CN112336737A - Preparation method of pharmaceutical composition containing deacetyl hairy flower glycoside - Google Patents

Preparation method of pharmaceutical composition containing deacetyl hairy flower glycoside Download PDF

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Publication number
CN112336737A
CN112336737A CN202011244615.0A CN202011244615A CN112336737A CN 112336737 A CN112336737 A CN 112336737A CN 202011244615 A CN202011244615 A CN 202011244615A CN 112336737 A CN112336737 A CN 112336737A
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injection
ethanol
water
glycerol
deacetyl
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胡慧
张帆
梁屹
杨易可
刘婧
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Shanghai Xudong Haipu Pharmaceutical Co ltd
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Shanghai Xudong Haipu Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Abstract

The invention discloses a preparation method of a pharmaceutical composition containing deacetyl hairy flower glycoside. The invention provides a preparation method of a desacetyl wool flower glycoside injection, which is characterized by comprising the following steps: sterilizing the mixture containing deacetyl hairy flower glycoside, ethanol, glycerol and water for injection by terminal sterilization at 121 deg.C for 15 min. The deacetyl hairy flower glycoside injection prepared by the prescription and the process has stable quality and small impurity content, and is placed for 5 days and 10 days at a high temperature (60 ℃) and for 1 day and 3 days at a high temperature (80 ℃), and the result shows that the product has stable quality and small impurity growth.

Description

Preparation method of pharmaceutical composition containing deacetyl hairy flower glycoside
Technical Field
The invention belongs to a preparation method of a desacetylhairy flower glycoside composition, and relates to a preparation which is prepared from desacetylhairy flower glycoside, has proper content and proper pH value, can be injected and administered, and mainly solves the problems of terminal sterilization, improvement of sterility guarantee level and impurity growth in the preparation and storage processes.
Background
The deacetyl-ouabain is a cardiac glycoside naturally present in digitalis, which can be hydrolyzed to lose glucose and acetic acid to form digoxin during extraction, and is a fast-acting cardiac glycoside, which acts faster than digitalis and digoxin but slower than curcuminoid K. The injection is mainly used for treating heart failure, and is suitable for patients with acute cardiac insufficiency or acute exacerbation of chronic cardiac insufficiency due to its rapid action; it can also be used for controlling atrial fibrillation with rapid ventricular rate and ventricular rate of atrial flutter patients. The desacetylhairoside is sensitive to heat, and is easy to generate process impurities in the process of preparing injection, and the process impurities can grow in the process of storage. Among the prior patents, there are the following patents related to the injection of desacetyl lanoside: patent application CN200710112913.2 discloses a method for preparing a desacetylhairoside injection, which is characterized in that the temperature of injection water for preparing the injection is reduced to 35-42 ℃; heat treatment is carried out at 100 ℃ for 30min or not; in addition, ethanol (redistilled) is changed into ethanol (medicinal), and the ethanol (medicinal) is directly used without redistilled, so that the time and the cost of redistilled are saved, and the quality can be ensured. The prepared deacetyl hairy flower glycoside injection has the advantages of high impurity level, low sterility guarantee level and high risk of the injection.
Disclosure of Invention
The deacetyl hairy flower glycoside injection produced according to the prior art has high impurity level and is easy to degrade during the stability period, and in order to ensure the due drug effect, the impurity increase level of the deacetyl hairy flower glycoside injection needs to be strictly controlled. The impurity degradation level can be effectively reduced by optimizing the nitrogen filling process, but the terminal sterilization process cannot be realized, and the deacetylated hairy flower glycoside injection is used as the injection, so that the sterility guarantee has higher risk. In order to overcome the defects in the prior art, the invention aims to provide a preparation method of a pharmaceutical composition containing the deacetyl hairy flower glycoside.
The invention provides a preparation method of a deacetyl hairy flower glycoside injection, which comprises the following steps: sterilizing the mixture containing deacetyl hairy flower glycoside, ethanol, glycerol and water for injection by terminal sterilization at 121 deg.C for 15 min.
