CN112156069B - Production process of deslanoside injection - Google Patents

Production process of deslanoside injection Download PDF

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Publication number
CN112156069B
CN112156069B CN202011244371.6A CN202011244371A CN112156069B CN 112156069 B CN112156069 B CN 112156069B CN 202011244371 A CN202011244371 A CN 202011244371A CN 112156069 B CN112156069 B CN 112156069B
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injection
water
ethanol
solution
deslanoside
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CN112156069A (en
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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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    • 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
    • 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

Abstract

The invention discloses a production process of a deacetyl hairy flower glycoside injection. The invention provides a production process of a deslanoside injection, which comprises the following steps: the mixture containing 0.2mg/ml of deacetyl hairy flower glycoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and water for injection is encapsulated, wherein nitrogen is respectively filled before and after encapsulation. The invention has simple production process, ensures the product quality, does not increase new cost, can reduce cost and energy consumption, and is suitable for large-scale industrial production.

Description

Production process of deslanoside injection
Technical Field
The invention belongs to a production process of a desacetylhairflower glycoside injection, and relates to a method for optimizing impurity level of the desacetylhairflower glycoside injection, which mainly solves the problem of impurity growth in the storage process.
Background
Deacetyl-eriocitrin is a cardiac glycoside naturally present in digitalis, which can be hydrolyzed to lose glucose and acetic acid to form digoxin during extraction, a fast acting cardiac glycoside, which acts faster than digitalis and digoxin but slower than curcuminoid-K. The deslanoside injection is mainly used for heart failure, and is suitable for patients with acute cardiac insufficiency or acute exacerbation of chronic cardiac insufficiency due to quick 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 preparation method of a deacetyl hairy flower glycoside injection, which is characterized in that the temperature of 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
In order to overcome the defects in the prior art, the invention aims to provide a production process of the desacetylhairoside injection, which reduces the impurity degradation degree of the desacetylhairoside injection in the stability period.
The invention provides a production process of a deslanoside injection, which comprises the following steps: the mixture containing 0.2mg/ml of deacetyl hairy flower glycoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and water for injection is encapsulated, wherein nitrogen is respectively filled before and after encapsulation.
In some embodiments of the present invention, the operation of filtering the mixture before potting is further included.
In some embodiments of the invention, the mixture is encapsulated in an ampoule; the ampoule bottle can be a Linuo medium boron ampoule bottle, a plain medium boron ampoule bottle or a plain low boron ampoule bottle, and is preferably a plain medium boron ampoule bottle. The ampoule bottle can be a 1ml ampoule bottle or a 2ml ampoule bottle.
In some embodiments of the invention, the mixture consists of 0.2mg/ml of deslanoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and water for injection.
In some embodiments of the invention, the mixture comprising 0.2mg/ml of deslanoside, 0.076g/ml of ethanol, 0.149g/ml of glycerol and water for injection is prepared by a process 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 water for injection described in step one has a temperature of 40 ℃ or less.
In some embodiments of the invention, the mixing is by stirring.
In some embodiments of the invention, the mixing time in step three 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 deslanoside injection comprises the steps of preparing a solution containing 0.2mg/ml of deslanoside, 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 percent of injection water into the dispensing tank, cooling the water to be less than or equal to 40 ℃, adding glycerol, and starting stirring; adding ethanol into a stainless steel barrel, adding a proper amount of water for injection, diluting the ethanol with the prescription amount into 70% ethanol solution, adding the desacetylhairflower glycoside into the 70% ethanol solution, and stirring until the mixture is dissolved uniformly to obtain liquid medicine; pouring the liquid medicine into a liquid preparation tank, stirring for at least 10 minutes, adding water for injection, stirring for at least 10 minutes, filtering, and filling into 2ml plain medium boron ampoule bottles by respectively filling nitrogen before and after filling.
The invention also provides a deacetyl hairy flower glycoside injection prepared by the production process of the deacetyl hairy flower glycoside injection.
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 because the glycerol has certain thickness and poor fluidity, the glycerol and the water for injection dilute the concentration of the glycerol and increase the fluidity after mixing, so that the solution of the desacetylhairflower glycoside can be more easily and uniformly dispersed in a desacetylhairflower glycoside injection liquid system.
Through experimental research, relevant substance indexes in the deacetyl hairy flower glycoside injection prepared by the production process are obviously reduced, the product quality is improved, and the product risk is better reduced. The product is fully inspected according to the standard of 'Chinese pharmacopoeia' 2015 edition, and the result shows that all indexes of the deacetyl hairy flower glycoside injection of the invention reach the standard specification.
