CN115778896A - Tranexamic acid injection and its preparation method and use - Google Patents
Tranexamic acid injection and its preparation method and use Download PDFInfo
- Publication number
- CN115778896A CN115778896A CN202211522329.5A CN202211522329A CN115778896A CN 115778896 A CN115778896 A CN 115778896A CN 202211522329 A CN202211522329 A CN 202211522329A CN 115778896 A CN115778896 A CN 115778896A
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- Prior art keywords
- acid
- tranexamic acid
- filtering
- water
- injection
- Prior art date
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- 229940100226 tranexamic acid injection Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title abstract description 62
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims abstract description 238
- 229960000401 tranexamic acid Drugs 0.000 claims abstract description 235
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- 239000002994 raw material Substances 0.000 claims abstract description 17
- 239000008215 water for injection Substances 0.000 claims abstract description 16
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to tranexamic acid injection and a preparation method and application thereof. In one aspect, the tranexamic acid injection comprises 5 to 15g of tranexamic acid per 100ml and water for injection added to the total amount. The tranexamic acid injection is prepared by the method comprising the following steps of: providing a tranexamic acid raw material medicament; adding 50-80% of injection water, tranexamic acid and optional other auxiliary materials into a concentration tank, and stirring until the injection water, the tranexamic acid and the optional other auxiliary materials are dissolved; adding activated carbon, stirring while keeping the temperature, filtering to remove carbon, transferring into a diluting preparation tank, cooling to room temperature, and adding water to nearly full volume; adjusting pH =7.2 + -0.5 with acid-base regulator, adding water to full volume, filtering with microporous membrane, bottling, and sterilizing. The tranexamic acid injection has excellent performance as described in the specification.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition of tranexamic acid, in particular to a pharmaceutical composition of a small-volume injection of tranexamic acid. Also relates to a preparation method of the pharmaceutical composition and pharmaceutical application thereof.
Background
Tranexamic acid (CAS 1197-18-8), also known as tranexamic acid and tranexamic acid, has the chemical name of trans-4- (Aminomethyl) cyclohexanecarboxylic acid (trans-4- (Aminomethyl) cyclohexaxylcarboxylic acid), has the molecular formula of C8H15NO2, the molecular weight of 157.21, and the chemical structural formula of:
in addition, the chemical structural formula of the isomer of tranexamic acid, cis-tranexamic acid, is as follows:
tranexamic acid is white crystalline powder, odorless, soluble in water, and practically insoluble in ethanol, acetone, chloroform or diethyl ether. Tranexamic acid is loaded in the current Chinese pharmacopoeia and comprises raw material medicines, tablets (125 mg/tablet and 250 mg/tablet), capsules (250 mg/capsule), injection (100 mg/2ml, 200mg/2ml, 1000mg/10ml and the like). Similar to clofenac, tranexamic acid is clinically used for various hemorrhagic diseases, abnormal bleeding during operation and the like.
There are many reports on the preparation of tranexamic acid. For example, CN102702005A (chinese patent application No. 201210205803.1, tianhe) discloses a method for purifying trans-tranexamic acid, which comprises mixing a trans-cis-tranexamic acid mixture with purified water, and heating to form a trans-cis-tranexamic acid aqueous solution; cooling the trans-cis tranexamic acid aqueous solution, and filtering to obtain a tranexamic acid mixture damp product; mixing the wet tranexamic acid mixture with purified water, heating, adjusting pH, adding activated carbon, filtering, taking filtrate, cooling for crystallization, filtering, taking solid, and drying to obtain the trans-tranexamic acid white crystal. The process provided by the invention is believed to greatly improve the purity of the obtained trans-tranexamic acid, can obtain the trans-tranexamic acid with the purity not lower than 99%, can recycle the solvent, is simple to operate, has low pollution and low cost, and is suitable for industrial production.
CN110156620B (Chinese patent application No. 201910589342.4, wanrun) discloses a preparation method of tranexamic acid, which comprises the steps of taking 1, 4-cyclohexanedimethanol as a starting material, reacting with HX acid, wherein X is Cl or I to generate 4-chloromethyl cyclohexyl methanol or 4-iodine methyl cyclohexyl methanol, then carrying out oxidation reaction in a gas atmosphere with the oxygen content of 21-100% to generate 4-chloromethyl cyclohexyl formic acid or 4-iodine methyl cyclohexyl formic acid, then carrying out ammonolysis reaction in a high-pressure kettle, introducing liquid ammonia or ammonia water with the ammonia content of 15-28% into the system during the ammonolysis reaction, and after the ammonolysis reaction is finished, carrying out alkali transformation to obtain the tranexamic acid. Compared with the prior art, the preparation method has the advantages of cheap and easily obtained raw materials and low cost. Meanwhile, the method has the advantages of simple and convenient operation, high yield, suitability for industrial production and the like.
CN113956173A (chinese patent application No. 202111324899.9, wanrun) discloses a preparation method of tranexamic acid: 1) Reacting 2- (aminomethyl) -1,3 butadiene with acrylic acid in an alcohol solvent in the presence of a Lewis acid catalyst, cooling and filtering to obtain 4- (aminomethyl) -3-cyclohexene-1-formic acid; 2) Adding 4- (aminomethyl) -3-cyclohexene-1-formic acid obtained in the step 1) into water, adding a catalyst, filtering to remove the catalyst after the reaction is finished, adding an alcohol solvent into the filtrate, and stirring for crystallization to obtain a tranexamic acid crude product; 3) Adding the tranexamic acid crude product into water, stirring and heating to 50-60 ℃ for dissolving, adding ethanol until the system becomes mixed, then heating to reflux and dissolve the solution clearly, cooling to 55-60 ℃, adding seed crystals for crystallization for 2-3 hours under heat preservation, cooling to 20-30 ℃, preserving heat for 1 hour, filtering and drying to obtain the tranexamic acid. The method disclosed by the invention is believed to have the characteristics of mild reaction conditions, simplicity in operation, environmental friendliness and high product quality, and is suitable for industrial production.
CN114181077A (chinese patent application No. 20211156127.0, wind-fire wheel) discloses a synthetic process of tranexamic acid (I), comprising the following steps: taking 3-cyclohexene carboxylic acid (V) as a raw material, and obtaining an intermediate 3-cyclohexene formate (IV) through an esterification reaction; the Intermediate (IV) and carbon monoxide/hydrogen mixed gas or synthesis gas are subjected to carbonyl insertion reaction in the presence of a catalyst to obtain an intermediate 4-formylcyclohexane-1-formate (III) with high selectivity; the intermediate (III) is subjected to reductive amination to obtain an intermediate 4-aminomethyl cyclohexanecarboxylate (II); finally hydrolyzing and transforming the intermediate (II) to obtain the tranexamic acid (I). The invention is believed to have cheap and easily obtained raw materials, environment-friendly carbon monoxide carbonyl insertion reaction, simple and efficient route and provides a new method for synthesizing tranexamic acid (I).
CN114380707A (chinese patent application No. 202210067729.5, krey bond) discloses a preparation method for converting cis-tranexamic acid or cis/trans mixture into trans-tranexamic acid, comprising the following steps: (1) Using a tranexamic acid cis-isomer or cis/trans-isomer mixture (1) as a starting material, and mixing the starting material with an alkali liquor; (2) heating to be clear, and evaporating the solvent; (3) The trans-tranexamic acid is obtained by configuration conversion under the approximate normal pressure. The invention is believed to solve the problems of large transformation pressure and high safety risk of tranexamic acid in the prior art; the method also overcomes the defect of long reaction time of the prior art, not only obviously improves the conversion efficiency of tranexamic acid, but also reduces the discharge amount of wastes, simplifies the production process, and simultaneously can save energy consumption and reduce the production cost.
Some processes similar to aminomethylbenzoic acid as starting material are also disclosed in the prior art. For example, CN103172528B (chinese patent application No. 201110437525.8, wangrun fineness) discloses a high-efficiency production method of tranexamic acid: using 4- (acetamidomethyl) benzoic acid as initial material, hydrogenating and reducing, filtering the hydrogenated liquid to remove catalyst, distilling to solidify the reaction liquid, heating and baking for transformation. Dissolving in water, regulating reaction liquid to neutrality with acid, adding p-toluenesulfonic acid to form salt, filtering, performing resin exchange with weak base anion exchange resin, distilling eluent until a large amount of solid is separated out, adding appropriate amount of ethanol for crystallization, cooling, filtering, washing, and drying to obtain tranexamic acid. The tranexamic acid produced by the method has a cis-isomer content of less than 0.05%. The quality completely accords with the standard of pharmacopoeia at home and abroad and is higher than the quality of the product currently reported at home. The production route of the invention is believed to have the advantages of few steps, simple operation, high yield, energy conservation, environmental protection and the like.
CN111574388A (chinese patent application No. 202010561044.7, dingwang) discloses a method for preparing tranexamic acid, which comprises using p-bromotoluene as a raw material, preparing p-bromotoluene into a grignard reagent, further performing an addition reaction with carbon dioxide, hydrolyzing under an acidic condition to obtain p-methylbenzoic acid, performing a bromine substitution reaction on the p-methylbenzoic acid and N-bromosuccinimide to obtain an intermediate 1, performing a phase transfer catalytic reaction on the intermediate 1 to obtain an intermediate 2, reacting the intermediate 2 with a saturated toluene solution of ammonia gas to replace an alcoholic hydroxyl group on the intermediate 2 with an amino group to obtain an intermediate 3, and hydrogenating the intermediate 3 with hydrogen under the action of a supported nickel catalyst to obtain the tranexamic acid.