The invention provides a preparation method of a deacetyl hairy flower glycoside injection, which comprises the following steps: sterilizing mixture containing deslanoside, ethanol, glycerol and water for injection at 116 deg.C for 30 min.
In some embodiments of the invention, the glycerol is derived from aug.
In some embodiments of the invention, the amount of deslanoside is 0.2 mg/ml.
In some embodiments of the invention, the ethanol is present in an amount of 0.076 g/ml.
In some embodiments of the invention, the glycerol is present in an amount of 0.149 g/ml.
In some embodiments of the invention, the nitrogen-filled potting operation is performed prior to sterilization; the nitrogen filling encapsulation can be performed before and after encapsulation respectively.
In some embodiments of the invention, the filtration is performed prior to nitrogen-filled potting.
In some embodiments of the invention, the mixture consists of deslanoside, ethanol, glycerol and water for injection.
In some embodiments of the present invention, the mixture containing deslanoside, ethanol, glycerol and water for injection is prepared by a method comprising the steps of:
the method comprises the following steps: mixing 60% of water for injection and glycerol to obtain a mixed solution;
step two: mixing ethanol and water for injection to obtain 70% ethanol solution, and mixing the ethanol solution and the deacetyl hairy flower glycoside to obtain mixed solution; the percentage is weight percentage;
step three: mixing the mixed solution obtained in the first step and the mixed solution obtained in the second step, and mixing the mixed solution with water for injection;
wherein, the sequence of the step one and the step two is not divided into sequence.
In some embodiments of the invention, the temperature of the water for injection described in step one is ≦ 40 ℃.
In some embodiments of the invention, the mixing is by stirring.
In some embodiments of the invention, in step three, the mixing time is 15 to 25 minutes (e.g., 20 minutes).
In some embodiments of the present invention, the mixing time in step three is 10 minutes or more.
In some embodiments of the present invention, the process for producing the injection of deacetyl hairy flower glycoside comprises the steps of adding 0.2mg/ml of deacetyl hairy flower glycoside, 0.076g/ml of ethanol, 0.149g/ml of glycerin, and a proper amount of water for injection;
the production process comprises the following steps: adding 60% of injection water into the dispensing tank, cooling the water to be less than or equal to 40 ℃, adding glycerol, and stirring; adding ethanol into a stainless steel barrel, adding a proper amount of water for injection, diluting the ethanol with the prescription amount into an ethanol solution with the concentration of 70%, adding the deacetyl hairy flower glycoside into the ethanol solution with the concentration of 70%, and stirring until the mixture is dissolved uniformly to obtain a liquid medicine; pouring the above medicinal liquid into a liquid preparation tank, stirring for at least 10 min, adding water for injection, stirring for at least 10 min, filtering, bottling in 2ml ampoule by nitrogen-filling respectively before and after bottling, and sterilizing at 121 deg.C for 15 min.
The invention also provides the deacetylated hairy flower glycoside injection prepared by the preparation method of the deacetylated hairy flower glycoside injection.
The invention also provides a desacetyl wool flower glycoside injection which comprises the desacetyl wool flower glycoside, ethanol, glycerol and water for injection, wherein the glycerol is derived from Aug.
In some embodiments of the invention, the amount of deslanoside is 0.2 mg/ml.
In some embodiments of the invention, the ethanol is present in an amount of 0.076 g/ml.
In some embodiments of the invention, the glycerol is present in an amount of 0.149 g/ml.
In some embodiments of the invention, the injection solution of the deslanoside comprises 0.2mg/ml of deslanoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and water for injection, wherein the glycerol is derived from Aug.Hedinger GmbH & Co.KG.
The invention adopts a mode that glycerin is firstly mixed with water for injection and then mixed with the solution of the deacetylated hairy flower glycoside, and the mode enables the solution of the deacetylated hairy flower glycoside to be more easily and uniformly dispersed in the injection liquid system of the deacetylated hairy flower glycoside. The inventor analyzes that the glycerol has certain thickness and poor fluidity, and the glycerol and the water for injection dilute the concentration of the glycerol and increase the fluidity after being mixed, so that the solution of the deacetyl hairy flower glycoside can be more easily and uniformly dispersed in the deacetyl hairy flower glycoside injection liquid system.
