CN110870848A - Preparation process of norcantharidinate sodium injection - Google Patents

Preparation process of norcantharidinate sodium injection Download PDF

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CN110870848A
CN110870848A CN201911145487.1A CN201911145487A CN110870848A CN 110870848 A CN110870848 A CN 110870848A CN 201911145487 A CN201911145487 A CN 201911145487A CN 110870848 A CN110870848 A CN 110870848A
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preparation process
injection
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norcantharidinate
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陈琼
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Hainan Yeshanyuan Pharmaceutical Co Ltd
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention relates to a preparation process of a norcantharidinate sodium injection, which comprises the following steps: weighing norcantharidin according to the prescription amount, adding strong base solution, slightly heating, and stirring to completely react; adding water for injection and sodium chloride, dissolving, and mixing to obtain primary mixed solution; adding a decoloring agent into the primary mixed solution for decoloring; measuring the content and pH of the main drug; regulating the content and pH value of the main medicine; fine filtering the main drug to be clear; bottling, capping, and sealing to obtain bottled liquid; sterilizing bottled liquid at high temperature, and cooling; checking, labeling, boxing and warehousing. The preparation method is simple, effectively meets the market demand, and improves the process production level of the Chinese medicine enterprises.

Description

Preparation process of norcantharidinate sodium injection
Technical Field
The patent application belongs to the technical field of medicine preparation, and more specifically relates to a preparation process of a norcantharidinate sodium injection.
Background
The sodium norcantharidinate injection is a sterilized solution of sodium norcantharidinate, and contains sodium norcantharidinate and norcantharidin (C)8H804) Calculated as 90-110% of the marked amount, the compound is an anticancer drug, is mainly used for liver cancer, esophageal cancer, gastric cancer, cardia cancer, lung cancer and the like, leucopenia, hepatitis, liver cirrhosis and hepatitis B virus carriers, can also be used as a drug for cancer before operation or in combined chemotherapy, and therefore, is quite wide in clinical application. However, at present, domestic manufacturers in ChinaLess, and causes huge contradiction with the vigorous market demand, so the process development of the medicine is urgently needed.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation process of the norcantharidin sodium acid injection, which is simple in process preparation, effectively meets market demands, and brings good medicines for treating diseases and saving lives for patients. And the process level of the sodium norcantharidinate injection in China is improved.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a preparation process of a norcantharidinate sodium injection comprises the following steps:
a. weighing norcantharidin according to the prescription amount, adding strong base solution, slightly heating, and stirring to completely react;
b. adding water for injection to 60-90% of the weight of the liquid preparation amount, adding sodium chloride, dissolving, and uniformly mixing to obtain a primary mixed liquid;
c. adding a decolorizing agent into the primary mixed solution, stirring at high temperature for several minutes for decolorizing, and coarsely filtering to obtain a main drug;
d. measuring the content and pH of the main drug;
e. regulating the content and pH value of the main medicine;
f. fine filtering the main drug to be clear;
g. bottling, capping, and sealing to obtain bottled liquid;
h. sterilizing the bottled liquid at high temperature, and cooling;
i. checking, labeling, boxing and warehousing.
The technical scheme of the invention is further improved as follows: in the step a, the alkali solution is 0.2mol/L NaOH solution, and the slight heating means heating to 30-40 ℃.
The technical scheme of the invention is further improved as follows: b, adding water for injection to 85% of the weight of the prepared solution, wherein the water for injection is deionized water; the added sodium chloride is 1.5 to 2.5 times of the weight of the norcantharidin.
The technical scheme of the invention is further improved as follows: in the step c, the decoloring agent is active carbon for needles, the weight of the active carbon is 0.01-0.02% of the weight of the preparation solution, the active carbon is stirred for 10-20 minutes at the temperature of 90-105 ℃ for decoloring, and the active carbon is removed through rough filtration.
The technical scheme of the invention is further improved as follows: e, adjusting the content of the main drug to 95.0-105.0% and adjusting the pH to 8.5-9.5;
the technical scheme of the invention is further improved as follows: in f, fine filtering the main medicine with 0.20-0.30 μm microporous membrane.
The technical scheme of the invention is further improved as follows: and g, filling the mixture into a tube-type antibiotic glass bottle according to the specification of 2 ml/bottle when bottling.
The technical scheme of the invention is further improved as follows: in the h, high-temperature sterilization means sterilization at a high temperature of 110-130 ℃ for 20-60 minutes, and the cooling mode is spray cooling.
