CN108245669B - Stable defibrase injection and preparation method thereof - Google Patents
Stable defibrase injection and preparation method thereof Download PDFInfo
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4806—Hydrolases (3) acting on peptide bonds (3.4) from animals other than mammals, e.g. snakes
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- 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
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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
- A61K9/08—Solutions
Abstract
The present invention belongs to the field of biological and biochemical pharmacy. The stable defibrase injection consists of the following components in parts by weight: each 1000ml of the preparation solution contains: 5000U or 10000U of defibrase, 1-50ml of stabilizer and the balance of water for injection; or freeze-dried powder injection: each 1000ml of the preparation solution contains: 5000U or 10000U of defibrase, 10.0g of excipient, 1-50ml of stabilizer and the balance of water for injection; the stabilizer is a glutamic acid-arginine stabilizing system. The present invention goes beyond the prior art concept of using a stabilizing system as a protectant. The key effect is that the unexpected effect is achieved, which is different from the prior art, that no excess feeding is needed and the stability is excellent.
Description
Technical Field
The present invention belongs to the field of biological and biochemical pharmacy.
Background
The defibrase has clear pharmacological action and obvious drug effect, is a therapeutic drug for sudden cerebral infarction and other vascular embolism diseases, and is also widely used for inhibiting thrombosis and improving microcirculation. Its predecessors were defibrase and antithrombosis enzyme for injection, which were multicomponent mixtures due to the limitations of the separation and purification techniques at the time. In 1996, the standard issued by the ministry of health department, institute of ministry of health, is unified by defibrase produced from snake venom of Agkistrodon acutus (Agkistrodon acutus) and antithrombosis enzyme produced from snake venom of Agkistrodon halys gesii. The preparation is lyophilized powder for injection and water injection, and the specification of each dosage form is 5U/bottle and 10U/bottle. The defibrase is a proteolytic enzyme with high specific activity, the specific activity is 1200U-3500U/mg, the quality of the defibrase in each bottle is extremely little in defibrase freeze-dried powder injection and water injection, the defibrase is easily influenced by various factors such as temperature, pH value, polymerization, degradation, oxidation and the like, and the enzyme activity is unstable. The titer of the defibrase preparation is easy to reduce in the links from preparation, freeze-drying, storage, transportation, sale and the like, so that in the production process of the defibrase preparation, in order to ensure that the content of the preparation meets the quality standard, manufacturers carry out the feeding with different degrees of over-limit according to the own experience, still cannot obtain a more stable result, and the inaccuracy of the titer of the finished product and the risk of clinical medication are increased. In the production, storage, transportation, sale and other links, the efficacy and safety of the reasonable medicine according to the prescription dosage are seriously influenced in the clinical use process due to the instability of the potency.
Chinese patent application No. 201410348725.X discloses an adjuvant for stabilizing a pharmaceutical composition and a pharmaceutical composition containing the adjuvant, the invention application provides an adjuvant for stabilizing a pharmaceutical composition and a pharmaceutical composition containing the adjuvant, and particularly relates to a pharmaceutical composition with high stability and taking defibrase as a main drug. The enzyme activity protective agent is added into the original defibrase powder injection and injection composition, the active component of the injection is defibrase, other inactive components in the composition are stabilizer, excipient dextran and enzyme activity protective agent, the enzyme activity protective agent is micromolecule enzyme activity protective agent or macromolecule enzyme activity protective agent or the combination of micromolecule enzyme activity protective agent and macromolecule enzyme activity protective agent, so as to ensure the stability of defibrase titer in the processes of production, storage and sale, reduce the production feed ratio, ensure the titer stability of finished products, and improve the safety and curative effect of clinical medication.
The prior technical proposal is that 0.01 to 5 percent of human serum albumin and 0.001 to 0.5 percent (W/V) of partially hydrolyzed gelatin or hydrolyzed gelatin are added into a medicine prescription in the production process of defibrase preparation as protective agents of enzyme activity. Of course, human serum albumin and gelatin or partially hydrolyzed gelatin and hydrolyzed gelatin do have a protective effect on enzyme activity, but have an antagonistic effect on the pharmacology of defibrase, which is used for blood vessel transfusion and blockage; the substances have swelling effect on defibrase, so that the defibrase is reduced in dosage and fed, the curative effect of reasonable administration according to the prescription dosage is seriously influenced, and the requirements of GMP are not met; the most fatal is that the sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the finished products does not meet the requirements of the standard at all, does not meet the standard and has stable titer according to the fact that the standard cannot be met, and the safety and the curative effect of clinical medication are improved in a word that the standard cannot be met. As far as the 1.0% -5% (W/V) mannitol or glycine described in this patent is concerned, there is no protective effect on the enzyme activity but rather a consumption effect.