The invention adopts a terminal sterilization process, greatly improves the sterility assurance level and reduces the use risk of the injection.
According to the invention, the quality of the injection is optimized by changing the types of auxiliary materials, the pH range is controlled to be 5-7, the pH value is close to the pH value of blood, and the stimulation of an injection part is reduced; in the preparation process, the deacetyl hairy flower glycoside injection is always under a lower temperature condition, so that the damage of high temperature to the raw material medicine is reduced; active carbon is not used, so that the risk of introducing impurities into the active carbon is eliminated; nitrogen is filled in the encapsulating process to reduce the generation of oxidation impurities of the medicine; and the sterility of the product can be effectively ensured by adopting a terminal sterilization mode.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention optimizes the quality of the injection by replacing the types of the auxiliary materials, reduces the impurities to the extent that the injection can be produced by a terminal sterilization process and conventional production equipment, and has the advantages of low cost, simple and convenient operation and easy control. In the preparation process, the deacetyl hairy flower glycoside is at a lower temperature, so that the damage of high temperature to the raw material medicine is reduced; the method does not use the active carbon, thereby eliminating the risk of introducing impurities into the active carbon; and the sterility of the product can be effectively ensured by adopting a terminal sterilization mode. The injection of the deacetyl hairy flower glycoside prepared according to the prescription and the process described in the technical scheme of the invention has stable quality and low impurity content, and is placed for 5 days and 10 days at a high temperature (60 ℃) and for 1 day and 3 days at a high temperature (80 ℃), and the result shows that the product has stable quality and the impurity growth is small.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The detection method of the total impurity content comprises the following steps:
(1) reagent and solution: water, acetonitrile, methanol
(2) Instruments and appliances: high performance liquid chromatograph, electronic analytical balance, volumetric flask
(3) Solution preparation: diluent agent: acetonitrile-methanol-water (232: 148: 620).
Test solution: taking the product as a test solution.
Control solution: precisely measuring 1.0ml of test solution, placing in a 100ml measuring flask, diluting with diluent to scale, and shaking.
Blank adjuvant solution: taking a 25ml measuring flask, filling a small amount of water, weighing 2.05g of ethanol and 4.375g of glycerol, placing in the measuring flask, adding water to a constant volume, and shaking uniformly to obtain the product.
(4) Chromatographic conditions
Performing high performance liquid chromatography (China pharmacopoeia 2015 edition rules 0512) test with octadecylsilane chemically bonded silica gel as filler [ Agilent ZORBAX SB C18(4.6mm × 250mm, 3.5 μm) or with similar polarity ]; taking water as a mobile phase A and acetonitrile-methanol (22: 14) as a mobile phase B; the detection wavelength was 220nm, the flow rate was 1.0ml/min, and the column temperature was 30 ℃. Gradient elution was performed as follows.
Time (min) Mobile phase A (%) Mobile phase B (%)
0 67 33
25 67 33
26 60 40
38 60 40
39 45 55
50 45 55
51 67 33
56 67 33
The relative retention times and correction factors for each impurity peak are shown in the following table:
compound (I) Relative Retention Time (RRT) Correction factor
Impurity C About 1.6
Impurity E About 1.7
Impurity F About 0.3 0.4
Impurity G About 0.5 0.5
Impurity H About 1.1 0.7
(5) Analytical procedure
And respectively injecting 20 mu l of blank solvent, blank auxiliary material solution, test solution and reference solution into a liquid chromatograph, and recording the chromatogram. The sample injection sequence and times are as follows:
sample introduction sequence number Name of solution Number of samples taken
1 Blank solvent 1
2 Blank adjuvant solution 1
3 Test solution 1
4 Control solution 1
The separation degree of the acetogenins peak and the adjacent impurity peaks meets the requirement.
(6) Calculating the formula:
(6.1) Total impurity% (% S. single impurity).