The technical scheme of the invention is further improved as follows: in the step i, the inspection adopts a lamp inspection and full inspection mode.
Due to the adoption of the technical scheme, the invention has the beneficial effects that: the process has the advantages of simple preparation, stable product performance, effective meeting of market demands, improvement of the process level of the sodium norcantharidinate injection in China, great economic benefit brought to enterprises, and remarkable social benefit.
The norcantharidin has the structure of external 1, 2-cis-3, 6-oxo-hexahydrophthalic anhydride, and can easily generate sodium norcantharidinate under the strong alkaline condition. The structure is 1, 2-cis-3, 6-oxo-hexahydro phthalic acid sodium salt, so that the strong alkali is 0.02mol/L NaOH solution, and the purchase is convenient.
The specification of the sodium norcantharidinate injection is 2ml according to the file of the national food and drug administration national drug standard WS-10001- (HD-0217) -2002: 10 mg/count, therefore we determined the specification of the injection to be 2 ml: 10 mg/piece.
The prepared norcantharidin acid sodium injection is detected according to the file of the second edition of the pharmacopoeia of the people's republic of China and the national drug standard WS-10001- (HD-0217) -2002 of the State drug administration in 2000, all the standards meet the requirements, and the norcantharidin acid sodium injection can be widely put into the market.
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FIG. 1 is a process flow diagram of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples.
The invention discloses a preparation process of a norcantharidinate sodium injection, which comprises the following steps:
a. weighing norcantharidin according to the prescription amount, adding strong base solution, slightly heating, and stirring to completely react;
b. adding water for injection to 60-90% of the weight of the prepared solution, adding sodium chloride, dissolving, and mixing uniformly to obtain a primary mixed solution;
c. adding a decolorizing agent into the primary mixed solution, stirring at high temperature for several minutes for decolorizing, and coarsely filtering to obtain a main drug;
d. measuring the content and pH of the main drug;
e. regulating the content and pH value of the main medicine;
f. fine filtering the main drug to be clear;
g. continuously adding water for injection to a predetermined volume, bottling, capping, and sealing to obtain bottled solution;
h. sterilizing the bottled liquid at high temperature, and cooling;
i. checking, labeling, boxing and warehousing.
In a, the alkali solution is 0.2mol/L NaOH solution, and slight heating means heating to 30-40 ℃.
b, adding water for injection to 85% of the weight of the prepared solution, wherein the water for injection is deionized water; the added sodium chloride is 1.5 to 2.5 times of the weight of the norcantharidin.
In the step c, the decoloring agent is active carbon for needles, the weight of the active carbon is 0.01-0.02% of the weight of the preparation solution, the active carbon is stirred for 10-20 minutes at the temperature of 90-105 ℃ for decoloring, and the active carbon is removed through rough filtration.
e, adjusting the content of the main drug to 95.0-105.0% and adjusting the pH to 8.5-9.5;
in f, fine filtering the main drug by a 0.20-0.30 μm microporous filter membrane.
And g, filling the mixture into a tube-type antibiotic glass bottle according to the specification of 2 ml/bottle when bottling.
In the h, high-temperature sterilization means sterilization at a high temperature of 110-130 ℃ for 20-60 minutes, and the cooling mode is spray cooling.
in the step i, the inspection adopts a lamp inspection and full inspection mode.
In the first embodiment, the process parameters are as follows:
norcantharidin: 10g of a mixture;
0.2mol/L NaOH solution: 600 ml; slightly heating to 30 ℃;
water for injection is added to: 2000 ml;
sodium chloride: 18g of a mixture;
the decolorant is needle activated carbon which accounts for 0.01 percent of the weight of the prepared liquid, and is stirred for 10 minutes at 90 ℃ for decoloration; regulating the content of the main drug to 95.0 percent and the pH value to 8.5-9.5;
fine filtering the main drug with a 0.22 mu m microporous filter membrane;
preparing: 1000 pieces;
specification: 2 ml: 10 mg;
sterilizing at 115 ℃ for 30 minutes at high temperature, spraying and cooling, and preparing for boxing and warehousing.
In the second embodiment, the process parameters are as follows:
norcantharidin: 10g of a mixture;
0.2mol/L NaOH solution: 610 ml; slightly heated to 35 ℃;
water for injection is added to: 2000 ml;
sodium chloride: 15g of the total weight of the mixture;
the decolorant is needle activated carbon which accounts for 0.02 percent of the weight of the prepared liquid, and is stirred for 20 minutes at 100 ℃ for decoloration;
regulating the content of the main drug to 100.0 percent and the pH value to 9.0;
fine filtering the main drug with a 0.25 mu m microporous filter membrane;
preparing: 1000 pieces;
specification: 2 ml: 10 mg;
sterilizing at 110 deg.C for 20 min, spray cooling, and preparing for boxing and warehousing.