Considering that the pharmacopoeias of various countries all relate to impurity aminomethylbenzoic acid as a starting material when detecting related substances of tranexamic acid, the method disclosed in the above documents does not use the classical method for preparing tranexamic acid.
CN108689870B (chinese patent application No. 201810851048.1, dao ping) discloses a preparation method of tranexamic acid, which comprises: (1) Mixing aminomethylbenzoic acid with pure water, slowly adding concentrated sulfuric acid under stirring, heating to a predetermined temperature, cooling for crystallization, and filtering to obtain pretreated aminomethylbenzoic acid; (2) Adding a sulfuric acid solution and a catalyst, carrying out hydrogenation reaction on the pretreated aminomethylbenzoic acid, and removing redundant sulfuric acid to obtain a hydrogenation product; (3) Adding alkali and pure water into the hydrogenation product, and controlling the mass ratio of the hydrogenation product to the alkali to be 1: and (3-6) heating to a set temperature to perform transposition reaction on the hydrogenation product to obtain tranexamic acid. According to the preparation method of tranexamic acid, the aminomethylbenzoic acid is pretreated to reduce the contents of organic amine and iron elements in the raw materials, prolong the service life of the catalyst and greatly reduce the production cost; the addition proportion of the alkali is properly increased, so that the proportion of trans-tranexamic acid in the transposition product is increased, and the transposition time is shortened.
CN114225929A (chinese patent application No. 202111644131.X, tianhe) discloses the use of cesium hydroxide or cesium oxide to catalyze the conversion of cis-form tranexamic acid to trans-form tranexamic acid, which is believed to improve the conversion rate of cis-form to trans-form, thereby reducing the refining difficulty of tranexamic acid, improving the yield of the product, and reducing the production cost.
Sun highlighting literature (Sun highlighting, research on the synthetic process of tranexamic acid raw material medicine, chinese Utility medicine 2011,6 (17): 160-161) discloses a method for synthesizing tranexamic acid by taking aminomethylbenzoic acid as a starting material.
CN107954887B (chinese patent application No. 201711209553.8, tiger, sheng) discloses a method for preparing tranexamic acid, comprising adding aminomethylbenzoic acid, water, concentrated sulfuric acid and a catalyst into a reaction vessel, stirring and heating, and then introducing hydrogen gas to perform hydrogenation reaction to obtain a hydrogenation reaction solution; and adding the hydrogenation reaction liquid and concentrated sulfuric acid into a reaction vessel, heating to 180-200 ℃, preserving heat and stirring for conversion reaction to obtain tranexamic acid. The method for preparing tranexamic acid is believed to simplify the process, shorten the reaction time and improve the synthesis efficiency. The above documents use relatively large amounts of platinum dioxide as the catalyst.
CN113042040A (chinese patent application No. 202110329879.4, mercy dune) discloses a platinum-carbon catalyst and a method for preparing tranexamic acid by using the platinum-carbon catalyst, firstly using activated carbon, water, hydrochloric acid, chloroplatinic acid and ethylene glycol to prepare the platinum-carbon catalyst; then adding the prepared platinum-carbon catalyst, p-aminomethyl benzoic acid, pure water and concentrated sulfuric acid into a hydrogenation kettle to perform catalytic hydrogenation reaction to prepare tranexamic acid, wherein the reaction conditions are 20-25 ℃,0.2 MPa and 1-1.5h, and the platinum content in the prepared platinum-carbon catalyst is believed to be 6.9-12%, and when the platinum-carbon catalyst is used for preparing the tranexamic acid, the platinum-carbon catalyst is lower in feeding quality compared with the p-aminomethyl benzoic acid, so that the amount of platinum metal in the catalytic hydrogenation reaction is reduced; and the catalytic hydrogenation reaction is carried out at room temperature without heating, so that the reaction condition is milder. In general, the invention uses a lower amount of platinum catalyst and uses aminomethylbenzoic acid as a starting material to prepare tranexamic acid, which is advantageous for cost control.
The clinical effect and safety of tranexamic acid in total hip replacement are explored in the literature of Xiyinlong (Xiyinlong, et al, tranexamic acid in combination with sucron reduces the initial total hip replacement blood transfusion rate: prospective random control test, chinese tissue engineering research 2018, 22 (27)). A total of 263 patients undergoing primary total hip replacement in orthopaedics, 174 patients were included in the study and randomized to tranexamic acid combination iron (combination), tranexamic acid and iron groups, 58 per group. Recording the hemoglobin concentration and the hematocrit of the patient at the time of admission, 1d before operation and 1,3 and 5d after operation; observing the thrombin time, partially activated thrombin time, fibrinogen, D-dimer levels at the time of admission and on day 1 post-surgery; recording the blood loss amount in the operation, the drainage amount after the operation and the number of patients with blood transfusion after the operation; and calculating preoperative blood volume and total blood loss. Results, (1) all preoperative basic data, 3 groups of patients with differences have no significance (P > 0.05); (2) The hemoglobin content concentration of the combined medicine group and the iron agent group before 1d is obviously higher than that of the tranexamic acid group (P is less than 0.05); the mass concentration of hemoglobin after the operation of the drug combination group is obviously higher than that of the other two groups (P < 0.05); (3) The total blood loss after the combined drug operation is obviously lower than that of a tranexamic acid group and an iron agent group (P is less than 0.05); (4) The blood coagulation indexes and the D-dimer level difference of 3 groups of patients have no significance (P is more than 0.05); (5) Complications such as joint infection, deep vein thrombosis, pulmonary embolism and the like do not occur in the follow-up period; (6) The kit prompts that the tranexamic acid and the iron sucrose can effectively improve the perioperative hemoglobin concentration, reduce the total blood loss and postoperative blood transfusion, does not increase the incidence rate of thrombus and other complications, and is safe and effective.
The clinical efficacy and safety of tranexamic acid in total knee replacement was explored in the literature of poplar serum (poplar serum, et al, randomized controlled study of tranexamic acid in combination with iron to reduce blood loss in total knee replacement, journal of orthopedics, 2018, 24 (06)). Total 180 patients with orthopedic row primary total knee replacement were randomly assigned to the tranexamic acid combined iron group (combination group), the tranexamic acid group and the iron group. The hemoglobin concentration and hematocrit were recorded at the time of admission, 1 day before surgery, 1,3, 5d after surgery. And recording the blood loss amount in the operation, the drainage amount after the operation and the number of patients with blood transfusion after the operation. And calculating preoperative blood volume and total blood loss. All preoperative baseline, three groups of patients were statistically insignificant (P > 0.05). The pre-operative hemoglobin concentration of the combination group and iron group was significantly higher than that of the tranexamic acid group (P < 0.05). The post-operative hemoglobin concentration of the combined group was significantly higher than that of the other two groups (P < 0.05), while the post-operative blood transfusion and total blood loss of the combined group were significantly lower than those of the tranexamic acid group and the iron group (P < 0.05). No complications such as joint infection, deep vein thrombosis, pulmonary embolism and the like appear during the follow-up period. The results show that the tranexamic acid and the ferralia can effectively improve the concentration of hemoglobin in perioperative period, reduce total blood loss and reduce postoperative blood transfusion. In the Yangqing literature, the administration method of tranexamic acid in combination with an iron agent comprises the following steps: iron sucrose 100mg (calculated as Fe, the same below) +100mL of normal saline, tranexamic acid 20mg/kg +100mL of normal saline. The clinically used ferric saccharate injection can only be diluted by using normal saline as a medium and then injected, and the tranexamic acid injection is diluted by 5% glucose injection mostly and then injected, but the dilution by 0.9% sodium chloride injection is not excluded. Therefore, the clinical application of 100mg of ferric saccharate, 20mg/kg of tranexamic acid and 100mL of physiological saline has a good application prospect, and the three-component mixed solution is required to have no incompatibility.
Therefore, the prior art still has the necessity of improving the process for preparing tranexamic acid; in addition, those skilled in the art expect a need for a tranexamic acid injection that can be well combined with ferric saccharate injection and 0.9% sodium chloride injection.
Disclosure of Invention
The present invention aims to provide an improved process for the synthesis of tranexamic acid, which process has been unexpectedly found to be improved in one or more aspects using the present process. Another object of the present invention is to provide a tranexamic acid injection, which can have good compatibility with 0.9% sodium chloride injection and/or ferric saccharate injection.
The present invention has been completed based on such findings.
To this end, the present invention provides in a first aspect a process for the synthesis of tranexamic acid comprising the steps of:
(S0) providing a platinum-carbon catalyst;
(S1) uniformly mixing a platinum-carbon catalyst, aminomethylbenzoic acid, water and concentrated sulfuric acid in a hydrogenation kettle;
(S2) replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating at the temperature of 20-25 ℃, and filtering to obtain hydrogenation reaction liquid;
(S3) adding barium hydroxide into the hydrogenation reaction liquid, carrying out high-temperature and high-pressure treatment in a hydrogenation kettle to convert the configuration, neutralizing with a sulfuric acid solution, cooling, and filtering to obtain a mother liquid;
(S4) concentrating, cooling and filtering the mother liquor to obtain a tranexamic acid crude product;
(S5) recrystallizing the tranexamic acid crude product by using water to obtain the tranexamic acid.
