohol, and the mixture is freeze-dried to obtain the miboplatin freeze-dried powder injection, wherein the volume ratio of the n-butyl alcohol to the tert-butyl alcohol in the mixed solvent is (1: 99) - (10: 90), the mixing temperature is 40-70 ℃, and the freeze-drying temperature interval comprises freeze-drying at-40 ℃ to-35 ℃ for 5-15 h, freeze-drying at-30 ℃ to-20 ℃ for 20-30 h, and freeze-drying at 30-40 ℃ for 10-20 h;

wherein the concentration of the miboplatin in the mixed solvent is 3 mg/mL-50 mg/mL.
9. The production method according to claim 8, wherein the volume ratio of n-butanol to t-butanol in the mixed solvent is (2:98) - (5: 95).
10. The production method according to claim 8, wherein the volume ratio of n-butanol to t-butanol in the mixed solvent is 3: 97.
11. The method of claim 9 or 10, wherein the miboplatin is more than 99% pure.
12. The method according to claim 9 or 10, wherein the concentration of the miboplatin in the mixed solvent is 5mg/mL to 30 mg/mL.
13. The method according to claim 9 or 10, wherein the concentration of the miboplatin in the mixed solvent is 10 mg/ml.
14. Use of the miriplatin freeze-dried powder injection of any in claims 1-7 in the field of preparing medicaments for treating cancers.
15. Use of the miriplatin freeze-dried powder injection of any of claims 1-7 in the field of preparation of drugs for treating hepatocellular carcinoma.