Disclosure of Invention
The invention aims to provide a more safe, more effective and more stable defibrase injection.
The invention also aims to provide a preparation method of the defibrase injection.
The stable defibrase injection consists of the following components in parts by weight: each 1000ml of the preparation solution contains: 5000U or 10000U of defibrase, 1-50ml of stabilizer and the balance of water for injection;
or freeze-dried powder injection: each 1000ml of the preparation solution contains: 5000U or 10000U of defibrase, 10.0g of excipient, 1-50ml of stabilizer and the balance of water for injection;
the stabilizer is a glutamic acid-arginine stabilizing system.
The excipient is common medical excipient, such as dextran 40.
The preparation method of the stable defibrase injection comprises the following steps:
the preparation method of the stabilizer comprises the following steps: weighing 14.713g of medical-grade glutamic acid, adding a proper amount of water for injection, heating to boil, adding medical-grade arginine, stirring, adjusting the pH value to 5.5-7.0, adding 200ml of water for injection, and preparing into a solution with a concentration of 0.5M calculated by glutamic acid for later use;
secondly, a preparation method of the preparation comprises the following steps: adding 1-50ml of the stabilizer in the step one into a measuring cylinder of 5000U defibrase or 10000U defibrase respectively, adding water for injection to 1000ml respectively, and preparing 1000 bottles of water injection or freeze-dried powder injection according to the preparation method of the water injection or freeze-dried powder injection.
Defibrase is an active proteolytic enzyme, has the basic property of a protease, is an amphoteric substance, i.e., each molecule is positively and negatively charged, is particularly active in particular in the solution state and during lyophilization, and is stabilized by the addition of a charge balancing agent which always remains in a dormant state regardless of the conditions under which it is added.
In order to find a suitable defibrase charge balancing agent, the applicant spends many years and makes a plurality of tests, and invests a great deal of funds and manpower to find the charge balancing agent, namely the stabilizing agent, which is disclosed in the application. The stabilizer is a new compound small molecular peptide, which is formed by the reaction and combination of acidic amino acid and basic amino acid, so the stabilizer is called as a stabilizing system in the application. The stabilizer has the advantages that: the molecular weight is small, and the amino acid is combined by two groups of amino acids needed by a human body; ② has no antagonism with defibrase as main drug and has synergy; ③ no ultraviolet absorption, and no interference to the determination of the purity of the preparation; fourthly, the charges of the two groups of amino acids are opposite, and the purity detection of the SDS electrophoresis of the preparation is not influenced; the potency measurement of the main drug is not interfered, so that the main drug can be accurately fed, and the accuracy, the safety and the curative effect of clinical medication are improved; sixthly, other PH value regulators are not needed to be added into the preparation, so that the preparation has single component, is convenient to identify and better meets the requirement of GMP.
The present invention goes beyond the prior art concept of using a stabilizing system as a stabilizer. The key effect is that the unexpected effect is achieved, which is different from the prior art, that no excess feeding is needed and the stability is excellent.
Experimental data:
comparative experiment:
preparation of comparative agent 1:
defibrase freeze-dried powder injection (Specification 5U/bottle)
Total defibrase amount of 5000U
Dextran 4010.0 g
Adding water for injection to 1000ml
And (3) detection: 5U is thrown into each bottle, and only 2.82U is measured after freeze-drying, which is not qualified.
Preparation of comparative agent 2:
defibrase freeze-dried powder injection (Specification 5U/bottle)
Total defibrase amount of 8000U
Dextran 4010.0 g
Adding water for injection to 1000ml
And (3) detection: 8U is added into each bottle, and 4.93U is obtained after freeze-drying, which meets the requirement, but does not meet the requirement after 1 month.