In the third embodiment, the process parameters are as follows:
norcantharidin: 10g of a mixture;
0.2mol/L NaOH solution: 590 ml; slightly heated to 40 ℃;
water for injection is added to: 2000 ml;
sodium chloride: 20g of the total weight of the mixture;
the decolorant is needle activated carbon which accounts for 0.015 percent of the weight of the prepared solution, and is stirred for 18 minutes at 105 ℃ for decoloration;
regulating the content of the main drug to 93.0 percent and the pH value to 8.3;
fine filtering the main drug with a 0.28 mu m microporous filter membrane;
preparing: 1000 pieces;
specification: 2 ml: 10 mg;
sterilizing at 120 deg.C for 30min, spray cooling, and preparing for boxing and warehousing.
Example four, the process parameters are as follows:
norcantharidin: 11g of a reaction solution;
0.2mol/L NaOH solution: 650 ml; slightly heated to 38 ℃;
water for injection is added to: 2000 ml;
sodium chloride: 23g of a mixture;
the decolorant is needle activated carbon which accounts for 0.015 percent of the weight of the prepared solution, and is stirred for 20 minutes at 103 ℃ for decoloration;
regulating the content of the main drug to 105.0 percent and the pH value to 9.8;
fine filtering the main drug with a 0.30 mu m microporous filter membrane;
preparing: 1000 pieces;
specification: 2 ml: 10 mg;
sterilizing at 130 ℃ for 40 minutes at high temperature, spraying and cooling, and preparing for boxing and warehousing.
In the fifth embodiment, the process parameters are as follows:
norcantharidin: 12g of a mixture;
0.2mol/L NaOH solution: 630 ml; slightly heated to 37 ℃;
water for injection is added to: 2000 ml;
sodium chloride: 25g of the total weight of the mixture;
the decolorant is 0.013 percent of the active carbon for the needle based on the weight of the prepared liquid, and is stirred for 16 minutes at 105 ℃ for decoloration;
regulating the content of the main drug to 102.0 percent and the pH value to 9.3;
fine filtering the main drug with a 0.24 mu m microporous filter membrane;
preparing: 1000 pieces;
specification: 2 ml: 10 mg;
sterilizing at 111 ℃ for 50 minutes, spraying and cooling, and preparing for boxing and warehousing.
Example six, various process parameters are as follows:
norcantharidin: 10.5 g;
0.2mol/L NaOH solution: 580 ml; slightly heated to 32 ℃;
water for injection is added to: 2000 ml;
sodium chloride: 21g of a basic amine;
the decolorant is active carbon for needles with the weight of 0.013 percent of the weight of the prepared liquid, and is stirred for 19 minutes at 98 ℃ for decoloration;
regulating the content of the main drug to 97.0 percent and the pH value to 8.6;
fine filtering the main drug with a 0.21 mu m microporous filter membrane;
preparing: 1000 pieces;
specification: 2 ml: 10 mg;
sterilizing at 113 deg.C for 60 min, spray cooling, and packaging.
Taking the finished products of the sodium norcantharidate injection in the first to sixth embodiments, respectively numbering 1-6, and then checking as follows:
the prepared norcantharidinate sodium injection with the number of 1-6 is colorless clear liquid.
And (3) identification: taking 2ml of the norcantharidin sodium injection samples with the numbers of 1-6 respectively, placing the samples in 50ml beakers, drying the samples by distillation on a water bath, adding a little sublimed resorcinol and a few drops of concentrated sulfuric acid, preserving the heat at 130 ℃, adding a sodium hydroxide solution to make the samples alkaline, and placing the samples under an ultraviolet lamp to make the samples with the numbers of 1-6 show blue-green fluorescence.
In the sodium norcantharidinate injection test samples with the numbers of 1 to 6, in the detection of high performance liquid chromatography, the single impurity is not more than 0.9 percent, the total impurity is not more than 1.8 percent, and the alkalinity is between 8.3 and 9.7.
HPLC: the retention time of the main peak of the product is consistent with that of the main peak of the reference substance.
IR: the infrared absorption spectrum of the product is consistent with the spectrum of a sodium norcantharidate reference substance.
