CN115400089A - Pharmaceutical composition containing tissue plasminogen activator modified body and preparation method thereof - Google Patents
Pharmaceutical composition containing tissue plasminogen activator modified body and preparation method thereof Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 53
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 title claims abstract description 27
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 title claims abstract description 27
- 229960000187 tissue plasminogen activator Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 30
- 108010039185 Tenecteplase Proteins 0.000 claims abstract description 20
- 229960000216 tenecteplase Drugs 0.000 claims abstract description 19
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000008215 water for injection Substances 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000004475 Arginine Substances 0.000 claims abstract description 9
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229950008882 polysorbate Drugs 0.000 claims abstract description 9
- 229920000136 polysorbate Polymers 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims description 24
- 238000004108 freeze drying Methods 0.000 claims description 18
- 239000007853 buffer solution Substances 0.000 claims description 12
- 239000011265 semifinished product Substances 0.000 claims description 12
- 238000007865 diluting Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 5
- 239000004615 ingredient Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 15
- 208000007536 Thrombosis Diseases 0.000 description 8
- 108010051181 TNK-tissue plasminogen activator Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 229940012957 plasmin Drugs 0.000 description 2
- 230000004952 protein activity Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940113038 tnkase Drugs 0.000 description 1
Classifications
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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)
- A61K38/482—Serine endopeptidases (3.4.21)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
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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
- A61K47/02—Inorganic compounds
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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
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21068—Tissue plasminogen activator (3.4.21.68), i.e. tPA
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- Oil, Petroleum & Natural Gas (AREA)
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Abstract
The invention relates to a pharmaceutical composition containing tissue plasminogen activator modified body and a preparation method thereof, wherein the pharmaceutical composition is prepared from the following raw materials: 15-30 mg/bottle of tenecteplase, 200-215 mg/bottle of arginine, 65-75 mg/bottle of phosphoric acid, 2-6 mg/bottle of water for injection and 1.2-2.0 mg/bottle of polysorbate; the ingredients and the preparation method adopted by the invention effectively solve the problem that the activity of the pharmaceutical composition prepared by the tissue plasminogen activator modified body is reduced after long-term storage in the prior art, and the pharmaceutical composition still has higher activity and single-chain content after long-term trial storage.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a pharmaceutical composition containing a tissue plasminogen activator modified body and a preparation method thereof.
Background
Thrombotic diseases are clinically common and important diseases, have the characteristics of high morbidity, disability rate and disease death rate, seriously harm human health, and are divided into venous thrombotic diseases and arterial thrombotic diseases. Arterial thrombotic diseases are mainly ischemic heart diseases and ischemic strokes, venous thrombotic diseases (VTE) are mainly Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE). The incidence of thrombotic disease is closely related to age, the incidence of thrombotic disease increases significantly after age 45, and there is a clear gender tendency, with men being higher than women. Recent Global Burden of Disease (GBD) studies have shown that thromboembolic diseases are the leading cause of Global death, accounting for 1/4 of the total number of deaths worldwide.
The tissue plasminogen activator modified form (tenecteplase, TNK-tPA) is a modified form of protein tissue plasminogen activator (t-PA) naturally existing in human body, is a glycoprotein composed of 527 amino acids, belongs to third-generation gene recombinant thrombolytic drug, has the characteristics of safety, high efficiency and convenient use, and is widely used for thrombolytic therapy of acute myocardial infarction and acute ischemic stroke clinically. During the fibrinolysis process, the molecules of the tissue plasminogen activator modified body (TNK-tPA) are cut to form double-chain molecules with higher activity, the deficiency of t-PA in a fibrinolysis system is made up, plasminogen is converted into plasmin, and the plasmin further degrades fibrin into soluble fragments to dissolve thrombus. The single chain content is related to the safety of the drug combination, and the higher the single chain content, the lower the bleeding risk in the thrombolysis process, and the better the safety.
However, the tissue plasminogen activator modified form (TNK-tPA) belongs to biological macromolecules and has natural instability, and the activity and single chain content of the tissue plasminogen activator modified form in the pharmaceutical composition prepared by the prior art after long-term storage are seriously reduced, so that a new technical scheme is needed to overcome the defects.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing a tissue plasminogen activator modified body and further provides a method for preparing the pharmaceutical composition.