Preparation of comparative agent 3:
defibrase freeze-dried powder injection (Specification 5U/bottle)
And (3) detection: 5U is added into each bottle, and only 4.12U is obtained after freeze-drying, which is not satisfactory.
Preparation of comparative agent 4:
defibrase freeze-dried powder injection (Specification 5U/bottle)
And (3) detection: 5U is added into each bottle, and only 3.67U is obtained after freeze-drying, which is not satisfactory.
Preparation of comparative agent 5:
defibrase freeze-dried powder injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
Dextran 4010.0 g
Adding water for injection to 1000ml
And (3) detection: the amount of the freeze-dried powder is 10U per bottle, and the amount of the freeze-dried powder is only 5.66U after freeze-drying, which is not satisfactory.
Preparation of comparative agent 6:
defibrase freeze-dried powder injection (Standard 10U/bottle)
Total amount of defibrase 16000U
Dextran 4010.0 g
Adding water for injection to 1000ml
And (3) detection: 16U is added into each bottle, and 9.8U is obtained after freeze-drying, which meets the requirement, but does not meet the requirement after 1 month.
Preparation of comparative agent 7:
defibrase freeze-dried powder injection (Standard 10U/bottle)
And (3) detection: the amount of the freeze-dried powder is 10U per bottle, and the amount of the freeze-dried powder is only 8.2U, which is not satisfactory.
Preparation of comparative agent 8:
defibrase freeze-dried powder injection (Standard 10U/bottle)
And (3) detection: the amount of the freeze-dried powder is 10U per bottle, and the amount of the freeze-dried powder is only 7.2U, which is not satisfactory.
Preparation of comparative agent 9:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 5000U
Adding water for injection to 1000ml
Precisely measuring defibrase 5000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: 5U is thrown into each bottle, 6.24U is required, but the requirement is not met after one month.
Preparation of contrast agent 10:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 8000U
Adding water for injection to 1000ml
Precisely measuring 8000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: 8U is thrown into each bottle, 9.90U is thrown into each bottle, the titer exceeds the upper limit, and the requirement is not met. Accelerated stability test, and the test does not meet the requirement after 1 month.
Preparation of comparative agent 11:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 5000U
Human serum albumin 0.3g
Adding water for injection to 1000ml
Weighing 0.3g of human serum albumin, adding a proper amount of water for injection to dissolve, and precisely weighing 10000U of defibrase. Preparing, sterilizing, filtering and packaging.
And (3) detection: 5U is thrown into each bottle, 7.1U is thrown into each bottle, the titer exceeds the upper limit, and the requirement is not met. The electrophoresis is unqualified, and the long-term stability experiment is not examined.
Preparation of comparative agent 12:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 5000U
Gelatin for injection 0.5g
Adding water for injection to 1000ml
Weighing 0.5g of gelatin for injection by using an analytical balance, adding a proper amount of water, heating until the gelatin is dissolved, and precisely weighing 5000U of defibrase. Preparing, sterilizing, filtering and packaging.
And (3) detection: 5U is thrown into each bottle, 7.54U is thrown into each bottle, the titer exceeds the upper limit, and the requirement is not met. The electrophoresis is unqualified, and the long-term stability experiment is not examined.
Preparation of comparative agent 13:
defibrase injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
Adding water for injection to 1000ml
Precisely measuring defibrase 10000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: the amount of the drug is 10U per bottle, 11.9U per bottle, which meets the requirement, but the drug does not meet the requirement after one month.
Preparation of comparative agent 14:
defibrase injection (Standard 10U/bottle)
Total amount of defibrase 16000U
Adding water for injection to 1000ml
Precisely weighing 16000U defibrase, preparing, sterilizing, filtering, and packaging.
And (3) detection: 16U is thrown into each bottle, 18U is thrown into each bottle, the titer exceeds the upper limit, and the requirement is not met. The long-term stability test is not satisfactory after 1 month.
Preparation of comparative agent 15:
defibrase injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
Human serum albumin 0.5g
Adding water for injection to 1000ml
Weighing 0.5g of human serum albumin, adding a proper amount of water for injection to dissolve, and precisely weighing 10000U of defibrase. Preparing, sterilizing, filtering and packaging.
And (3) detection: the dosage of each bottle is 10U, the dosage is 14.2U, the titer exceeds the upper limit, and the requirement is not met. The electrophoresis is unqualified, and the long-term stability experiment is not examined.