The single impurity is calculated according to the main component self-comparison method, and the formula is as follows:
Figure BDA0002769572960000061
wherein: a is the peak area of a single known impurity and a single unknown impurity in a test solution;
the pair A is the peak area of the main peak in the reference solution;
the C pair is the concentration of a main peak in the reference solution, mg/ml;
c, the concentration of the test solution is mg/ml;
f is the correction factor corresponding to the impurity, F is 0.4, G is 0.5, and H is 0.7.
(6.2) content calculation formula:
calculated by peak area according to an external standard method, the formula is as follows:
Figure BDA0002769572960000062
in the formula: the A supply is the peak area of the deacetyl hairy flower glycoside in the test solution;
the pair A is the peak area of the deacetyl hairy flower glycoside in the reference solution;
the C pair is the concentration of the deacetyl hairy flower glycoside in the reference solution, mg/ml;
the C supply is the concentration of the test solution, mg/ml.
(7) Acceptance criteria
(7.1) deducting a blank auxiliary material peak, wherein the peak areas of the impurity C and the impurity E in a chromatogram of a sample solution are respectively not more than 0.5 times (0.5%) of the main peak area of a control solution, the peak area of the impurity F is calculated after correction (multiplied by a correction factor of 0.4), the peak area of the impurity F is not more than 1.5 times (1.5%) of the main peak area of the control solution, the peak area of the impurity G is calculated after correction (multiplied by a correction factor of 0.5), the peak area of the impurity H is calculated after correction (multiplied by a correction factor of 0.7), the peak area of the other single impurity is not more than 1.5 times (1.5%) of the main peak area of the control solution, the peak areas of the other single impurities are not more than 1.0% of the main peak area of the control solution, and the sum of the peak areas of the impurities is not more than 6 times (6.0%) of the main peak area. The peaks in the chromatogram of the test solution, which are smaller than 0.05 times the area of the main peak of the control solution, are ignored (0.05%).
The content of (7.2) should be 90.0% -110.0% of the marked amount.
Example 1
The prescription composition is as follows:
prescription Prescription 1a Prescription 2b
Deacetylhairy flower glycoside 12.9g 43g
Ethanol (95%)c 5.29kg 17.63kg
Glycerol 9.59kg 31.98kg
Water for injection is added to 65.89kg 219.9kg
Remarking:
a: the batch is 3 million pieces, the loading is 2.15 ml/piece, the glycerol manufacturer is Hunan Erkang pharmaceutical Co., Ltd, and the total weight of the liquid medicine is calculated according to the density of 1.0216g/ml of the solution.
b: the batch is 10 thousands of pieces, the loading is 2.15 ml/piece, the glycerol manufacturer is Aug.Hedinger GmbH & Co.KG, and the total weight of the liquid medicine is calculated according to the solution density of 1.0228 g/ml.
c: the density of 95% ethanol is 0.81g/cm3The mass of 5.29kg of ethanol in 95% ethanol was 4.9kg, and the mass of 17.63kg of ethanol in 95% ethanol was 16.33 kg.
Prescription 1 preparation process: 60% (about 39.55kg) of injection water is added into a preparation tank, the temperature is reduced to less than or equal to 40 ℃, then the glycerol with the prescription amount (the glycerol manufacturer is Hunan Erkang pharmaceutical Co., Ltd.) is poured, and stirring is started. A stainless steel barrel was charged with a prescribed amount of ethanol diluted with water for injection to a 70% ethanol solution (by weight), 1.89kg of water for injection was required. The prescribed amount of desacetylhairoside is added to the above ethanol solution (keeping the solution temperature ≦ 40 ℃) and stirred for about 20 minutes until completely dissolved. Pouring the dissolved liquid medicine into a dispensing tank, and stirring for about 10 minutes. Diluting with water for injection to the total preparation amount, and stirring for at least 10 min. After the solution is filtered, the solution is encapsulated by adopting a double nitrogen filling mode during encapsulation, and the residual oxygen content standard is controlled to be less than or equal to 2.0 percent. And detecting the quality of the sample.