In order to achieve the purpose of the invention, the following technical scheme is adopted:
a pharmaceutical composition containing tissue plasminogen activator modified form is prepared from the following raw materials: 15-30 mg/bottle of tenecteplase, 200-215 mg/bottle of arginine, 65-75 mg/bottle of phosphoric acid, 2-6 mg/bottle of water for injection and 1.2-2.0 mg/bottle of polysorbate.
Preferably, the pharmaceutical composition is prepared from the following raw materials: 20 mg/bottle of tenecteplase, 209.5 mg/bottle of arginine, 71.2 mg/bottle of phosphoric acid, 4 mg/bottle of water for injection and 1.64mg/bottle of polysorbate.
Preferably, the single-chain content of the tenecteplase in the pharmaceutical composition is more than 65%.
Preferably, the storage temperature of the pharmaceutical composition is 2 to 8 ℃.
Preferably, the preparation method of the pharmaceutical composition is as follows:
s1: adjusting the pH value of the water for injection to 7.5-8.5 by using phosphoric acid, and then filtering by using a 0.22um filter to obtain a semi-finished buffer solution;
s2: diluting the tenecteplase to 5.5mg/ml by using a semi-finished product buffer solution, then sterilizing by using a 0.22 mu m filter to obtain a semi-finished product, and filling;
s3: and after filling, freeze-drying by using a medical vacuum freeze dryer to obtain the pharmaceutical composition.
Preferably, the step of lyophilization in step S3 is as follows:
keeping the temperature of a condenser of the medical vacuum freeze dryer at less than or equal to minus 45 ℃, operating a vacuum pump after 190 minutes, controlling the vacuum degree at 0.09-0.25 mbar, and performing primary drying and secondary drying on the filled product in sequence by a freeze drying procedure.
Preferably, in the step of freeze-drying, the temperature for primary drying is-25 ℃ to-5 ℃, and the time is 3000-3200 min.
Preferably, in the step of freeze-drying, the temperature for secondary drying is 0-30 ℃ and the time is 900-1100 min.
Compared with the prior art, the invention has the following beneficial effects:
the ingredients and the preparation method adopted by the invention effectively solve the problem that the activity of the pharmaceutical composition prepared by the tissue plasminogen activator modified body is reduced after long-term storage in the prior art, and the pharmaceutical composition still has higher activity and single-chain content after long-term trial storage.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments.
The invention provides a pharmaceutical composition containing a tissue plasminogen activator modified body, which is prepared from the following raw materials: 15-30 mg/bottle of tenecteplase, 200-215 mg/bottle of arginine, 65-75 mg/bottle of phosphoric acid, 2-6 mg/bottle of water for injection and 1.2-2.0 mg/bottle of polysorbate. The storage temperature of the pharmaceutical composition is 2-8 ℃.
Based on the raw materials, the invention also provides a method for preparing the pharmaceutical composition; the method comprises the following steps:
s1: adjusting the pH value of the water for injection to 7.5-8.5 by using phosphoric acid, and then filtering by using a 0.22um filter to obtain a semi-finished buffer solution;
s2: diluting the tenecteplase to 5.5mg/ml by using a semi-finished product buffer solution, then sterilizing by using a 0.22 mu m filter to obtain a semi-finished product, and filling;
s3: after filling, freeze-drying by using a medical vacuum freeze dryer to obtain the pharmaceutical composition; specifically, the lyophilization steps are as follows:
keeping the temperature of a condenser of the medicinal vacuum freeze dryer at less than or equal to-45 ℃, operating a vacuum pump after 190 minutes, controlling the vacuum degree at 0.09-0.25 mbar, and performing primary drying and secondary drying on the filled product in sequence by entering a freeze drying program; wherein the temperature of primary drying is-25 ℃ to-5 ℃, and the time is 3000-3200 min; the temperature for secondary drying is 0-30 ℃, and the time is 900-1100 min.