Preparation of contrast agent 16:
defibrase injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
Gelatin for injection 1.0g
Adding water for injection to 1000ml
Weighing 1.0g of gelatin for injection by using an analytical balance, adding a proper amount of water, heating until the gelatin is dissolved, precisely weighing 10000U of defibrase, preparing, sterilizing, filtering and subpackaging.
And (3) detection: the dosage of each bottle is 10U, 15.2U, the titer exceeds the upper limit, and the requirement is not met. The electrophoresis is unqualified, and the long-term stability experiment is not examined.
TABLE 1 accelerated stability test
The conditions for accelerated stability experiments were temperature 25. + -. 1 ℃ and humidity 60. + -. 5%.
The experimental method comprises the following steps: and randomly extracting 5 bottles of samples, adding 1.0ml of sample dilution buffer solution, and detecting according to a method under the titer item. In examples 1 to 12, the data had fluctuations due to the difference in the amount of charge and the detection error, and the overall trend was not significantly decreased, and the stability and the amount-effect relationship of the stabilizer were all in accordance with the stability requirements of biochemical drugs. Examples 1-12, long term stability experiments were performed for 6 months, and the data were stable and not tabulated.
The titers of the contrast agents 1, 3, 4, 5, 7, 8, 0 days did not meet the specification, so the experiments were not continued. The titer of the contrast agents 2, 6, 10 and 14 was in accordance with the specification in 0 day due to overdosing, but the titer was not in accordance with the specification after 1 month, so that the experiment was not continued. It is not necessary to perform long-term stability experiments. The contrast agents 11, 12, 15 and 16 have swelling effect on the titer due to the human serum albumin and the gelatin, the titer exceeds the upper limit, the electrophoresis is unqualified, and the accelerated stability examination is not carried out. The titers were acceptable for the first formulation of contrast agents 9 and 13, but were not as specified after 1 month.
In summary, overdosing can temporarily meet the requirement of acceptable potency, but the stability does not meet the requirement. The titer of the freeze-dried powder injection added with human serum albumin or gelatin still can not meet the requirement, the titer of the water injection is deficient and high, but the titer is not qualified after 1 month. The stability requirement can be satisfied no matter the freeze-dried powder injection or the water injection is added with the stabilizing system.
Detailed Description
Example 1:
defibrase freeze-dried powder injection (Specification 5U/bottle)
10.0g of dextran 40 for injection is weighed by a balance, added with a proper amount of water for injection, boiled and dissolved until the mixture is clear, and cooled to room temperature for later use. Preparation of a 0.5M pH6.2 aspartic acid-arginine stabilizing system: 14.713g of medical glutamic acid is weighed, an appropriate amount of water for injection is added, the mixture is heated to boil, medical arginine is added, the mixture is stirred, the pH value is adjusted to 6.2, the water for injection is added to 200ml for standby, and 10ml of water for injection is taken for practical use. Adding the dextran 40 solution and 10ml of glutamic acid-arginine solution into a 1000ml measuring cylinder, uniformly mixing, taking 5000U of defibrase solution, uniformly mixing in the measuring cylinder, adding injection water to 1000ml, sterilizing, filtering, subpackaging into 3ml western bottles according to 1.0 ml/bottle, semi-pressing, feeding into a freeze-drying box, freezing to below-35 ℃, vacuumizing, setting the heating temperature to 1-5 ℃ on a shelf per hour, keeping the highest preset temperature not more than 28 ℃ for 3 hours after reaching the preset highest temperature, and then fully pressing, taking out and rolling a cover.
And (3) detection: 5U is thrown into each bottle, 5.38U is actually measured after freeze-drying, and the requirements are met.
Example 2:
defibrase freeze-dried powder injection (Specification 5U/bottle)
10.0g of dextran 40 for injection is weighed by a balance and treated in the same way as in example 1. Preparation of 0.5M pH5.5 glutamic acid-arginine stabilizing System: the same as example 1, except that the pH was adjusted to 5.5 and 1.0ml was used. Precisely measuring 5000U of defibrase. The preparation, subpackaging and freeze-drying are the same as the example 1.
And (3) detection: 5U is put into each bottle, 5.23U is actually measured after freeze-drying, and the requirements are met.