Chromatographic conditions and system adaptability experiment: octadecyl bonded silica gel is used as a filling agent, water-ethanol (85: water) (adjusted to 3.1 by phosphoric acid) is used as a mobile phase, the detection wavelength is 211nm, the number of theoretical plates is not less than 1500 calculated according to the peak of sodium norcantharidinate, and the separation degree between the sodium norcantharidinate and adjacent impurities is in accordance with the requirement.
Content of main ingredient (main ingredient is norcantharidin C)8H804) Measured by absorbance to norcantharidin (C)8H804) In the norcantharidinate sodium injection samples with the numbers of 1-6, the amounts are 93.0-107% of the marked amount.
The judgment method comprises the following steps: based on example 1 (the rest of examples 2-6 can also be performed according to the following data), 5ml of the injection sample prepared in example 1 is measured, placed in a 10ml measuring flask, added with 3ml of 0.2mol/L hydrochloric acid solution, diluted to scale by mobile phase, and placed for 30min to serve as a sample solution; precisely measuring 1ml, placing in a 10ml measuring flask, adding mobile phase for diluting to scale, and shaking up to obtain control solution; precisely measuring 20 mu l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, recording the chromatogram until the time of the main component peak area is 3 times, wherein if an impurity peak exists in the chromatogram of the test solution, the peak area of a single impurity in the injection test solution is not larger than the main peak area (1.0%) of the control solution except the solvent peak, and the sum of the areas of the impurities is not larger than 2 times (2.0%) of the main peak area of the control solution. Wherein, 5mL is taken as the prepared sample, 1mL is taken as the control solution, the concentration of the prepared sample is 10g/2000mL, and the final concentration is 2.5g/L after the prepared sample is diluted to 10mL from 5 mL. In this case, the concentration of the control solution was 0.025 g/L.
Insoluble microparticles: 20 samples of the injection samples with the numbers 1-6 are taken, the labels of the containers are removed, and the outer walls of the containers are wiped clean. The neck of the container is held by hand, the container is slightly rotated and turned, the content is poured out and placed in a sampling cup, the sampling cup is placed for 2 minutes, and the container is placed on a sampler after air bubbles are removed. Stirring is started to uniformly mix the solution (avoiding generating bubbles), and the sampling is determined according to the method, wherein the sampling amount is not less than 5ml each time. Judging that the content of more than 10un (more than or equal to 10un) of the particles in each sample container is not more than 6000 particles; the content of particles containing more than 25un (more than or equal to 25un) is less than 600 particles.
Visible foreign matter: taking 5 injection samples of numbers 1-6, totally 24 samples, removing container label, and wiping off outer wall of container. Holding the neck of the container, rotating and turning the container slightly to suspend visible foreign matter in the liquid medicine (taking care not to make the liquid medicine generate bubbles), and visually inspecting under black and white background respectively, and repeating for 3 times. The result shows that no visible foreign matter can be detected in the product.
And (4) sterile inspection: taking 5 injection samples of numbers 1-6, respectively, 30 samples in total, checking according to 'sterile check operation regulation', washing and filtering by adopting a closed membrane filtration method, adding a thioglycolate fluid culture medium and a trypticase soy peptone liquid culture medium for culturing respectively, inoculating each culture medium, wherein the minimum test quantity required by inoculating is 2% or 10 (taking fewer samples), increasing the minimum test quantity of 1/2 for positive control, and judging that a positive control tube needs to grow well and a negative control tube does not have bacteria to grow.
Heat source: examination was performed according to the pyrogen examination method.
Loading: taking 5 injection samples of numbers 1-6, respectively, opening to avoid loss, completely sucking out the contents with dry syringe and injection needle of corresponding volume, and slowly and continuously injecting into standardized measuring cylinder (the measuring cylinder is sized to make the volume to be measured at least 40% of its rated volume, and not discharging the liquid in the needle). The filling quantity of each bottle is not less than the marked quantity when the bottle is inspected at room temperature.
