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CN-121971436-A - Production method of concentrated solution medicinal composition for injection

CN121971436ACN 121971436 ACN121971436 ACN 121971436ACN-121971436-A

Abstract

The invention provides a production method of a concentrated solution medicinal composition for injection, and in particular relates to a production method of a concentrated solution for injection of edaravone, which comprises the steps of firstly injecting propylene glycol and water into a liquid preparation tank according to the weight ratio, heating to 50-60 ℃ to add the edaravone, stirring and dissolving, then adding the pre-dissolved dextroamphravone with propylene glycol, stirring uniformly, adding water with a nearly constant volume, cooling to below 25 ℃, adding sodium metabisulfite, regulating the pH value to 4.0-5.0, keeping the volume to a full volume, keeping/reducing the temperature of the liquid medicine to below 25 ℃, and conveying the liquid medicine into an ampoule bottle by using a fluoropolymer pipe for filling. The production method solves the problem that the drug components are easy to be adsorbed in the preparation process, especially in the long-time production process, and can be matched with a production type liquid preparation system and filling and sealing equipment by optimizing the material of the conveying pipe and the production process parameters, and the industrialized production is convenient and the cost is low.

Inventors

  • YANG JIANGLING
  • CHEN SHENGYING
  • FENG YIHONG
  • WU SUQI
  • YANG HONG
  • YANG WEI

Assignees

  • 广东粤和泽药物研究有限公司

Dates

Publication Date
20260505
Application Date
20260205

Claims (10)

  1. 1. The production method of the edaravone right camphene concentrated solution for injection is characterized in that the production method is characterized in that the edaravone right camphene concentrated solution for injection is prepared according to a prescription table, and then liquid medicine is conveyed into a medicinal glass bottle by adopting a fluoropolymer pipe for filling.
  2. 2. The production method according to claim 1, wherein the edaravone-dextroamphaeol injection concentrated solution comprises 2mg/ml edaravone, 0.5mg/ml dextroamphaeol, 0.08ml/ml propylene glycol and 1.0mg/ml sodium metabisulfite.
  3. 3. The method of claim 2 wherein said fluoropolymer tubing is free of elemental silicon.
  4. 4. The method according to claim 3, wherein the fluoropolymer pipe is fluorocarbon and/or oxygen polymer selected from any one of polytetrafluoroethylene, fluorinated ethylene propylene copolymer, tetrafluoroethylene-perfluoroalkoxy vinyl ether copolymer, perfluoroalkoxyalkane, ethylene-tetrafluoroethylene copolymer, and combinations thereof.
  5. 5. The production method according to claim 4, wherein the conveying speed of the production method in the pipe is 1.5-2L/min.
  6. 6. The production method according to any one of claims 1 to 5, wherein propylene glycol and water are injected into a liquid preparation tank according to the weight ratio, the mixture is heated to 50 to 60 ℃ to add edaravone, the mixture is stirred and dissolved, then right camphol which is dissolved by propylene glycol in advance is added, the mixture is stirred uniformly and then added into water with a nearly constant volume, the temperature is reduced to below 25 ℃, sodium metabisulfite is added, the pH value is regulated to 4.0 to 5.0, the constant volume is kept to a full volume, the temperature of the liquid medicine is kept/reduced to below 25 ℃, and the liquid medicine is conveyed into an ampoule bottle by adopting a pipe for filling, wherein the pipe is a fluorine polymer pipe.
  7. 7. The production method according to claim 6, characterized in that the production method is as follows: (1) Injecting propylene glycol with the prescription amount of 75% and water for injection with the prescription amount of 25% into a liquid preparation tank, uniformly mixing and heating to 60 ℃; (2) Maintaining the temperature of the solution in the solution preparing tank at 60 ℃, adding edaravone into the solution preparing tank, and stirring to completely dissolve the edaravone; (3) Cooling the solution in the liquid preparation tank in the step (2) to 50 ℃, adding the dexamphetamol dissolved in the residual prescription amount of propylene glycol in advance, and stirring until the solution is dissolved; (4) Maintaining a stirring state, adding water with a volume close to a fixed volume into a liquid distribution tank, and stirring to uniformly mix the water; (5) Cooling the liquid medicine to below 25 ℃, adding sodium metabisulfite, stirring until the sodium metabisulfite is completely dissolved, adding hydrochloric acid and/or sodium hydroxide to adjust the pH value of the liquid medicine to 4.0-5.0, and fixing the volume to the full volume; (6) The temperature of the liquid medicine is kept/reduced to below 25 ℃, and then the liquid medicine is conveyed into an ampoule bottle by adopting a fluoropolymer fluoroplastic type pipe.
  8. 8. The production method according to claim 7, wherein the step (1) is performed under an inert gas atmosphere, more preferably the whole production method is performed under an inert gas atmosphere.
  9. 9. The method according to claim 8, wherein the conveying speed of step (6) is not less than 1L/min, preferably the conveying time of step (6) is not less than 0.5h.
  10. 10. The method of any one of claims 1-9, wherein the step (6) cools the medical fluid to below 15 ℃.