Example 3:
defibrase freeze-dried powder injection (Specification 5U/bottle)
10.0g of dextran 40 for injection is weighed by a balance and treated in the same way as in example 1. 0.5M pH7.0 glutamic acid-arginine stabilization system was prepared as in example 1, except that pH was adjusted to 7.0 and 50ml was used. Precisely measuring 5000U of defibrase. The preparation, subpackaging and freeze-drying are the same as the example 1.
And (3) detection: 5U is thrown into each bottle, 5.46U is actually measured after freeze-drying, and the requirements are met.
Example 4:
defibrase freeze-dried powder injection (Standard 10U/bottle)
10.0g of dextran 40 for injection is weighed by a balance and treated in the same way as in example 1. 0.5M PH6.25 glutamic acid-arginine stabilization system, the preparation method is the same as example 1, but the PH value is adjusted to 6.25, and 10ml is measured for practical use. 10000U of defibrase is precisely measured. The preparation, subpackaging and freeze-drying are the same as the example 1.
And (3) detection: and (3) putting 10U into each bottle, and actually measuring 10.5U after freeze-drying to meet the requirements.
Example 5:
defibrase freeze-dried powder injection (Standard 10U/bottle)
10.0g of dextran 40 for injection is weighed by a balance and treated in the same way as in example 1. 0.5M PH5.5 glutamic acid-arginine stabilization system, the preparation method is the same as example 1, but the PH value is adjusted to 5.5, and the amount is measured to 1.0ml for practical use. 10000U of defibrase is precisely measured. The preparation, subpackaging and freeze-drying are the same as the example 1.
And (3) detection: and (3) putting 10U into each bottle, and actually measuring 10.3U after freeze-drying to meet the requirements.
Example 6:
defibrase freeze-dried powder injection (Standard 10U/bottle)
10.0g of dextran 40 for injection is weighed by a balance and treated in the same way as in example 1. 0.5M pH7.0 glutamic acid-arginine stabilization system, the preparation method was the same as example 1, except that the pH was adjusted to 7.0 and 50ml was measured for practical use. 10000U of defibrase is precisely measured. The preparation, subpackaging and freeze-drying are the same as the example 1.
And (3) detection: and (3) putting 10U into each bottle, and actually measuring 10.5U after freeze-drying to meet the requirements.
Example 7:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 5000U
0.5M pH6.2 glutamic acid-arginine 20ml
Adding water for injection to 1000ml
The preparation method of the glutamic acid-arginine stabilizing system is the same as that of the embodiment 1, and the concentration of the glutamic acid-arginine stabilizing system is 20 ml. Precisely measuring defibrase 5000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: 5U is thrown into each bottle, and 6.0U is actually measured, thereby meeting the requirements.
Example 8:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 5000U
0.5M pH5.5 glutamic acid-arginine 2ml
Adding water for injection to 1000ml
0.5M PH5.5 glutamic acid-arginine stabilizing system, the preparation method is the same as that of the embodiment 1, only the PH value is adjusted to 5.5, 2ml practical measuring is carried out, 5000U defibrase is precisely measured, and the preparation, the sterilization, the filtration and the split charging are carried out.
And (3) detection: 5U is thrown into each bottle, 5.6U is actually measured, and the requirements are met.
Example 9:
defibrase injection (Specification 5U/bottle)
Total defibrase amount of 5000U
0.5M pH7.0 glutamic acid-arginine 50ml
Adding water for injection to 1000ml
0.5M PH7.0 glutamic acid-arginine stabilization system, the preparation method is the same as example 1, but the PH value is adjusted to 7.0, and 50ml is measured for practical use. Precisely measuring defibrase 10000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: 5U is thrown into each bottle, and 5.8U is actually measured, thereby meeting the requirements.
Example 10:
defibrase injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
0.5M pH6.2 glutamic acid-arginine 20ml
Adding water for injection to 1000ml
Preparation of 0.5M, pH6.2 glutamic acid-arginine was performed as in example 1, and 20ml of the solution was measured out and used. Precisely measuring defibrase 10000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: and (4) putting 10U per bottle, actually measuring 11.2U per bottle, and meeting the requirements.