Example 1
A pharmaceutical composition containing tissue plasminogen activator modified body is prepared from the following raw materials: 15 mg/bottle of tenecteplase, 200 mg/bottle of arginine, 65 mg/bottle of phosphoric acid, 2 mg/bottle of water for injection and 1.2mg/bottle of polysorbate.
The preparation method of the pharmaceutical composition comprises the following steps:
s1: adjusting the pH value of the water for injection to 7.5-8.5 by using phosphoric acid, and then filtering by using a 0.22um filter to obtain a semi-finished buffer solution;
s2: diluting the tenecteplase to 5.5mg/ml by using a semi-finished product buffer solution, then sterilizing by using a 0.22 mu m filter to obtain a semi-finished product, and filling;
s3: after filling, freeze-drying by a vacuum freeze-drying machine to obtain the pharmaceutical composition; specifically, the lyophilization steps are as follows:
keeping the temperature of a condenser of the medicinal vacuum freeze dryer at less than or equal to-45 ℃, operating a vacuum pump after 190 minutes, controlling the vacuum degree at 0.09-0.25 mbar, and performing primary drying and secondary drying on the filled product in sequence by entering a freeze drying program; wherein the temperature of primary drying is-25 ℃ to-5 ℃ and the time is 3000min; the temperature for secondary drying is 0-30 ℃ and the time is 900min.
Example 2
A pharmaceutical composition containing tissue plasminogen activator modified form, the pharmaceutical composition is prepared from the following raw materials: 20 mg/bottle of tenecteplase, 209.5 mg/bottle of arginine, 71.2 mg/bottle of phosphoric acid, 4 mg/bottle of water for injection and 1.64mg/bottle of polysorbate.
The preparation method of the pharmaceutical composition comprises the following steps:
s1: adjusting the pH value of the water for injection to 7.5-8.5 by using phosphoric acid, and then filtering by using a 0.22um filter to obtain a semi-finished buffer solution;
s2: diluting tenecteplase to 5.5mg/ml by using a semi-finished product buffer solution, then sterilizing by using a 0.22 mu m filter to obtain a semi-finished product, and filling;
s3: after filling, freeze-drying by a vacuum freeze-drying machine to obtain the pharmaceutical composition; specifically, the lyophilization steps are as follows:
keeping the temperature of a condenser of the medicinal vacuum freeze dryer at less than or equal to-45 ℃, operating a vacuum pump after 190 minutes, controlling the vacuum degree at 0.09-0.25 mbar, and performing primary drying and secondary drying on the filled product in sequence by entering a freeze drying program; wherein the primary drying temperature is-25 ℃ to-5 ℃ and the time is 3120min; the temperature for secondary drying is 0-30 ℃ and the time is 1000min.
Example 3
A pharmaceutical composition containing tissue plasminogen activator modified form, the pharmaceutical composition is prepared from the following raw materials: 30 mg/bottle of tenecteplase, 215 mg/bottle of arginine, 75 mg/bottle of phosphoric acid, 6 mg/bottle of water for injection and 2.0 mg/bottle of polysorbate.
The preparation method of the pharmaceutical composition comprises the following steps:
s1: adjusting the pH value of the water for injection to 7.5-8.5 by using phosphoric acid, and then filtering by using a 0.22um filter to obtain a semi-finished buffer solution;
s2: diluting the tenecteplase to 5.5mg/ml by using a semi-finished product buffer solution, then sterilizing by using a 0.22 mu m filter to obtain a semi-finished product, and filling;
s3: after filling, freeze-drying by using a medical vacuum freeze dryer to obtain the pharmaceutical composition; specifically, the lyophilization steps are as follows:
keeping the temperature of a condenser of the medical vacuum freeze dryer at less than or equal to minus 45 ℃, operating a vacuum pump after 190 minutes, controlling the vacuum degree at 0.09-0.25 mbar, and performing primary drying and secondary drying on the filled product in sequence by a freeze drying procedure; wherein the temperature of primary drying is-25 ℃ to-5 ℃ and the time is 3200min; the temperature for secondary drying is 0-30 ℃ and the time is 1100min.
Comparative example
TNKase (TM), commercially available.