Description

Production method of concentrated solution medicinal composition for injection Technical Field The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a concentrated solution pharmaceutical composition for injection, namely a production method of a concentrated solution for edaravone dextroamphetamine injection. Background Cerebral apoplexy belongs to cardiovascular diseases, and has acute onset and poor prognosis, and has developed into diseases which pose a serious threat to human health. Ischemic stroke is the most common type of stroke and is also the main cause of long-term disability, and especially acute ischemic stroke is an important factor causing death, disability and shortened life expectancy worldwide, and especially forms a huge threat to the health and even life of middle-aged and elderly people. The edaravone and dextroamphetamine concentrated solution for injection is independently researched and developed by the Jiangsu pioneer pharmaceutical industry and is marketed in batches in 2020, and becomes an innovative medicament for global treatment of stroke diseases. Clinical trials show that the traditional Chinese medicine composition can prolong the time window of stroke treatment to 48 hours after onset, and can remarkably improve the recovery of the nerve function of patients. The edaravone right camphol is prepared into injection which is suitable for emergency treatment, the treatment effect depends on the effective drug concentration of target organs (brain tissues), so the concentration of the preparation needs to be optimized to balance the curative effect, safety and administration portability, and the clinical approved dosage form is concentrated solution for injection. However, the active ingredient thereof is poorly soluble in water, wherein edaravone is very slightly soluble or hardly soluble in water, and dexbornyl alcohol is hardly soluble in water and is volatile. Thus, there are still problems in the preparation process. In addition, right borneol, which is chemically named as (1R, 2S, 4R) -1, 7-trimethyl-bicyclo [2.2.1] heptan-2-ol, contains a polar group hydroxyl (-OH), and the whole molecule is in a 'weak polarity to medium polarity', and the polarity characteristics directly affect the equipment and consumable selection of the preparation production process. In the field of pharmaceutical production, silica gel materials are widely used because of their excellent chemical stability and mechanical strength. However, the surface of the silica gel is not smooth, but has a porous or rough structure with a large number of silicon hydroxyl groups (-Si-OH), which are core active sites of the silica gel, and the specific surface area is large, increasing the contact probability with the right kaempferol molecule. When the silica gel tube is used for conveying the liquid medicine containing the right camphol during production, the hydroxyl groups in the right camphol molecules are easy to form double hydrogen bonds with the silicon hydroxyl groups on the surface of the silica gel tube, and the hydrogen bonds are intermolecular acting forces stronger than Van der Waals force and are main driving forces for adsorption. In production scenarios, temperature, solvent system, contact time and flow rate can further exacerbate adsorption phenomena. The patent application CN116472035A of the prior sound pharmaceutical industry discloses a pharmaceutical composition of edaravone and dextro-camphene and a preparation method thereof, namely, propylene glycol is heated to 50-60 ℃, edaravone is added, stirring is carried out until the mixture is completely dissolved, a liquid medicine is obtained, the liquid medicine is cooled to below 25 ℃, and the dextro-camphene is added into the liquid medicine and stirred until the mixture is completely dissolved, however, the preparation method does not disclose the problem of drug adsorption caused by equipment. CN120284868a finds that the production equipment has high adsorption rate to dexkaempferol in the preparation process, resulting in the problem of greatly reducing the effective components of the drug, and solves the problem of high adsorption rate of the concentrate solution for edaravone dexkaempferol injection in the production process by optimizing the production equipment and process parameters of the pipe components, however, the inventor finds that the preferable pipe is an ultra-smooth inner surface platinum silicon sulfide pipe, and the inner surface of the silicon pipe is coated with a polydimethylsiloxane or fluorosilane coating, thereby improving the problems of porous and coarse structure of the silicon pipe and easy adsorption of other polar groups by strong polar groups. In addition, according to the technical guidelines for compatibility study of plastic components for chemical injection production (trial run) and the technical guidelines for compatibility study of chemicals and el