The method according to the first aspect of the present invention, wherein in the step (S0), the platinum-carbon catalyst is prepared using: boiling activated carbon with water to obtain clean activated carbon, treating with hydrochloric acid, filtering to remove liquid, and oven drying; mixing the activated carbon with a chloroplatinic acid solution, adding sodium hydroxide into the mixture to adjust the pH value to 9-10, refluxing, cooling, filtering and washing with water to obtain the platinum-carbon catalyst.
The method according to the first aspect of the present invention, wherein in step (S0), the platinum-carbon catalyst is prepared using the following materials and operations in proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 100-150 ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25-35 ml of acetone, and mixing with the mixture A to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
The method according to the first aspect of the present invention, wherein in step (S0), the platinum-carbon catalyst is prepared using the following materials and operations in proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, mixing with the mixture A, adding 25-35 ml of acetone such as 30ml of acetone, and uniformly mixing to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2 hours, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain the platinum-carbon catalyst.
The method according to the first aspect of the present invention, wherein in the step (S0), the platinum-carbon catalyst is prepared using the following materials and operations in the proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing with the mixture A to obtain a mixture B; and (2) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, adding 25-35 ml of acetone such as 30ml of acetone, uniformly mixing, heating and refluxing for 2 hours, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
The method according to the first aspect of the present invention, wherein the step (S1) uses the following operation procedure: a platinum-carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water, and 80ml of concentrated sulfuric acid were sequentially added to a hydrogenation reactor, and the mixture was stirred uniformly.
The method according to the first aspect of the present invention, wherein the step (S2) uses the following operational procedure: replacing the air in the hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting the reactants at 20-25 ℃ for 1 hour, and filtering to obtain hydrogenation reaction liquid;
the method according to the first aspect of the present invention, wherein the step (S3) uses the following operation procedure: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at the temperature of 220 ℃ and the pressure of 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH of the reaction liquid to be 6.0-6.5, continuously cooling to room temperature and staying overnight, and filtering to obtain a mother liquid D;
the method according to the first aspect of the present invention, wherein the step (S4) uses the following operational procedure: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
the method according to the first aspect of the present invention, wherein the step (S5) uses the following operational procedure: recrystallizing the tranexamic acid crude product obtained in the step S4 with water for 2 times, and drying to obtain the refined tranexamic acid.
Further, the second aspect of the present invention provides a tranexamic acid synthesized by the method comprising the steps of:
(S0) providing a platinum-on-carbon catalyst;
(S1) uniformly mixing a platinum-carbon catalyst, aminomethylbenzoic acid, water and concentrated sulfuric acid in a hydrogenation kettle;
(S2) replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating at the temperature of 20-25 ℃, and filtering to obtain hydrogenation reaction liquid;
(S3) adding barium hydroxide into the hydrogenation reaction solution, carrying out high-temperature and high-pressure treatment in a hydrogenation kettle to convert the configuration, neutralizing with a sulfuric acid solution, cooling, and filtering to obtain a mother solution;
(S4) concentrating the mother liquor, cooling and filtering to obtain a tranexamic acid crude product;
(S5) recrystallizing the tranexamic acid crude product by using water to obtain the tranexamic acid.
Tranexamic acid according to the second aspect of the present invention, wherein in the step (S0), a platinum-carbon catalyst is prepared using: boiling activated carbon with water to obtain clean activated carbon, treating with hydrochloric acid, filtering to remove liquid, and oven drying; mixing the activated carbon with the chloroplatinic acid solution, adding sodium hydroxide to adjust the pH value to 9-10, refluxing, cooling, filtering, and washing with water to obtain the platinum-carbon catalyst.
Tranexamic acid according to the second aspect of the present invention, wherein in step (S0), a platinum-carbon catalyst is prepared using the following materials and operations in the following proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 100-150 ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25-35 ml of acetone, and mixing with the mixture A to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
Tranexamic acid according to the second aspect of the present invention, wherein in step (S0), a platinum-carbon catalyst is prepared using the following materials and operations in proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, mixing with the mixture A, adding 25-35 ml of acetone such as 30ml of acetone, and uniformly mixing to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2 hours, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain the platinum-carbon catalyst.
Tranexamic acid according to the second aspect of the present invention, wherein in step (S0), a platinum-carbon catalyst is prepared using the following materials and operations in the following proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing the chloroplatinic acid and the mixture A to obtain a mixture B; and (2) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, adding 25-35 ml, such as 30ml of acetone, uniformly mixing, heating and refluxing for 2 hours, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
Tranexamic acid according to the second aspect of the present invention, wherein the step (S1) uses the following procedure: a platinum-carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water, and 80ml of concentrated sulfuric acid were sequentially added to a hydrogenation reactor, and the mixture was stirred uniformly.
Tranexamic acid according to the second aspect of the present invention, wherein the step (S2) uses the following procedure: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
tranexamic acid according to the second aspect of the present invention, wherein the step (S3) uses the following procedure: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
tranexamic acid according to the second aspect of the present invention, wherein the step (S4) uses the following procedure: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
tranexamic acid according to the second aspect of the present invention, wherein the step (S5) uses the following procedure: and (5) recrystallizing the tranexamic acid crude product obtained in the step (S4) for 2 times by using water, and drying to obtain the refined tranexamic acid.
Further, the third aspect of the present invention provides a method for preparing a platinum-carbon catalyst, comprising the steps of: boiling activated carbon with water to obtain clean activated carbon, treating with hydrochloric acid, filtering to remove liquid, and oven drying; mixing the activated carbon with the chloroplatinic acid solution, adding sodium hydroxide to adjust the pH value to 9-10, refluxing, cooling, filtering, and washing with water to obtain the platinum-carbon catalyst.
The method according to the third aspect of the invention, comprising the steps of: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 100-150 ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25-35 ml of acetone, and mixing with the mixture A to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
The method according to the third aspect of the present invention comprises the steps of: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, mixing with the mixture A, adding 25-35 ml of acetone such as 30ml of acetone, and uniformly mixing to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
The method according to the third aspect of the invention, comprising the steps of: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing with the mixture A to obtain a mixture B; and (2) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, adding 25-35 ml, such as 30ml of acetone, uniformly mixing, heating and refluxing for 2 hours, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
Further, the present invention provides a tranexamic acid injection solution, comprising: tranexamic acid, water for injection.
The tranexamic acid injection solution according to the fourth aspect of the present invention comprises 5 to 15g of tranexamic acid per 100ml and water for injection added to the total amount.
The tranexamic acid injection solution according to the fourth aspect of the present invention comprises 5 to 10g of tranexamic acid per 100ml and water for injection added to the total amount.
The tranexamic acid injection according to the fourth aspect of the present invention further comprises sodium acetate. 1-2 g of sodium acetate, for example 1.5g of sodium acetate, are included per 100 ml.
The tranexamic acid injection solution according to the fourth aspect of the present invention further comprises propylene glycol. 1 to 5g of propylene glycol, for example 1.5 to 3.75g of sodium acetate, are contained per 100 ml.
The tranexamic acid injection according to the fourth aspect of the present invention further comprises an acid-base modifier. For example, the amount of the acid-base modifier is to adjust the pH =6.0 to 8.5 of the injection solution. For example, the amount of the acid-base modifier is to adjust pH =6.5 to 8.0 of the injection solution. For example, the pH adjusting agent is hydrochloric acid and/or sodium hydroxide and aqueous solutions thereof, for example, 1M aqueous solution.
The tranexamic acid injection according to the fourth aspect of the present invention is prepared by a method comprising the steps of: providing a tranexamic acid raw material medicine; adding 50-80% of the prescription amount, such as 60%, of injection water at 50-80 ℃, such as 60 ℃, and the prescription amount of tranexamic acid and optional other auxiliary materials into a concentration tank, and stirring until the mixture is dissolved; adding (for example, 0.5%) activated carbon, stirring at constant temperature (for example, 15-30 min, for example, 20 min), filtering to remove carbon, transferring into a diluting tank, cooling to room temperature, and adding water to nearly full volume; adjusting pH =7.2 + -0.5 such as pH =7.2 + -0.1 with acid and alkali regulator (such as 1M hydrochloric acid solution or 1M sodium hydroxide solution), adding water to full volume, filtering with (such as 0.45 μ M and/or 0.22 μ M) microporous membrane (such as filtering with 0.45 μ M microporous membrane for 2 times and then filtering with 0.22 μ M microporous membrane for 2 times), filling into glass bottle, and sterilizing (such as autoclaving at 121 deg.C for 15 min).
The tranexamic acid injection according to the fourth aspect of the present invention, wherein the tranexamic acid is the tranexamic acid of the second aspect or the tranexamic acid prepared by the method of the first aspect.
Further, the fifth aspect of the present invention provides a method for preparing tranexamic acid injection, which comprises the steps of: providing a tranexamic acid raw material medicine; adding 50-80% of the prescription amount, such as 60%, of injection water at 50-80 ℃, such as 60 ℃, and the prescription amount of tranexamic acid and optional other auxiliary materials into a concentration tank, and stirring until the mixture is dissolved; adding (for example, 0.5%) activated carbon, stirring at constant temperature (for example, 15-30 min, for example, 20 min), filtering, decarbonizing, transferring to a dilution tank, cooling to room temperature, and adding water to nearly full dose; adjusting pH =7.2 + -0.5 such as pH =7.2 + -0.1 with acid and alkali regulator (such as 1M hydrochloric acid solution or 1M sodium hydroxide solution), adding water to full volume, filtering with (such as 0.45 μ M and/or 0.22 μ M) microporous membrane (such as filtering with 0.45 μ M microporous membrane for 2 times and then filtering with 0.22 μ M microporous membrane for 2 times), filling into glass bottle, and sterilizing (such as autoclaving at 121 deg.C for 15 min).