Content determination: based on example 1 (examples 2 to 6 were also performed according to the following data), 5ml of the injection sample prepared in example 1 was precisely measured, placed in a 50ml measuring flask, diluted to the scale with 0.2mol/L hydrochloric acid solution, shaken, left for 1 hour, and measured for absorbance at a wavelength of 210nm by a spectrophotometric method. And drying phosphorus pentoxide under reduced pressure, placing the dried phosphorus pentoxide into a constant-weight norcantharidin container of about 65mg, precisely weighing, placing the container in a 50ml measuring flask, adding 0.05mol/L sodium hydroxide solution of 15ml, heating to dissolve, standing at room temperature, diluting with 0.2mol/L hydrochloric acid solution to scale, shaking, and standing for 4 hours. Precisely measuring 10ml of the injection prepared in the example 1, putting the injection into a 25ml measuring flask, diluting the injection to a scale with 0.2mol/L hydrochloric acid solution, shaking up, measuring by the same method, and calculating to obtain the injection. The product is calculated by norcantharidin and is 93.0-107% of the labeled amount. Wherein the calculation process of the content (93.0-107%) of the main drug is as follows:
Figure BDA0002282055010000081
in the formula: a. theSample (A)Is the absorbance of the sample;
Ato pairThe absorbance of the control;
Wto pairWeighing the reference substance (dry or pure), mg;
Dsample (A)Is the sample dilution factor;
Dto pairIs the dilution multiple of the reference substance.
The concentration of norcantharidin in the injection sample is calculated based on the concentration and absorbance of a standard (65mg norcantharidin) and the absorbance corresponding to 5ml of the injection sample, although the concentration of sodium hydroxide in the standard and the concentration of sodium hydroxide in the injection sample are greatly different (in the standard, the concentration of sodium hydroxide is 0.05mol/L, 15ml/50ml, 0.015mol/L, and in the injection sample, the concentration of sodium hydroxide is 0.2mol/L, 600ml/2000ml, 0.06mol/L), the influence on absorbance can be ignored.

Claims (9)

1. A preparation process of a norcantharidinate sodium injection is characterized by comprising the following steps:
a. weighing norcantharidin according to the prescription amount, adding strong base solution, slightly heating, and stirring to completely react;
b. adding water for injection to 60-90% of the weight of the prepared solution, adding sodium chloride, dissolving, and mixing uniformly to obtain a primary mixed solution;
c. adding a decolorizing agent into the primary mixed solution, stirring at high temperature for several minutes for decolorizing, and coarsely filtering to obtain a main drug;
d. measuring the content and pH of the main drug;
e. regulating the content and pH value of the main medicine;
f. fine filtering the main drug to be clear;
g. bottling, capping, and sealing to obtain bottled liquid;
h. sterilizing the bottled liquid at high temperature, and cooling;
i. checking, labeling, boxing and warehousing.
2. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: in a, the alkali solution is 0.2mol/L NaOH solution, and slight heating means heating to 30-40 ℃.
3. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: b, adding water for injection to 85% of the weight of the prepared solution, wherein the water for injection is deionized water; the added sodium chloride is 1.5 to 2.5 times of the weight of the norcantharidin.
4. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: in the step c, the decoloring agent is active carbon for needles, the weight of the active carbon is 0.01-0.02% of the weight of the preparation solution, the active carbon is stirred for 10-20 minutes at the temperature of 90-105 ℃ for decoloring, and the active carbon is removed through rough filtration.
5. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: e, adjusting the content of the main drug to 95.0-105.0% and adjusting the pH to 8.3-9.7.
6. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: in f, fine filtering the main drug by a 0.20-0.30 μm microporous filter membrane.
7. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: and g, filling the mixture into a tube-type antibiotic glass bottle according to the specification of 2 ml/bottle when bottling.
8. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: in the h, high-temperature sterilization means sterilization at a high temperature of 110-130 ℃ for 20-60 minutes, and the cooling mode is spray cooling.
9. The preparation process of the sodium norcantharidinate injection according to claim 1, wherein the preparation process comprises the following steps: in the step i, the inspection adopts a lamp inspection and full inspection mode.
CN201911145487.1A 2019-11-21 2019-11-21 Preparation process of norcantharidinate sodium injection Pending CN110870848A (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN111437255A (en) * 2020-05-28 2020-07-24 河南创鑫生物科技有限公司 Preparation method of norcantharidin sodium injection and norcantharidin sodium injection

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Publication number Priority date Publication date Assignee Title
CN103585101A (en) * 2013-11-19 2014-02-19 江苏红豆杉药业有限公司 Norcantharidin sodium injection and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103585101A (en) * 2013-11-19 2014-02-19 江苏红豆杉药业有限公司 Norcantharidin sodium injection and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111437255A (en) * 2020-05-28 2020-07-24 河南创鑫生物科技有限公司 Preparation method of norcantharidin sodium injection and norcantharidin sodium injection

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Application publication date: 20200310