The drugs of example 2 and the comparative example were tested, and the test items include protein concentration, pH, protein activity, single chain content, and HPLC purity, and the results are shown in table 1 below.
The method for detecting the protein concentration refers to the fourth method (BCA method) of the general rule (0731) of the Chinese pharmacopoeia 2020 edition.
The pH measurement method refers to the fourth method (BCA method) of the general rule of China pharmacopoeia 2020 edition (0731).
The protein activity is determined by a bubble lysis method.
The single chain content is measured according to the current pharmacopoeia of the people's republic of China (general rules 0512); measuring the content of single chain by high performance liquid chromatography.
The HPLC purity is measured according to the current ' pharmacopoeia of the people's republic of China ' (general rules 0512). The chromatographic column adopts octyl silane bonded silica gel as a filling agent, and the pore diameter
The particle size is 5 μm, the diameter is 4.6mm, and the length is 25cm; a phase (0.1% trifluoroacetic acid solution) and a phase B (0.1% trifluoroacetic acid solution in acetonitrile) were used as mobile phases, and gradient elution was performed at room temperature. The sample amount is 20ul, the detection is carried out at the wavelength of 280nm, and the number of theoretical plates calculated by TNK-tPA chromatographic peak is not less than 2000. The area of the main peak of the tenecteplase monomer is not less than 95.0% of the total area calculated by an area normalization method.
Gradient elution procedure:
table 1 results of changes in quality attribute (CQA) of the pharmaceutical compositions of example 2 and comparative example after storage at 2 to 8 ℃ for 36 months
Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention.
Claims (8)
1. A pharmaceutical composition containing a tissue plasminogen activator modified form is characterized in that: the pharmaceutical composition is prepared from the following raw materials: 15-30 mg/bottle of tenecteplase, 200-215 mg/bottle of arginine, 65-75 mg/bottle of phosphoric acid, 2-6 mg/bottle of water for injection and 1.2-2.0 mg/bottle of polysorbate.
2. The pharmaceutical composition containing a modified form of tissue plasminogen activator according to claim 1, characterized in that: the pharmaceutical composition is prepared from the following raw materials: 20 mg/bottle of tenecteplase, 209.5 mg/bottle of arginine, 71.2 mg/bottle of phosphoric acid, 4 mg/bottle of water for injection and 1.64mg/bottle of polysorbate.
3. The pharmaceutical composition containing a modified form of tissue plasminogen activator according to claim 1 or 2, characterized in that: in the pharmaceutical composition, the single-chain content of the tenecteplase is more than 65%.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition comprises a modified form of tissue plasminogen activator: the storage temperature of the pharmaceutical composition is 2-8 ℃.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises a modified form of tissue plasminogen activator: the preparation method of the pharmaceutical composition comprises the following steps:
s1: adjusting the pH value of the water for injection to 7.5-8.5 by using phosphoric acid, and then filtering by using a 0.22um filter to obtain a semi-finished buffer solution;
s2: diluting the tenecteplase to 5.5mg/ml by using a semi-finished product buffer solution, then sterilizing by using a 0.22 mu m filter to obtain a semi-finished product, and filling;
s3: and after filling, freeze-drying by using a vacuum freeze-drying machine to obtain the pharmaceutical composition.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises a modified form of tissue plasminogen activator: the step of lyophilization in step S3 is as follows:
keeping the temperature of a condenser of the medicinal vacuum freeze dryer at less than or equal to minus 45 ℃, operating a vacuum pump after 190 minutes, controlling the vacuum degree at 0.09-0.25 mbar, and entering a freeze drying program to sequentially carry out primary drying and secondary drying on the filled product.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a modified form of tissue plasminogen activator: in the step of freeze-drying, the temperature for primary drying is-25 ℃ to-5 ℃, and the time is 3000-3200 min.
8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a modified form of tissue plasminogen activator: in the step of freeze-drying, the temperature for secondary drying is 0-30 ℃ and the time is 900-1100 min.
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| CN202210997845.7A CN115400089A (en) | 2022-08-19 | 2022-08-19 | Pharmaceutical composition containing tissue plasminogen activator modified body and preparation method thereof |
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