The method according to the fifth aspect of the present invention, wherein the tranexamic acid injection solution comprises 5 to 15g of tranexamic acid per 100ml and water for injection added to the total amount.
The method according to the fifth aspect of the present invention, wherein the tranexamic acid injection solution comprises 5 to 10g of tranexamic acid per 100ml and water for injection added to the total amount.
The method according to the fifth aspect of the present invention, wherein the tranexamic acid injection further comprises sodium acetate. It contains 1-2 g of sodium acetate, for example 1.5g of sodium acetate, per 100 ml.
The method according to the fifth aspect of the present invention, wherein the tranexamic acid injection further comprises propylene glycol. 1 to 5g of propylene glycol, for example 1.5 to 3.75g of sodium acetate, are contained per 100 ml.
The method according to the fifth aspect of the present invention, wherein the tranexamic acid injection further comprises an acid-base modifier. For example, the amount of the acid-base modifier is to adjust pH =6.0 to 8.5 of the injection solution. For example, the amount of the acid-base modifier is to adjust pH =6.5 to 8.0 of the injection solution. For example, the pH adjusting agent is hydrochloric acid and/or sodium hydroxide and aqueous solutions thereof, for example, 1M aqueous solution.
The process according to the fifth aspect of the present invention, wherein the tranexamic acid is prepared as follows:
(S0) providing a platinum-on-carbon catalyst;
(S1) uniformly mixing a platinum-carbon catalyst, aminomethylbenzoic acid, water and concentrated sulfuric acid in a hydrogenation kettle;
(S2) replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating at the temperature of 20-25 ℃, and filtering to obtain hydrogenation reaction liquid;
(S3) adding barium hydroxide into the hydrogenation reaction liquid, carrying out high-temperature and high-pressure treatment in a hydrogenation kettle to convert the configuration, neutralizing with a sulfuric acid solution, cooling, and filtering to obtain a mother liquid;
(S4) concentrating the mother liquor, cooling and filtering to obtain a tranexamic acid crude product;
(S5) recrystallizing the tranexamic acid crude product by using water to obtain the tranexamic acid.
The method according to the fifth aspect of the present invention, wherein in the step (S0), the platinum-carbon catalyst is prepared using: boiling activated carbon with water to obtain clean activated carbon, treating with hydrochloric acid, filtering to remove liquid, and oven drying; mixing the activated carbon with the chloroplatinic acid solution, adding sodium hydroxide to adjust the pH value to 9-10, refluxing, cooling, filtering, and washing with water to obtain the platinum-carbon catalyst.
The method according to the fifth aspect of the present invention, wherein in the step (S0), the platinum-carbon catalyst is prepared using the following materials and operations in proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 100-150 ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25-35 ml of acetone, and mixing with the mixture A to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2 hours, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain the platinum-carbon catalyst.
The method according to the fifth aspect of the present invention, wherein in the step (S0), the platinum-carbon catalyst is prepared using the following materials and operations in the proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, mixing with the mixture A, adding 25-35 ml of acetone such as 30ml of acetone, and uniformly mixing to obtain a mixture B; and (3) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
The method according to the fifth aspect of the present invention, wherein in the step (S0), the platinum-carbon catalyst is prepared using the following materials and operations in proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing with the mixture A to obtain a mixture B; and (2) dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, adding 25-35 ml of acetone such as 30ml of acetone, uniformly mixing, heating and refluxing for 2 hours, cooling, filtering to obtain a filter product C, and washing with water to obtain the platinum-carbon catalyst.
The method according to the fifth aspect of the present invention, wherein the step (S1) uses the following operation procedure: a platinum-carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water, and 80ml of concentrated sulfuric acid were sequentially added to a hydrogenation reactor, and the mixture was stirred uniformly.
The method according to the fifth aspect of the present invention, wherein the step (S2) uses the following operation procedure: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
the method according to the fifth aspect of the present invention, wherein the step (S3) uses the following operation procedure: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
the method according to the fifth aspect of the present invention, wherein the step (S4) uses the following operation procedure: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
the method according to the fifth aspect of the present invention, wherein the step (S5) uses the following operation procedure: recrystallizing the tranexamic acid crude product obtained in the step S4 with water for 2 times, and drying to obtain the refined tranexamic acid.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
Tranexamic Acid (Tranexamic Acid), trans-4- (aminomethyl) cyclohexanecarboxylic Acid, which is commercially available under the trade name: anvitoff (Abbott), cyklokapron (Pfizer), exacryl (Sanofi-Synthelabo), spiramin (Mitsui), spotof (CCD), tracex (Lusofamanco), transamin (Daiichi), ugurol (Rottacharm). Early literature on tranexamic acid included:
the preparation method comprises the following steps: einhorn, c.ladisch, ann.310,194 (1900); m.levine, r.sedlecky, j.org.chem.24,115 (1959); NL 6503605; naito et al, US 3499925 (1965, 1970, holder Daiichi Seiyaku and Mitsubishi chem.).
Pharmacological aspects: andersson et al, scand.j.haemantol.2, 230 (1965); isomer resolution and antifibrase activity: m.shimizu et al, chem.pharm.bull.16,357 (1968), t.naito et al, ibid.,728; toxicity data: melander et al, acta pharmacol. Toxicol.22,340 (1965); clinical studies on the treatment of acute upper gastrointestinal bleeding and the like: d.barrer et al, n.engl.j.med.308,1571 (1983); j.bonnar, b.l.sheppard, br.med.j.313,579 (1996); overview of pharmacological and therapeutic applications: dunn, K.L.Goa, drugs 57,1005-1032 (1999).
Physicochemical properties of tranexamic acid: the melting point is 386-392 ℃; dissolving in water 1g/6ml, slightly dissolving in ethanol and diethyl ether, and hardly dissolving in all other organic solvents; is not crystalline. LD50 (mg/kg) in mouse and rat: 1500. 1200.
Fibrinolysis is associated with fibrinolysis and increased vascular permeability of the body in physiological or pathological states, and is also associated with the development and cure of body reactions, various bleeding symptoms, allergic reactions, and the like caused by fibrinolysis. Tranexamic acid can inhibit the action of plasmin and has hemostatic, antiallergic and anti-inflammatory effects. Tranexamic acid can strongly adsorb Lysine Binding Site (LBS) on fibrin affinity site on plasmin and plasminogen, and inhibit the combination of plasmin, plasminogen and fibrin, thereby strongly inhibiting the decomposition of fibrin caused by plasmin; in addition, in the presence of antiplasmin such as alpha 2 macroglobulin in serum, the antiplasmin effect of tranexamic acid is more obvious, and the hemostatic effect is more obvious. Plasmin with increased abnormality causes inhibition of platelet aggregation and degradation of coagulation factors. Mild hyperactivity first leads to the breakdown of fibrin. Thus, it is considered that tranexamic acid suppresses fibrinolysis to stop bleeding in general bleeding. Anti-allergic and anti-inflammatory effects: tranexamic acid can inhibit the production of kinins and other active peptides (guinea pig, rat) which cause enhanced vascular permeability, allergic response and inflammatory disorders, and has anti-inflammatory effect.
In the aspect of pharmacokinetics of tranexamic acid, the pharmacokinetic parameters of a single dose (500 mg tablet) of the product orally taken by healthy adults with blood concentration are as follows: pharmacokinetic parameters of tranexamic acid when administered orally as a single dose (500 mg) (n = 5). When a single rat dose is orally administered with C-tranexamic acid, the total blood concentration in most organs is the same, and the maximum concentration is shown after 2 hours of administration; the blood concentration of kidney and liver is higher than that of blood, and the blood concentration of other organs is lower than that of blood. After the single dose of the tranexamic acid tablet is taken by 500mg or 250mg by healthy adults, the absorption is quick. At 24 hours after administration, 40-70% of the administered amount was excreted through urine as the original.
Tranexamic acid is clinically used for trauma or operation bleeding of organs rich in plasminogen activators, such as prostate, urethra, lung, brain, uterus, adrenal gland, thyroid, liver and the like; as thrombolytic agents, such as tissue plasminogen activator (t-PA), streptokinase and urokinase antagonists; tranexamic acid can also be used for induced abortion, placenta early stage exfoliation, dead fetus and fibrinolytic hemorrhage caused by amniotic fluid embolism. Tranexamic acid can be used for local hyperfibrinolysis, anterior chamber bleeding and severe epistaxis. Tranexamic acid can be used for preventing or reducing bleeding after tooth extraction or oral surgery in hemophiliacs deficient in factor VIII or factor IX. Tranexamic acid can be used for mild bleeding caused by rupture of central aneurysm, such as subarachnoid hemorrhage and intracranial aneurysm hemorrhage, and the application of tranexamic acid is superior to other antifibrinolytic drugs in hemostasis, but attention must be paid to the risks of cerebral edema or cerebral infarction. For patients with severe symptoms and operative indications, the product can only be used as an adjuvant drug. Tranexamic acid can be used for treating hereditary angioedema, and can reduce the number of attacks and severity. Tranexamic acid can be used for active bleeding in hemophiliacs. Tranexamic acid can be used for treating chloasma with definite therapeutic effect.