In the invention, the Linuo medium boron ampoule bottle refers to an ampoule bottle with an inner packaging material from Shandong Linuo special glass GmbH and a colorless medium boron silicon glass inner packaging material.
In the invention, the plain medium boron ampoule bottle refers to an ampoule bottle of which the inner packaging material is colorless medium boron silicon glass and is from Chengdu plain Nipple pharmaceutical packaging Limited company.
In the invention, the plain low-boron ampoule bottle refers to an ampoule bottle of which the inner packaging material is colorless low-boron silicon glass and is from Chengdu plain Nipple pharmaceutical packaging Limited company.
The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the 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: according to the invention, the impurity degradation degree of the deacetylated hairy glycoside injection during the stability period is improved by respectively charging nitrogen before and after encapsulation in the encapsulation process. The deacetyl hairy flower glycoside injection prepared according to the prescription and the process described in the technical scheme of the invention has stable quality and small impurity content, and is sampled and detected after being placed for 10 days at high temperature (60 +/-2 ℃), and the result shows that the product adopting the double nitrogen filling process has stable quality and small impurity growth; the production process is simple, the product quality is ensured, meanwhile, new cost is not increased, the cost and energy consumption can be reduced, and the method is suitable for large-scale industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
The Linuo medium boron ampoule bottle is an ampoule bottle which is made of colorless medium boron silicon glass and is made of inner packaging materials from Shandong Linuo special glass GmbH.
The ampoule bottle of boron in plain refers to the ampoule bottle of which the inner packaging material is colorless medium borosilicate glass, and is from Chengdu plain Nipulo pharmaceutical industry packaging Co.
The plain low-boron ampoule bottle refers to an ampoule bottle with an inner packaging material from Chengdu plain Nipple pharmaceutical packaging Limited company and the inner packaging material of colorless low-boron silicon glass.
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.
Test solution: taking the product as a test solution.
Control solution: precisely measuring 1.0ml of test solution, placing into 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 up to obtain the product.
(4) Chromatographic conditions
Performing high performance liquid chromatography (2015 year version of Chinese pharmacopoeia 0512) with octadecylsilane chemically bonded silica gel as filler [ Agilent ZORBAX SB C18 (4.6 mm. Times.250mm, 3.5 μm) or similar polarity ] column; water as mobile phase a, acetonitrile-methanol (22; the detection wavelength was 220nm, the flow rate was 1.0ml/min, and the column temperature was 30 ℃. Gradient elution was performed as follows.
Figure BDA0002769503180000041
Figure BDA0002769503180000051
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
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% impurities = ∑ single impurities%.
The single impurity is calculated according to the main component self-comparison method, and the formula is as follows:
Figure BDA0002769503180000061
wherein: a is the peak area of a single known impurity and a single unknown impurity in a test sample 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, and is mg/ml;
c, the concentration of the test solution is mg/ml;
f is a correction factor corresponding to the impurity, F is 0.4, G is 0.5, and H is 0.7.
(6.2) content calculation formula:
the method is calculated by peak area according to an external standard method, and the formula is as follows:
Figure BDA0002769503180000062
in the formula: a is the peak area of the desacetyl eriocitrin in the test solution;
pair A is the peak area of desacetylhairflower 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 of the control solution according to the corrected peak areas. 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:
composition (A) Dosage (3 ten thousand per batch, 2.15ml per batch)
Deacetylhairy flower glycoside 12.9g
Ethanol (95%) a 5.29kg
Glycerol 9.59kg
Water for injection is added to b 65.89kg
Remarking: a: the density of 95% ethanol is 0.81g/cm 3 Wherein the mass of ethanol in 5.29kg of 95 percent ethanol is 4.9kg; b: the total weight of the liquid medicine is calculated according to the density of the solution of 1.0216 g/ml.
60 percent (39.55 kg) of injection water is added into a preparation tank, the temperature is reduced to be less than or equal to 40 ℃, then the glycerol with the amount according to the prescription is poured, and the stirring is started. The stainless steel barrel was filled with the prescribed amount of ethanol diluted to 70% ethanol solution (by weight) with water for injection, 1.89kg of water for injection was required. Adding the formula amount of the desacetylhairflower glycoside into the ethanol solution (keeping the solution temperature less than or equal to 40 ℃), and stirring for 20 minutes until the desacetylhairflower glycoside is completely dissolved. Pouring the dissolved liquid medicine into a dispensing tank, and stirring for 10 minutes. Diluting with water for injection to total preparation amount, and stirring for at least 10 min. After the solution is filtered, the solution is respectively encapsulated in a 2ml plain medium boron ampoule bottle in a nitrogen-free manner and a nitrogen-filled manner before and after encapsulation. When nitrogen is respectively filled before and after encapsulation, the residual oxygen content standard is controlled to be less than or equal to 2.0 percent.
Placing the samples in different modes, and detecting according to the method for related substances and contents, wherein the detection result is as follows:
Figure BDA0002769503180000071
Figure BDA0002769503180000081