Example 11:
defibrase injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
0.5M pH5.5 glutamic acid-arginine 2ml
Adding water for injection to 1000ml
0.5M PH5.5 glutamic acid-arginine stabilization system, the preparation method is the same as example 1, but the PH value is adjusted to 5.5, and 2ml is measured for practical use. Precisely measuring 5000U of defibrase. Preparing, sterilizing, filtering and packaging.
And (3) detection: 10U is thrown into each bottle, and 10.8U is actually measured, thereby meeting the requirements.
Example 12:
defibrase injection (Standard 10U/bottle)
The total amount of defibrase is 10000U
0.5M pH7.0 glutamic acid-arginine 50ml
Adding water for injection to 1000ml
0.5M pH7.0 glutamic acid-arginine was prepared in the same manner as in example 1 except that the pH was adjusted to 7.0 and 50ml of the solution was measured and used. Precisely measuring defibrase 10000U, preparing, sterilizing, filtering, and packaging.
And (3) detection: and (4) putting 10U per bottle, actually measuring 11.9U per bottle, and meeting the requirements.
The preparation method of the above injection and lyophilized powder for injection can be conventional method. The arginine in the preparation process of the stabilizer can be dry arginine powder or arginine solution with conventional concentration.
Claims (2)
1. A stable defibrase injection is characterized by comprising the following components in percentage by weight: each 1000ml of the preparation solution contains: 5000U or 10000U of defibrase, 1-50ml of stabilizer and the balance of water for injection;
or freeze-dried powder injection: each 1000ml of the preparation solution contains: 5000U or 10000U of defibrase, 10.0g of excipient, 1-50ml of stabilizer and the balance of water for injection;
the stabilizer is a glutamic acid-arginine stabilizing system;
the stabilizer is prepared by the following method: 14.713g of medical glutamic acid is weighed, added with a proper amount of water for injection and heated to boiling, added with medical arginine, stirred and adjusted to pH value of 5.5-7.0, and added with water for injection to 200ml to prepare the concentration of 0.5M calculated by glutamic acid.
2. The process for preparing a stabilized defibrase injection as claimed in claim 1, which comprises the steps of:
the preparation method of the stabilizer comprises the following steps: weighing 14.713g of medical-grade glutamic acid, adding a proper amount of water for injection, heating to boil, adding medical-grade arginine, stirring, adjusting the pH value to 5.5-7.0, adding 200ml of water for injection, and preparing into a solution with a concentration of 0.5M calculated by glutamic acid for later use;
secondly, a preparation method of the preparation comprises the following steps: adding 1-50ml of the stabilizer in the step one into a measuring cylinder of 5000U defibrase or 10000U defibrase respectively, adding water for injection to 1000ml respectively, and preparing 1000 bottles of water injection or freeze-dried powder injection according to the preparation method of the water injection or freeze-dried powder injection.
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| CN1456352A (en) * | 2003-05-30 | 2003-11-19 | 江苏安格药业有限公司 | Medicinal composition containing fiber eliminating enzyme |
| KR100624013B1 (en) * | 2004-06-25 | 2006-09-19 | 주식회사 녹십자홀딩스 | Pharmaceutical preparation of recombinant factor ? lyophilized without albumin as a stabilizer |
| CN101371921B (en) * | 2008-10-08 | 2013-02-13 | 余美伦 | Instant lyophilized fibrinogen and fibrin ferment formulation composition, preparation method and use thereof |
| CN101926999B (en) * | 2009-06-22 | 2012-02-29 | 北京赛升药业股份有限公司 | Hemostatic disinfectant and preparation method thereof |
| AR097762A1 (en) * | 2013-09-27 | 2016-04-13 | Intervet Int Bv | DRY FORMULATIONS OF VACCINES THAT ARE STABLE AT ENVIRONMENTAL TEMPERATURE |
| CN104083756B (en) * | 2014-07-22 | 2015-12-02 | 张庆宇 | A kind of adjuvant of stabilizing pharmaceutical composition and the pharmaceutical composition containing this adjuvant |
| CN105816879A (en) * | 2016-03-17 | 2016-08-03 | 广州市嘉合生物技术有限公司 | Freeze-drying stabilizer for maintaining effectiveness of freeze-dried viral vaccines at room temperature |
-
2018
- 2018-02-06 CN CN201810115670.6A patent/CN108245669B/en active Active
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