Tranexamic acid injection can be administered by intravenous drip, generally 0.25-0.5 g for adult, and 1-2 g for daily administration for 1-2 times if necessary. The dosage can be increased or decreased according to age and symptoms, or according to medical advice.
Tranexamic acid has the same hemostatic mechanism as aminocaproic acid and aminomethylbenzoic acid, has better curative effect than aminomethylbenzoic acid, and has especially obvious effect on traumatic hemorrhage. The maintenance time is longer. Can be used for treating hemorrhage caused by acute, chronic, local or systemic hyperfibrinolytic system. For central nervous system hemorrhage, such as subarachnoid space and intracranial aneurysm hemorrhage, the application of the product has better hemostasis than other antifibrolytic drugs.
Clinical studies have shown that tranexamic acid can safely and reliably reduce mortality in patients with traumatic bleeding. In view of this, tranexamic acid, a cheap, non-proprietary drug, has been listed in the WHO's mandatory drug list and will find wide application in high, medium and low income countries of the world. In addition, studies have shown that patients with craniocerebral patients who receive tranexamic acid have a reduced chance of developing progressive bleeding and a reduced mortality rate. Although neither study leads to a well-defined conclusion, it suggests that the prognosis of the potential for improvement of traumatic brain injury by tranexamic acid will lay the foundation for follow-up studies, such as the implementation of the CRASH-3 study in craniocerebral injured patients, which will provide reliable evidence for the efficacy of tranexamic acid in improving mortality and disability rates. In addition, tranexamic acid can significantly reduce the loss of blood volume in women with menorrhagia. An evaluation of the Cochrane system for the treatment of menorrhagia with an anti-fibrinolytic agent (mainly tranexamic acid) indicated that the anti-fibrinolytic formulation could reduce the loss of blood volume in women with menorrhagia more than placebo or other treatments, without increasing the incidence of side effects. The U.S. food and drug administration has approved tranexamic acid oral tablets as a treatment for women with severe menorrhagia on day 11/13 of 2009. Studies have shown that tranexamic acid significantly reduces postpartum hemorrhage. However, due to the somewhat lower quality of the methodology of the three randomized trials incorporated, there is currently no evidence from high quality studies to support the use of antifibrinolytic drugs for postpartum hemorrhage. Currently, a randomized double-blind placebo-controlled Trial known as WOMAN (The World Maternal antibacterial Trial) is being conducted, which will recruit 15000 patients globally and provide reliable evidence for early application of tranexamic acid for improvement of mortality, hysterectomy, etc. in postpartum hemorrhage patients. Surgically, a Cochrane systemic evaluation, which was included in 65 randomized controlled trials, indicated that tranexamic acid reduced the risk of postoperative blood transfusion by nearly 1/3 (RR 0.61, 95% CI 0.53to 0.70) and reduced intraoperative and postoperative bleeding while not increasing the incidence of thromboembolic events. In addition, tranexamic acid is also used as a second-line regimen for the pre-and post-operative adjuvant treatment of hemophiliacs with factor viii deficiency. And also for hereditary angioedema.
Detailed Description
The following examples are provided for the purpose of illustration only and are not intended to, and should not be construed as, limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications can be made to the following embodiments without departing from the spirit or scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified. In the present invention, when the injection is subjected to microfiltration membrane filtration, a Polyethersulfone (PES) microfiltration membrane is used.
Detection method example 1: HPLC method for determining impurities or related substances in aminomethyl ring raw material, intermediate or preparation composition
Or content of
The determination is carried out by referring to the determination method of pages 4504 of European pharmacopoeia EP10.1 and the specification of high performance liquid chromatography of the general rules of the four departments 0512 of 2020 edition of Chinese pharmacopoeia;
test solution: dissolving the sample in water (raw material or its intermediate) and/or diluting (injection) to obtain solution containing 10mg per 1 ml;
control solution (a): diluting 1.0mL of test solution to 100.0mL with water, and then diluting 1.0mL of the test solution to 20.0mL with water;
control solution (b): dissolving 5.0mg of the impurity D in water and diluting to 50.0mL;
control solution (c): diluting 5.0mL of the control solution (b) to 100.0mL with water;
control solution (d): dissolving 2.5mg of impurity E in water, diluting to 50.0mL, and diluting 1.0mL of the solution to 10.0mL with water;
control solution (e): dissolving 2.5mg of impurity C, 2.5mg of impurity F and 7.5mg of impurity B in 25mL of water, and mixing 1mL of the solution, 1mL of a control solution (B) and 18mL of a test solution;
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as a packing (4.6X 250mm,5 μm, waters)
Mobile phase: dissolving 11.0g of anhydrous sodium dihydrogen phosphate in 500mL of water, adding 5mL of triethylamine and 1.4g of sodium dodecyl sulfate, adjusting pH to 2.0 with phosphoric acid, diluting with water to 600mL, and adding 400mL of methanol;
flow rate: 0.9mL/min;
detection wavelength: 220nm;
sample introduction amount: 40. Mu.L of the test solution and the control solutions (a), (c), (d) and (e);
recording time: 2.5 times of the retention time of tranexamic acid;
impurity attribution: determining impurity D peak by using chromatogram of control solution (C), determining impurity E peak by using chromatogram of control solution (D), and determining impurity B, C and F peaks by using chromatogram of control solution (E)
Relative retention time was calculated as tranexamic acid (retention time about 13 min): about 0.3 of impurity F, about 1.1 of impurity C, about 1.2 of impurity D, about 1.3 of impurity E, about 1.5 of impurity B;
system suitability was performed using control solution (e):
separation degree: the resolution of tranexamic acid from impurity C peak is at least 2.0, and the resolution of impurity C from impurity D peak is at least 1.5;
calculating the percentage:
the peak areas of the following impurities were multiplied by the corresponding correction factors to obtain their contents: impurity B correction factor =1.3, impurity C correction factor =0.4, impurity F correction factor =0.6,
the contents of impurities C and D were calculated using the concentration of impurity D in the control solution (C),
the contents of impurities E and F were calculated using the concentration of impurity E in the control solution (d),
calculating the content of impurities other than C, D, E, F using the tranexamic acid concentration in the control solution (a);
the determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, recording chromatogram, and calculating impurity content.
The structural formula of each impurity is as follows:
impurity A: (1r,4r,1 'r,4' r) -4,4'- [ azabicyclo bis (methylene) ] bis (cyclohexane-1-carboxylic acid), also known as trans, trans-4,4' - [ iminobis (methylene) ] bicyclohexanoic acid,
impurity B: (1s, 4s) -4- (aminomethyl) cyclohexane-1-carboxylic acid, also known as Z-tranexamic acid or cis-tranexamic acid or Z isomer,
impurity C: (4 RS) -4- (aminomethyl) cyclohex-1-ene-1-carboxylic acid,
impurity D:4- (aminomethyl) benzoic acid, also known as aminomethylbenzoic acid,
impurity E: (1r, 4r) -4- [ [ (1 r) -4- (aminomethyl) cyclohexane-1-carboxamido ] methyl ] cyclohexane-1-carboxylic acid,
impurity F: (1r, 4r) -4- (carboxamidomethyl) cyclohexane-1-carboxylic acid.
General requirements of bulk drugs with respect to substance limits: less than or equal to 0.1 percent of impurity C (cycloolefine), less than or equal to 0.1 percent of impurity D (aminobenzoic acid), less than or equal to 0.2 percent of impurity B (Z-isomer), and less than or equal to 0.1 percent of other single impurities.
General requirements for injection-related substance limits when referring to injections: less than or equal to 0.1 percent of impurity C (cycloolefin), less than or equal to 0.1 percent of impurity D (aminobenzoic acid), less than or equal to 0.2 percent of impurity B (Z-isomer), and less than or equal to 0.1 percent of other single impurities.
With the method of the above detection method example 1, the relative retention time of the impurity a is 2.0, and the relative response factor with tranexamic acid is 1.0, and since the pharmacopoeia of each country version does not pay close attention to the limit of the impurity a in many cases, the impurity a is not calculated when the present invention relates to the drug substance, but the impurity a shows an unexpected significant increase in the case of the injection solution of the present invention to which sodium acetate is added.
When referring to injection solutions, the assay of the injection solutions is as follows:
test solution: precisely measuring a proper amount of tranexamic acid injection (about equal to 0.1g of tranexamic acid), placing the injection into a 50ml measuring flask, diluting the injection with water to a scale, and shaking up;
control solution: precisely weighing a proper amount of tranexamic acid reference substance, adding water to dissolve the tranexamic acid reference substance, and quantitatively diluting the tranexamic acid reference substance to prepare a solution containing about 2mg of tranexamic acid in each 1ml of the solution;
system applicability solution, chromatographic conditions and system applicability requirements: see above under related substances;
the determination method comprises the following steps: precisely measuring a test solution and a reference solution, respectively injecting into a liquid chromatograph, and recording a chromatogram; and calculating the content of tranexamic acid in the injection by peak area according to an external standard method.
Comparative example 1: preparation of tranexamic acid
This comparative example 1 refers to the method of example three of CN113042040A, firstly preparing platinum carbon catalyst, and then preparing tranexamic acid, as follows.
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 150ml of ethylene glycol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 11.8ml of ethylene glycol, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2 hours, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 154.3g of refined tranexamic acid (yield is 74.2%).
The yield is equivalent to the yield of 100 times of the input amount of CN113042040A example III.