experimental results show that the quality of 0 day samples subjected to nitrogen charging before and after nitrogen charging and nitrogen charging after and after encapsulation are equivalent, the quality of 0 day samples subjected to the two nitrogen charging modes is similar, after heat treatment at 100 ℃ for 30min, the samples subjected to the heat treatment are simultaneously placed in a high-temperature 80 ℃ oven, and sampling detection is carried out after the samples are placed for 1 day, the total impurity growth of the double-nitrogen-charged samples at 80 ℃ for 1d is found to be smaller than that of the samples not subjected to the nitrogen charging, after the samples are placed for 10 days at high temperature (60 +/-2 ℃), the content of the samples subjected to the nitrogen charging before and after encapsulation is reduced by 2.8%, the content of related substances is increased by 1.9%, the content of the samples subjected to the nitrogen charging is reduced by 5.0%, and the content of the related substances is increased by 2.6%, so that the impurity degradation level in the stability process of the deacetyl piloside injection can be reduced by respectively carrying out the nitrogen charging before and after encapsulation, and the encapsulation is more stable in quality.
Example 2
The recipe and the process method of example 1 were adopted, wherein no nitrogen was filled in number 1, and the nitrogen filled ampoule bottles were filled in 2ml before and after number 2, and the boron filled ampoule bottles were filled in 1ml before and after number 3. Placing the samples in different modes, and detecting according to the method for related substances and contents, wherein the detection result is as follows:
Figure BDA0002769503180000082
Figure BDA0002769503180000091
the experimental results show that: the same packaging material is adopted, and the nitrogen filling effect has influence on the stability of the injection. The total impurities in the stability of the injection filled with nitrogen are increased less than the total impurities in the stability without nitrogen, the lower the head space residual oxygen is, the better the nitrogen filling effect is represented, and the smaller the total impurities in the stability of the injection is increased when the nitrogen filling effect is better.
Example 3
The formula and the process method of the embodiment 1 are adopted, and the ampoule bottles are respectively filled with nitrogen before and after filling. Placing the samples in different modes, and detecting according to the method for related substances and contents, wherein the detection result is as follows:
Figure BDA0002769503180000092
Figure BDA0002769503180000101
the experimental results show that: the injection encapsulated in the boron packing material in plain is placed at 60 ℃ for 10 days, the total impurity is increased by 1.9 percent, and the total impurity is increased by 7.7 percent after being placed for 20 days; the injection encapsulated in the boron packing material in plain is placed at 60 ℃ for 10 days, the total impurity is increased by 5.1 percent, and the total impurity is increased by 8.7 percent; the total impurity growth of the injection encapsulated in the boron packaging material in the Linuo is 6.5 percent after being placed at 60 ℃ for 10 days, and the total impurity growth is 10.3 percent after being placed for 20 days. The total miscellaneous result that increases among the stable in-process of contrast injection can know, and the embedment increases littleer in the stable total miscellaneous of ampoule of plain production than the embedment in the ampoule of li nuo production, and the same embedment is in the colorless ampoule of 2ml of plain production, and the material is that the total miscellaneous stability that increases of borosilicate is less than the total miscellaneous stability that increases of low boron silicon ampoule for well borosilicate.
Comparative example 1
Prescription:
Figure BDA0002769503180000102
Figure BDA0002769503180000111
60 percent (360 ml) of injection water is added into a beaker, the temperature is reduced to less than or equal to 40 ℃, then the glycerol with the amount of the prescription is poured, and the stirring is started. Another beaker was added with the prescribed amount of ethanol and diluted with water for injection to give a 70% ethanol solution (by weight), which required 17.6g of water for injection. The prescribed amount of deacetylhairoside is added to the above ethanol solution (keeping the solution temperature ≦ 40 ℃), and stirred for 20 minutes until completely dissolved. Pouring the dissolved liquid medicine into a dispensing tank, and stirring for 10 minutes. Diluting with water for injection to the total preparation amount, and stirring for at least 10 min. Filtering the solution, and filling and sealing. And (3) placing the filled sample for 3 months under an accelerated condition, and sampling to detect the characters, the content, the pH value and related substances.
The detection is carried out according to the method of the related substances and the content, the detection results are as follows:
Figure BDA0002769503180000112
the nitrogen-unfilled sample accelerated a 1.9% increase in total impurities over 3 months.

Claims (2)

1. A production method of a deslanoside injection is characterized in that the deslanoside injection is a solution containing 0.2mg/ml of deslanoside, 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 percent of injection water into the dispensing tank, cooling the water to be less than or equal to 40 ℃, adding glycerol, and starting stirring; adding ethanol into a stainless steel barrel, adding a proper amount of water for injection, diluting the ethanol with the prescription amount into 70% ethanol solution, adding the desacetylhairflower glycoside into the 70% ethanol solution, and stirring until the mixture is dissolved uniformly to obtain liquid medicine; pouring the liquid medicine into a liquid preparation tank, stirring for at least 10 minutes, adding water for injection, stirring for at least 10 minutes, filtering, and filling into 2ml plain medium boron ampoule bottles by respectively filling nitrogen before and after filling; the inner package material of boron ampoule in the plain is borosilicate glass's in the colourless ampoule.
2. A deslanoside injection prepared by the method for producing a deslanoside injection according to claim 1.
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