Prescription 2 preparation process: 60 percent (about 131.94kg) of injection water is added into a preparation tank, the water temperature is reduced to be less than or equal to 40 ℃, the prescription amount of glycerol (Aug.Hedinger GmbH & Co.KG) is added, and the stirring is started. The prescribed amount of ethanol was added to a stainless steel barrel, followed by addition of water for injection (about 6.30kg), and the prescribed amount of ethanol was diluted to an approximately 70% ethanol solution. The prescribed amount of desacetylhairoside is added to the above approximately 70% ethanol solution and stirred for at least 20 minutes until dissolution is uniform. Pouring the liquid medicine into a liquid preparation tank, and stirring for at least 10 minutes. Adding water for injection to the total preparation amount, and stirring for at least 10 minutes. After the solution is filtered, the solution is encapsulated by adopting a double nitrogen filling mode during encapsulation, and the residual oxygen content standard is controlled to be less than or equal to 2.0 percent. The quality of the sample was checked (test method as above).
The injections of the two prescriptions are respectively sampled and tested for the change of characters, contents, pH values and related substances at the high temperature of 80 ℃ for 1 day, 3 days and at the high temperature of 60 ℃ for 10 days, and the results are as follows:
Figure BDA0002769572960000081
Figure BDA0002769572960000091
the experimental result shows that the injection prepared by adopting Aug.Hedingger GmbH & Co.KG glycerin has lower related substances than the injection prepared by lake Nankang glycerin for 0 day, the high temperature has larger influence on the quality of the deacetylated hairy glycoside injection, and the total impurities increase along with the lengthening of the placing time. The total impurity of the injection prepared from Aug.Hedinger GmbH & Co.KG glycerin is increased slowly at high temperature compared with the injection prepared from Hunan Erkang glycerin, so that the quality of the injection can be optimized by replacing the source of the glycerin serving as the auxiliary material, and the stability of the injection in the storage process is improved.
Example 2
The samples of recipe 2 were terminally sterilized at 116 ℃ for 30 minutes and 121 ℃ for 15 minutes, respectively. Comparing the quality of the products before sterilization with that of the products under different sterilization conditions, and sampling the sterilized samples at 60 ℃ for 5 days, 10 days and 80 ℃ for 1 day and 3 days to detect the quality of the products (the test method is the same as the above). The detection results are as follows:
Figure BDA0002769572960000092
Figure BDA0002769572960000101
the experimental result shows that the deacetyl hairy flower glycoside injection can resist the terminal sterilization process and has small impurity growth in the stability process.
Example 3:
the prescription composition is as follows:
composition (I) Dosage (20 ten thousand pieces/batch, 2.15 ml/piece)
Deacetylhairy flower glycoside 86.0g
Ethanol (95%) 35.26kg
Glycerol 63.96kg
Water for injection is added toa 439.80kg
a: the total weight of the liquid medicine is calculated according to the density of the solution 1.0228 g/ml.
60 percent (about 264.00kg) of injection water is added into a preparation tank, the water temperature is reduced to be less than or equal to 40 ℃, the glycerol with the amount of the prescription is added, and the stirring is started. The prescribed amount of ethanol was diluted to an approximately 70% strength ethanol solution in a stainless steel barrel, to which was added an appropriate amount of water for injection (about 12.60 kg). The prescribed amount of desacetylhairoside is added to the above approximately 70% ethanol solution and stirred for at least 20 minutes until dissolution is uniform. Pouring the liquid medicine into a liquid preparation tank, and stirring for at least 10 minutes. Adding water for injection to the total preparation amount, and stirring for at least 10 minutes. Filtering the solution, and filling and sealing by nitrogen filling before and after filling and sealing respectively. When nitrogen is filled, the residual oxygen content is controlled to be less than or equal to 2.0 percent. And (3) carrying out damp-heat sterilization on the filled sample by adopting circulating steam, wherein the sterilization condition is 121 ℃ for 15 minutes. And (3) placing the sterilized sample at the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5%, and sampling for detecting characters, contents, pH values and related substances in 1 month, 2 months, 3 months and 6 months respectively. The related substances are detected according to the method, and the content detection method comprises the following steps:
the content detection method comprises the following steps:
(1) reagent and solution: water, acetonitrile, methanol
(2) Instruments and appliances: high performance liquid chromatograph, electronic analytical balance (sensitive quantity 0.01mg), volumetric flask
(3) Solution preparation: diluent agent: acetonitrile-methanol-water (232: 148: 620).