Example 1: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 30ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing the air in the hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting the reactants at 20-25 ℃ for 1 hour, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 184.5g of refined tranexamic acid (yield is 88.7%).
The above refined tranexamic acid is detected according to the method under the item of tranexamic acid, page 1364 of the second part of the Chinese pharmacopoeia, 2020 edition, and the results all meet the regulations of the standard, for example: calculated according to the dry product, the content of C8H15NO2 is 99.73 percent, the white crystalline powder has the pH value of 7.43 measured by alkalinity, related substances of aminomethylbenzoic acid and Z-isomer are respectively 0.046 percent and 0.118 percent, and the weight loss on drying is 0.17 percent.
Example 2: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 150ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 185.9g of refined tranexamic acid (yield is 89.4%).
Example 3: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 100ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 35ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 183.4g of refined tranexamic acid (yield is 88.2%).
Example 4: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, mixing with the mixture A, adding 30ml of acetone, and uniformly mixing to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 189.3g of refined tranexamic acid (yield is 91.0%).
Example 5: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, adding 30ml acetone, uniformly mixing, heating and refluxing for 2 hours, cooling, filtering to obtain a filter product C, and washing with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at the temperature of 220 ℃ and the pressure of 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH of the reaction liquid to be 6.0-6.5, continuously cooling to room temperature and staying overnight, and filtering to obtain a mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 188.1g of refined tranexamic acid (yield is 90.5%).
Example 6: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum-carbon catalyst (part of the catalyst obtained in the step S0 is equivalent to the amount prepared from 1.1g of chloroplatinic acid), 200g of aminomethylbenzoic acid (namely p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing air in a hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting reactants at 20-25 ℃ for 1h, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid obtained in the step S4 with water for 2 times, and drying to obtain 166.8g of refined tranexamic acid (yield is 80.2%).
Example 7: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use;
s1: sequentially adding a platinum-carbon catalyst (part of the catalyst obtained in the step S0 is equivalent to the amount of 0.8g of chloroplatinic acid), 200g of aminomethylbenzoic acid (namely p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
s2: replacing the air in the hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting the reactants at 20-25 ℃ for 1 hour, and filtering to obtain hydrogenation reaction liquid;
s3: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at 220 ℃ and 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH = 6.0-6.5 of the reaction liquid, continuously cooling to room temperature and staying overnight, and filtering to obtain mother liquid D;
s4: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product;
s5: recrystallizing the crude tranexamic acid product obtained in the step S4 with water for 2 times, and drying to obtain 142.3g of refined tranexamic acid (yield is 68.4%).
Comparative example 2: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, then heating and refluxing for 2 hours, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use; steps S1 to S5 were carried out in accordance with the present invention in example 1 to obtain 140.7g (yield: 67.7%) of purified tranexamic acid.
Comparative example 3: preparation of tranexamic acid
S0: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of ethylene glycol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 30ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst for later use; steps S1 to S5 were carried out in the same manner as in example 1 of the present invention to obtain 147.2g (yield: 70.8%) of purified tranexamic acid.
From the results of the above examples 1 to 7 and comparative examples 1 to 3, it was unexpectedly found that when glycerin is used as a solvent in the preparation of the catalyst and a small amount of acetone is added, the resulting catalyst can significantly improve the yield of the product when used for the preparation of tranexamic acid, while the yield is significantly lower when ethylene glycol is used in combination with acetone or only glycerin is used without acetone, and the amount of the catalyst used in the hydrogenation reaction is reduced. This shows that the catalyst obtained by the method of the invention can improve the yield of the product, or can reduce the using amount of the catalyst under the condition of equivalent yield. It should be noted that, although the yield of the product is improved by only 14 to 17% in examples 1 to 5 as compared with comparative example 1, the cost of the material and process for preparing the catalyst is not increased as compared with comparative example 1, so that such a high yield is very significant.
Measuring the relevant substances in the refined tranexamic acid obtained in the step S5 by using the HPLC operation and conditions of the detection method example 1; the results of the measurements showed that the purified tranexamic acid of comparative examples 1 to 3 and the purified tranexamic acid of examples 1 to 7: impurity C (cycloolefine) = 0.027-0.091%, impurity D (aminobenzoic acid) = 0.033-0.072%, impurity B (Z-isomer) = 0.041-0.163%, and other single impurities are all less than 0.091%; for example, comparative example 1 purified tranexamic acid: impurity C (cycloolefine) =0.063%, impurity D (aminobenzoic acid) =0.045%, impurity B (Z-isomer) =0.137%, and other single impurities are all less than 0.072%; as another example, example 1 refines tranexamic acid: impurity C (cycloolefine) =0.051%, impurity D (aminobenzoic acid) =0.049%, impurity B (Z-isomer) =0.114%, and other single impurities are all less than 0.064%; these results show that the individual impurity levels of the various samples are not significantly different and all meet the general regulations.
The contents of API (trans-tranexamic acid which is an object of the present invention), impurity B (Z-isomer), and impurity C (cycloolefin) in the hydrogenation reaction solution obtained in step S2 of preparing tranexamic acid were measured and calculated using the HPLC operation and conditions of detection method example 1, and the apparent hydrogenation rate (%) was calculated by the following formula:
as a result: comparative example 1 the hydrogenation reaction liquid obtained in step S2 had an apparent hydrogenation rate of 91.7%, and comparative examples 2 and 3 had an apparent hydrogenation rate of 90.3% and 92.4%, respectively; the hydrogenation reaction liquids obtained in steps S2 of examples 1 to 5 had apparent hydrogenation rates of 97.2 to 98.7%, for example, the hydrogenation reaction liquid of example 1 had an apparent hydrogenation rate of 98.4%, and the hydrogenation reaction liquids of examples 6 and 7 had apparent hydrogenation rates of 94.2% and 88.4%, respectively.
The apparent hydrogenation rates of the mother liquors D obtained in the steps S3 of the comparative examples 1 to 3 and examples 1 to 7 were measured in the same manner as above, and all of them were in the range of 99.2 to 99.6%, and for example, the apparent hydrogenation rate of the mother liquor D obtained in the step S3 of example 1 was 99.47%.
Using the HPLC operation and conditions of test method example 1, the contents of API (trans-tranexamic acid, which is an object of the present invention) and impurity B (Z-isomer) in the hydrogenation reaction liquid of step S2 and the mother liquid D of step S3 for preparing tranexamic acid were measured and calculated, and the cis ratio (%) was calculated as follows:
as a result: the cis-form ratios of the hydrogenation reaction liquids obtained in the steps S2 of the comparative examples 1 to 3 and examples 1 to 7 were all in the range of 49.3 to 51.4%, for example, the cis-form ratio of the hydrogenation reaction liquid obtained in the step S2 of example 1 was 49.7%; the cis-forms of the mother liquors D obtained in the steps S3 of the comparative examples 1 to 3 and examples 1 to 7 were all in the range of 0.11 to 0.24%, for example, the cis-form of the mother liquor D obtained in the step S3 of example 1 was 0.141%, and the results substantially agreed with the final product obtained in the step S5.
The above results concerning the apparent hydrogenation rate and the cis-form rate show that the hydrogenation reaction liquids obtained by the different methods have significantly different contents of the cycloolefin impurity C, the hydrogenation reaction liquids obtained in examples 1 to 5 have significantly less contents of the impurity C, and the hydrogenation reaction liquids of the other examples have significantly higher contents of the impurity C; however, in the mother liquor D obtained after undergoing the configuration conversion, the impurity C was not substantially detected; this indicates that the use of the catalyst obtained in the S0 step of the present invention enables more complete hydrogenation, and that some of the reasons for the low reaction yield may be partly due to incomplete hydrogenation, and that the cycloolefin impurity C which is incompletely hydrogenated may be largely removed in the subsequent configuration conversion. It has been found that the catalysts obtained by the process of the invention exhibit the above-mentioned results which were not at all expected by the prior art.
Some preparation examples of injection solutions are described below, in which various raw and auxiliary materials used meet the corresponding regulations of the preparation, for example, the tranexamic acid raw material prepared in example 1 completely meets the standard regulations by the method under the item of the same second article of the chinese pharmacopoeia 2020 edition, and the tranexamic acid used is the raw material prepared by the method in example 1 unless otherwise stated below.
Preparation example 1: preparation of tranexamic acid injection
Tranexamic acid injection was prepared with reference to the formulation and preparation method of example 1 of CN 110876718A (chinese patent application No. 201911256257.2).
Prescription (1000, 0.2g/2 ml/bottle): tranexamic acid 200g and water for injection are added to 2000ml (optionally an acid-base regulator (hydrochloric acid and/or sodium hydroxide) in an amount such that the pH of the injection is = 7.0-7.5).
The preparation method comprises the following steps of: adding 60-degree-of-freedom injection water with the prescription amount of 60% and tranexamic acid with the prescription amount into a concentration tank, and stirring until the water and the tranexamic acid are dissolved; adding 0.5% of active carbon, keeping the temperature and stirring for 20 minutes, filtering and decarbonizing, transferring into a diluting preparation tank, cooling to room temperature, and adding water to nearly full dose; adjusting pH =7.2 + -0.1 with 1M hydrochloric acid solution or 1M sodium hydroxide solution, adding water to full volume, filtering with 0.45 μ M microporous membrane for 2 times, filtering with 0.22 μ M microporous membrane for 2 times, filling into treated ampoule bottle, sealing, and sterilizing at 121 deg.C under hot pressure for 15 min.
Preparation example 2: preparation of tranexamic acid injection
Prescription (1000, 0.2g/2 ml/bottle): tranexamic acid 200g, sodium acetate 30g and water for injection are added to 2000ml (optionally, an acid-base regulator (hydrochloric acid and/or sodium hydroxide) is added in a proper amount to ensure that the pH of the injection is = 7.0-7.5).
The preparation method comprises the following steps of: adding 60% of injection water at 60 ℃ in the amount of the prescription, tranexamic acid and sodium acetate in the amount of the prescription into a thick preparation tank, and stirring until the injection water is dissolved; adding 0.5% of activated carbon, keeping the temperature and stirring for 20 minutes, filtering to remove the carbon, transferring into a diluting preparation tank, cooling to room temperature, and adding water to nearly full dose; adjusting pH =7.2 + -0.1 with 1M hydrochloric acid solution or 1M sodium hydroxide solution, adding water to full volume, filtering with 0.45 μ M microporous membrane for 2 times, filtering with 0.22 μ M microporous membrane for 2 times, filling into treated ampoule bottle, sealing, and sterilizing at 121 deg.C under hot pressure for 15 min.
Preparation example 3: preparation of tranexamic acid injection
Prescription (1000, 0.2g/2 ml/bottle): 200g of tranexamic acid, 50g of propylene glycol and water for injection are added to 2000ml (an optional acid-base regulator (hydrochloric acid and/or sodium hydroxide) is added in a proper amount to ensure that the pH of the injection is = 7.0-7.5).
The preparation method comprises the following steps: adding 60% of injection water at 60 ℃ in the amount of the prescription, tranexamic acid in the amount of the prescription and propylene glycol into a concentration tank, and stirring until the injection water, the tranexamic acid and the propylene glycol are dissolved; adding 0.5% of activated carbon, keeping the temperature and stirring for 20 minutes, filtering to remove the carbon, transferring into a diluting preparation tank, cooling to room temperature, and adding water to nearly full dose; adjusting pH =7.2 + -0.1 with 1M hydrochloric acid solution or 1M sodium hydroxide solution, adding water to full volume, filtering with 0.45 μ M microporous membrane for 2 times, filtering with 0.22 μ M microporous membrane for 2 times, filling into treated ampoule bottle, sealing, and sterilizing at 121 deg.C under hot pressure for 15 min.
Preparation example 4: preparation of tranexamic acid injection
Prescription (1000, 0.2g/2 ml/bottle): tranexamic acid 200g, sodium acetate 30g, propylene glycol 50g and water for injection are added to 2000ml (optionally, an acid-base regulator (hydrochloric acid and/or sodium hydroxide) is added in a proper amount to ensure that the pH of the injection is = 7.0-7.5).
The preparation method comprises the following steps: adding 60% of injection water at 60 ℃ in the amount of the prescription and tranexamic acid, sodium acetate and propylene glycol in the amount of the prescription into a thick preparation tank, and stirring until the injection water is dissolved; adding 0.5% of active carbon, keeping the temperature and stirring for 20 minutes, filtering and decarbonizing, transferring into a diluting preparation tank, cooling to room temperature, and adding water to nearly full dose; adjusting pH =7.2 + -0.1 with 1M hydrochloric acid solution or 1M sodium hydroxide solution, adding water to full volume, filtering with 0.45 μ M microporous membrane for 2 times, filtering with 0.22 μ M microporous membrane for 2 times, filling into treated ampoule bottle, sealing, and sterilizing at 121 deg.C under hot pressure for 15 min.
Injection performance test example 1: formulation miscibility test
5ml of tranexamic acid injection solution, 2.5ml of sucralfate injection solution (50mg in terms of Fe, H20057617), and 50ml of 0.9% sodium chloride injection solution (H20173233) obtained in preparation example 1 were placed in a glass tube, mixed, left to stand at room temperature for 24 hours, 50.0g of the supernatant was carefully removed, and a brown precipitate was observed at the bottom of the glass tube, 50ml of water for injection was accurately added to the glass tube, mixed, and subjected to ultrasonic treatment for 15 minutes, and then the absorbance was measured at 505nm on a spectrophotometer, and as a result, the absorbance A =0.527;
the tranexamic acid injection solution obtained in formulation example 2 was treated by the miscibility test method of formulation example 1, and as a result, no precipitate was observed at the bottom of the glass tube and the absorbance a =0.097;
when the tranexamic acid injection obtained in formulation example 3 was treated by the miscibility test method of formulation example 1, a brown precipitate was observed at the bottom of the glass tube and the absorbance a =0.513;
the tranexamic acid injection solution obtained in formulation example 4 was treated by the miscibility test method of formulation example 1, and as a result, no precipitate was observed at the bottom of the glass tube and the absorbance a =0.102.
Based on the above formulation miscibility tests, it was surprisingly found that the addition of a suitable amount of sodium acetate to tranexamic acid injection (formulation examples 2 and 4) significantly prevented the formation of precipitates when mixed with ferric saccharate injection and sodium chloride injection, but that the mixture produced a distinct brown precipitate when acetic acid was not added (formulation examples 1 and 3), which precipitate should be derived from ferric saccharate in terms of color, in the sense that the addition of a suitable amount of sodium acetate to tranexamic acid to prevent the formation of precipitates when mixed with ferric saccharate injection and sodium chloride injection is beneficial. Namely, when tranexamic acid injection, iron sucrose injection and sodium chloride injection are mixed for use, the formulations 2 and 4 in which sodium acetate is added are advantageous. It should be noted that although the specification of the sucroferric injection does not explicitly mention that it can not be used in combination with other therapeutic drugs, the development of clinical application and the advancement of technology, as described in the xi yilong and yangqing documents, cannot negate the great clinical significance of the combination of sucroferric acid and tranexamic acid in joint replacement.
Injection performance test example 2: test for investigating impurities
The inventor finds in further research that a tranexamic acid dimer impurity, namely the impurity a in the invention, is easily generated in the storage process of a tranexamic acid injection in the preparation example 2 containing sodium acetate, and when a proper amount of propylene glycol, namely the preparation example 4, is added to the injection in the preparation example 2, the injection can inhibit the generation of the impurity a, and specific experiments are as follows:
the injections of formulation examples 1 to 4 were allowed to stand at 40 ℃ for 6 months, samples were taken at 0, 3 and 6 months and the content of impurity a in the injections was measured by the HPLC method of detection method example 1, and the increase rate (%) of impurity a for 6 months was calculated for a certain injection according to the following formula:
the impurity a growth rate for 3 months can also be calculated similarly.
As a result: the impurity A content of the injection of the preparation example 1 in 0 month, 3 month and 6 month is 0.317%, 0.422% and 0.496% respectively, and the increase rate of the impurity A calculated in the injection of the preparation example 1 in 3 month and 6 month is 33.1% and 56.5% respectively; formulation example 2 the increase rates of impurity a in injections at months 3 and 6 were 446.1% and 798.0%, respectively (impurity a contents at three time points were 0.304%, 1.66% and 2.73%, respectively); preparation example 3 the growth rates of impurity a in the injection solution for 3 months and 6 months were 37.3% and 52.4%, respectively; preparation example 4 the growth rates of impurity a in the injections of 3 months and 6 months were 32.6% and 59.4%, respectively; preparation examples 2 to 4 the content of impurity A in the injections at 0 month was 0.297 to 0.343%.
In view of the fact that the content of impurity A in tranexamic acid is less than 1% as specified in British pharmacopoeia 2021 edition, the injection of the preparation examples 1,3 and 4 can still meet the pharmacopoeia specifications after being left for 6 months at 40 ℃.
Further, referring to the formulation and the preparation method of preparation example 4, 10g of propylene glycol, 20g of propylene glycol, 30g of propylene glycol and 75g of propylene glycol were added to prepare three kinds of injections (referred to as injection 41, injection 42 and injection 43, respectively), and the growth rates of impurity a were measured in the same manner as above; as a result: the growth rates of the impurity A in 3 months and 6 months after the addition of 10g of propylene glycol are respectively 125.2% and 302.4%, the growth rates of the impurity A in 3 months and 6 months after the addition of 20g of propylene glycol are respectively 57.4% and 124.6%, the growth rates of the impurity A in 3 months and 6 months after the addition of 30g of propylene glycol are respectively 37.2% and 66.4%, and the growth rates of the impurity A in 3 months and 6 months after the addition of 75g of propylene glycol are respectively 31.6% and 58.3%; this result shows that the addition of propylene glycol in an amount of 30 to 75g in the formulation of formulation example 4 can avoid the increase of impurity A.
Injection performance test example 3: quality of injection
The injection (referred to as injection 4) obtained in preparation example 4, injection 41, injection 42 and injection 43 are respectively placed at 0 month and 40 ℃ for 6 months to measure each index according to the method of the tranexamic acid injection carried on the second part of the 2020 edition of Chinese pharmacopoeia on page 1366, and the indexes of 0 month and 6 months of the four injections all accord with the specification of the pharmacopoeia. For example: the content of the four injections in 0 month and 6 month is respectively 98.7% -101.2% and 97.2% -99.7% of the marked amount, for example, the content of the injection 4 in 0 month and 6 month is respectively 99.6% and 99.3% of the marked amount; the cycloolefin impurity content of each of the four injections is less than 0.1%, for example, the cycloolefin impurity content of injection 4 in 0 month and 6 month is 0.048% and 0.044%, respectively; the impurity content of the aminomethylbenzoic acid in 0 month and 6 month of the four injections is less than 0.1 percent, for example, the impurity content of the aminomethylbenzoic acid in 0 month and 6 month of the injection 4 is 0.044 percent and 0.052 percent respectively; z-isomer impurities of the four injections in month 0 and month 6 are less than 0.2 percent, for example, the Z-isomer impurities in month 0 and month 6 of the injection 4 are respectively 0.119 percent and 0.127 percent.