Test solution: taking the product as a test solution.
Control solution: precisely weighing 20mg of the control product of the deacetyl hairy flower glycoside, putting the control product into a 100ml measuring flask, adding a proper amount of methanol for dissolving, diluting the control product to a scale by using a diluent, and shaking up uniformly.
(4) Chromatographic conditions are as follows: measuring by high performance liquid chromatography (2015 version of Chinese pharmacopoeia 0512), and using octadecylsilane chemically bonded silica as filler; acetonitrile-methanol-water (232: 148: 620) is used as a mobile phase, the detection wavelength is 220mn, the flow rate is 1.0ml/min, the column temperature is 30 ℃, the number of theoretical plates is not less than 2000 calculated according to the peak of the deacetyl hairoside, and the separation degree of the peak of the deacetyl hairoside and the adjacent impurity peak is in accordance with the requirement.
(5) The analysis process comprises the following steps: and respectively injecting 20 mu l of blank solvent, reference solution and test solution into a liquid chromatograph, and recording the chromatogram. The sample injection sequence and times are as follows:
sample introduction sequence number Name of solution Number of samples taken
1 Blank solvent 1
2 Control solution 1 5
3 Control solution 2 2
4 Test solution 1 2
5 Test solution 2 2
6 Control solution 1 1
The number of theoretical plates is not less than 2000 calculated according to the peak of the deacetylated hairy flower glycoside, and the separation degree of the deacetylated hairy flower glycoside peak and the adjacent impurity peak is in accordance with the requirement; the recovery rate of the 2 nd reference substance is 98.0-102.0%; in the chromatogram of the 5-needle continuous sample injection reference solution, the peak area RSD of the main peak is not lower than 2.0%.
(6) Calculating the formula: calculated by peak area according to an external standard method, the formula is as follows:
Figure BDA0002769572960000121
in the formula: a. theFor supplying toIs the peak area of the deacetyl hairy flower glycoside in the test solution;
Ato pairThe peak area of the deacetyl hairy flower glycoside in the reference solution is shown;
Cto pairThe concentration of the deacetyl hairy flower glycoside in the reference solution is mg/ml;
Cfor supplying toThe concentration of the test solution is mg/ml.
(7) Acceptance criteria: should be 90.0% to 110.0% of the indicated amount.
The detection result is as follows:
Figure BDA0002769572960000122
the experimental result shows that the total impurity increase of the sample is 0.44% in 3 months and 0.64% in 6 months when the sample is placed at the temperature of 40 +/-2 ℃ and the relative humidity of 75% +/-5%.

Claims (10)

1. A preparation method of a deacetyl hairy flower glycoside injection is characterized by comprising the following steps: sterilizing the mixture containing deacetyl hairy flower glycoside, ethanol, glycerol and water for injection by terminal sterilization at 121 deg.C for 15 min.
2. A preparation method of a deacetyl hairy flower glycoside injection is characterized by comprising the following steps: sterilizing mixture containing deslanoside, ethanol, glycerol and water for injection at 116 deg.C for 30 min.
3. The process for producing the deslanoside injection according to claim 1 or 2,
the glycerol is derived from Aug.Hedinger GmbH & Co.KG;
and/or the content of the deacetyl hairy flower glycoside is 0.2 mg/ml;
and/or the content of the ethanol is 0.076 g/ml;
and/or the content of the glycerol is 0.149 g/ml;
and/or, nitrogen filling and sealing operation is carried out before sterilization; the nitrogen filling encapsulation can be performed before and after encapsulation respectively; preferably, the operation of filtering is carried out before filling and sealing by nitrogen;
and/or the mixture consists of the deacetyl hairy flower glycoside, ethanol, glycerol and water for injection.