The present invention is illustrated in detail by the examples given above, but the present invention is not limited to the details given above, which means that the present invention is not limited to the details given above. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A tranexamic acid injection comprising: tranexamic acid, water for injection.
2. Tranexamic acid injection according to claim 1, which comprises 5 to 15g of tranexamic acid per 100ml and water for injection added to the total amount; alternatively, 5 to 10g of tranexamic acid and water for injection added to the total amount are contained.
3. The tranexamic acid injection according to claim 1, which further comprises sodium acetate; alternatively, it contains 1-2 g of sodium acetate, for example 1.5g of sodium acetate, per 100 ml; or, further comprising propylene glycol; alternatively, 1 to 5g of propylene glycol, for example 1.5 to 3.75g of sodium acetate, per 100 ml; or, the composition also comprises an acid-base regulator; for example, the amount of the acid-base modifier is to adjust the pH =6.0 to 8.5 of the injection solution; for example, the amount of the acid-base modifier is to adjust the pH =6.5 to 8.0 of the injection solution; for example, the pH adjusting agent is hydrochloric acid and/or sodium hydroxide and aqueous solutions thereof, for example, 1M aqueous solution.
4. Tranexamic acid injection according to claim 1, which is prepared according to a process comprising the steps of: providing a tranexamic acid raw material medicament; adding 50-80% of the prescription amount, such as 60%, of injection water at 50-80 ℃, such as 60 ℃, and the prescription amount of tranexamic acid and optional other auxiliary materials into a concentration tank, and stirring until the mixture is dissolved; adding (for example, 0.5%) activated carbon, stirring at constant temperature (for example, 15-30 min, for example, 20 min), filtering to remove carbon, transferring into a diluting tank, cooling to room temperature, and adding water to nearly full volume; adjusting pH =7.2 + -0.5 such as pH =7.2 + -0.1 with an acid-base modifier (e.g. 1M hydrochloric acid solution or 1M sodium hydroxide solution), adding water to full volume, filtering with (e.g. 0.45 μ M and/or 0.22 μ M) microfiltration membrane (e.g. first filtering with 0.45 μ M microfiltration membrane for 2 times and then filtering with 0.22 μ M microfiltration membrane for 2 times), filling into glass bottles, and sterilizing (e.g. autoclaving at 121 deg.C for 15 min).
5. Tranexamic acid injection according to claim 1, wherein the tranexamic acid is the tranexamic acid of the second aspect or the tranexamic acid prepared by the process of the first aspect.
6. A method for preparing tranexamic acid injection, which comprises the following steps: providing a tranexamic acid raw material medicine; adding 50-80% of the prescription amount, such as 60%, of injection water at 50-80 ℃, such as 60 ℃, and the prescription amount of tranexamic acid and optional other auxiliary materials into a concentration tank, and stirring until the mixture is dissolved; adding (for example, 0.5%) activated carbon, stirring at constant temperature (for example, 15-30 min, for example, 20 min), filtering to remove carbon, transferring into a diluting tank, cooling to room temperature, and adding water to nearly full volume; adjusting pH =7.2 + -0.5 such as pH =7.2 + -0.1 with acid and alkali regulator (such as 1M hydrochloric acid solution or 1M sodium hydroxide solution), adding water to full volume, filtering with (such as 0.45 μ M and/or 0.22 μ M) microporous membrane (such as filtering with 0.45 μ M microporous membrane for 2 times and then filtering with 0.22 μ M microporous membrane for 2 times), filling into glass bottle, and sterilizing (such as autoclaving at 121 deg.C for 15 min).
7. The method according to claim 6, wherein the tranexamic acid injection solution comprises 5 to 15g of tranexamic acid and water for injection added to the total amount per 100 ml; or, comprises 5-10 g of tranexamic acid and water for injection added to the total amount; alternatively, it contains 1-2 g of sodium acetate, for example 1.5g of sodium acetate, per 100 ml; or, further comprising propylene glycol; alternatively, it may contain 1 to 5g of propylene glycol, for example 1.5 to 3.75g of sodium acetate, per 100 ml.
8. The method according to claim 6, wherein the tranexamic acid injection further comprises an acid-base modifier; for example, the amount of the acid-base modifier is to adjust the pH =6.0 to 8.5 of the injection solution; for example, the amount of the acid-base modifier is to adjust the pH =6.5 to 8.0 of the injection solution; for example, the pH adjusting agent is hydrochloric acid and/or sodium hydroxide and aqueous solutions thereof, for example, 1M aqueous solution.
9. The process according to claim 6, wherein the tranexamic acid is prepared as follows:
(S0) providing a platinum-on-carbon catalyst;
(S1) uniformly mixing a platinum-carbon catalyst, aminomethylbenzoic acid, water and concentrated sulfuric acid in a hydrogenation kettle;
(S2) replacing the atmosphere in the hydrogenation kettle with hydrogen, hydrogenating at the temperature of 20-25 ℃, and filtering to obtain hydrogenation reaction liquid;
(S3) adding barium hydroxide into the hydrogenation reaction solution, carrying out high-temperature and high-pressure treatment in a hydrogenation kettle to convert the configuration, neutralizing with a sulfuric acid solution, cooling, and filtering to obtain a mother solution;
(S4) concentrating the mother liquor, cooling and filtering to obtain a tranexamic acid crude product;
(S5) recrystallizing the tranexamic acid crude product by using water to obtain the tranexamic acid.
10. The method of claim 9, wherein:
in step (S0), a platinum-carbon catalyst was prepared using the following procedure: boiling activated carbon with water to obtain clean activated carbon, treating with hydrochloric acid, filtering to remove liquid, and oven drying; mixing activated carbon with chloroplatinic acid solution, adding sodium hydroxide to adjust the pH value to 9-10, refluxing, cooling, filtering, and washing with water to obtain a platinum-carbon catalyst;
in step (S0), a platinum-carbon catalyst was prepared using the following materials and operations in the following proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 100-150 ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 25-35 ml of acetone, and mixing with the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst;
in step (S0), a platinum-carbon catalyst was prepared using the following materials and operations in the following proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, mixing with the mixture A, adding 25-35 ml of acetone such as 30ml of acetone, and uniformly mixing to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, heating and refluxing for 2h, cooling and filtering to obtain a filter product C, and washing the filter product C with water to obtain a platinum-carbon catalyst;
in the step (S0), a platinum-carbon catalyst was prepared using the following materials and operations in proportions: adding 5g of activated carbon and 25ml of water into a container, heating and boiling for 20min, cooling, filtering to obtain clean activated carbon, uniformly mixing the clean activated carbon with 25ml of 1M hydrochloric acid, stirring for 4h, filtering to remove liquid, drying at 80 ℃, cooling to room temperature, and mixing with 120ml of glycerol to obtain a mixture A; dissolving 1.475g of chloroplatinic acid in 20ml of glycerol, and mixing the chloroplatinic acid and the mixture A to obtain a mixture B; dropwise adding 1M sodium hydroxide glycerol solution into the mixture B, adjusting the pH value of the mixture B to 9-10, adding 25-35 ml, such as 30ml of acetone, uniformly mixing, heating and refluxing for 2h, cooling, filtering to obtain a filter product C, and washing with water to obtain a platinum-carbon catalyst;
the step (S1) uses the following operation procedure: sequentially adding a platinum carbon catalyst (prepared from 1.475g of chloroplatinic acid obtained in the step S0), 200g of aminomethylbenzoic acid (p-aminomethylbenzoic acid), 6L of pure water and 80ml of concentrated sulfuric acid into a hydrogenation kettle, and uniformly stirring;
the step (S2) uses the following operation procedure: replacing the air in the hydrogenation kettle with nitrogen for 2 times, replacing the nitrogen with hydrogen for 2 times, adjusting the hydrogen pressure to 0.2MPa, reacting the reactants at 20-25 ℃ for 1 hour, and filtering to obtain hydrogenation reaction liquid;
the step (S3) uses the following operation procedure: concentrating the hydrogenation reaction liquid obtained in the step S2 to 2000ml, adding 400g of barium hydroxide, treating for 2h in a hydrogenation kettle at the temperature of 220 ℃ and the pressure of 2.0-2.5 mPa to convert the configuration, cooling to 60-70 ℃, dropwise adding 30% sulfuric acid solution to adjust the pH of the reaction liquid to be 6.0-6.5, continuously cooling to room temperature and staying overnight, and filtering to obtain a mother liquid D;
the step (S4) uses the following operation procedure: concentrating the mother liquor D obtained in the step S3 to 1000ml, cooling to room temperature, and filtering to obtain a tranexamic acid crude product; and/or
The step (S5) uses the following operation procedure: recrystallizing the tranexamic acid crude product obtained in the step S4 with water for 2 times, and drying to obtain the refined tranexamic acid.
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| CN116115561A (en) * | 2023-03-17 | 2023-05-16 | 湖南浩森制药有限公司 | Tranexamic acid injection and preparation method thereof |
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