4. The method for preparing a deslanoside injection according to any one of claims 1 to 3, wherein said mixture comprising deslanoside, ethanol, glycerol and water for injection is prepared by the steps of:
the method comprises the following steps: mixing 60% of water for injection and glycerol to obtain a mixed solution;
step two: mixing ethanol and water for injection to obtain 70% ethanol solution, and mixing the ethanol solution and the deacetyl hairy flower glycoside to obtain mixed solution; the percentage is weight percentage;
step three: mixing the mixed solution obtained in the first step and the mixed solution obtained in the second step, and mixing the mixed solution with water for injection;
wherein, the sequence of the step one and the step two is not divided into sequence.
5. The method for preparing the desacetylhairoside injection according to claim 4,
the temperature of the water for injection in the first step is less than or equal to 40 ℃;
and/or the mixing mode is stirring;
and/or, in step three, the mixing time is 15-25 minutes, such as 20 minutes;
and/or, in the third step, the mixing time is more than or equal to 10 minutes.
6. A production process of a deacetyl hairy flower glycoside injection is characterized in that the deacetyl hairy flower glycoside injection is a solution containing 0.2mg/ml of deacetyl hairy flower glycoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and a proper amount of water for injection;
the production process comprises the following steps: adding 60% of injection water into the dispensing tank, cooling the water to be less than or equal to 40 ℃, adding glycerol, and stirring; adding ethanol into a stainless steel barrel, adding a proper amount of water for injection, diluting the ethanol with the prescription amount into an ethanol solution with the concentration of 70%, adding the deacetyl hairy flower glycoside into the ethanol solution with the concentration of 70%, and stirring until the mixture is dissolved uniformly to obtain a liquid medicine; pouring the above medicinal liquid into a liquid preparation tank, stirring for at least 10 min, adding water for injection, stirring for at least 10 min, filtering, bottling in 2ml ampoule by respectively filling nitrogen before and after bottling, and sterilizing at 121 deg.C for 15min or 116 deg.C for 30 min.
7. A method for preparing a de-acetyleriocitrin injection as claimed in any one of claims 1 to 6.
8. A desacetylhairy flower glycoside injection is characterized by comprising desacetylhairy flower glycoside, ethanol, glycerol and water for injection, wherein the glycerol is derived from Aug.
9. The desacetylhairoside injection according to claim 8,
the content of the deacetyl hairy flower glycoside is 0.2 mg/ml;
and/or the content of the ethanol is 0.076 g/ml;
and/or the content of the glycerol is 0.149 g/ml.
10. The desacetylhairoside injection according to claim 8, comprising 0.2mg/ml of desacetylhairoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and water for injection, wherein the glycerol is derived from aug.
CN202011244615.0A 2020-11-10 2020-11-10 Preparation method of pharmaceutical composition containing deacetyl hairy flower glycoside Pending CN112336737A (en)

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WO2016067179A1 (en) * 2014-10-29 2016-05-06 Wockhardt Limited A drug delivery device for delivery of two or more independently user selectable multiple doses of medicaments with user operable variable dose locking mechanisms
CN112336687A (en) * 2019-08-09 2021-02-09 南京科宁检测科技有限公司 Composition of deacetyl hairy flower glycoside injection and preparation method thereof

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Publication number Priority date Publication date Assignee Title
CN102961326A (en) * 2012-11-27 2013-03-13 上海朝晖药业有限公司 Preparation method of deslanoside injection
WO2016067179A1 (en) * 2014-10-29 2016-05-06 Wockhardt Limited A drug delivery device for delivery of two or more independently user selectable multiple doses of medicaments with user operable variable dose locking mechanisms
CN112336687A (en) * 2019-08-09 2021-02-09 南京科宁检测科技有限公司 Composition of deacetyl hairy flower glycoside injection and preparation method thereof

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Application publication date: 20210209