CN116942604A - Butylphthalide injection and preparation method thereof - Google Patents

Butylphthalide injection and preparation method thereof Download PDF

Info

Publication number
CN116942604A
CN116942604A CN202311040362.9A CN202311040362A CN116942604A CN 116942604 A CN116942604 A CN 116942604A CN 202311040362 A CN202311040362 A CN 202311040362A CN 116942604 A CN116942604 A CN 116942604A
Authority
CN
China
Prior art keywords
injection
butylphthalide
mixture
phospholipid
cholate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311040362.9A
Other languages
Chinese (zh)
Inventor
钱莉苹
程开生
吴青青
王军
李静
张颖
秦梦丽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Yifan Biological Pharmaceutical Co ltd
Original Assignee
Hefei Yifan Biological Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hefei Yifan Biological Pharmaceutical Co ltd filed Critical Hefei Yifan Biological Pharmaceutical Co ltd
Priority to CN202311040362.9A priority Critical patent/CN116942604A/en
Publication of CN116942604A publication Critical patent/CN116942604A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The application provides a butylphthalide injection and a preparation method thereof, and relates to the technical field of medicines, wherein the butylphthalide injection comprises butylphthalide, cholate, phospholipid and water for injection, wherein the cholate is prepared by reacting cholic acid and sodium hydroxide; the molar ratio of the phospholipid to the cholic acid is 0.3-1.2:1. The mass fraction of the butylphthalide in the butylphthalide injection is 0.025% -1%, the butylphthalide, cholate and phospholipid are mixed and proportioned under the condition of a certain molar ratio at a certain concentration and mass ratio, and the butylphthalide injection of clear solution is prepared; the butylphthalide injection disclosed by the application is simple in preparation process, and the stability of the injection is further improved by utilizing multiple dissolution and stirring, so that the clinical medicine requirement is met, and the industrial production is facilitated.

Description

Butylphthalide injection and preparation method thereof
Technical Field
The application belongs to the technical field of medicines, and in particular relates to a butylphthalide injection and a preparation method thereof.
Background
Butylphthalide (NBP), 3-butyl-1 (H) -isobenzofuranone, apigenin, and its chemical formula is C 12 H 14 O 2 Is a levorotatory body extracted from celery seed, or can be synthesized artificially. Butylphthalide is an oily liquid, insoluble in water, has a strong celery taste, and contains a chiral carbon atom in the molecule, so that it has two optical isomers, namely, levobutylphthalide and dextrorotatory butylphthalide. Butylphthalide is a medicine for treating ischemic cerebral apoplexy, can be used for treating hypertension, has neuroprotective effect, reduces infarct focus after focal cerebral ischemia, reduces the degree of nerve function injury, improves the energy metabolism of brain after whole brain ischemia, and the like.
At present, cyclodextrin inclusion technology is mostly adopted in injection products of butylphthalide. For example, chinese patent No. CN109985035B discloses a sodium butylphthalide chloride injection containing hydroxypropyl- β -cyclodextrin, the volume of the injection prepared is 100mL, which includes 25mg of butylphthalide and 0.9g of sodium chloride, the molar ratio of hydroxypropyl- β -cyclodextrin to butylphthalide is 3-5:1, and the calculated amount of hydroxypropyl- β -cyclodextrin in 100mL injection is 0.51-0.9g, and 200mL of the injection is administered daily in combination with the description of sodium butylphthalide chloride injection, i.e. the amount of hydroxypropyl- β -cyclodextrin is close to the daily maximum approved exposure (required by FDA database of pharmaceutical inactive ingredients in the united states, the daily maximum exposure is 3mg when the hydroxypropyl- β -cyclodextrin is administered by intravenous injection and intramuscular injection), and the hydroxypropyl- β -cyclodextrin is removed by glomerular filtration, which has a clear limitation on the renal function of the patient. Moreover, the volume of the butylphthalide injection prepared by the technology is 100mL, and the injection can only be used for intravenous drip, and cannot well meet clinical medication requirements.
The phospholipid and the bile salt can obviously improve the solubility of the insoluble drugs, and have been successfully applied to solubilization of drugs such as tranquilization, vitamin K1, compound vitamin (12) and the like. The phospholipid and bile salt system have good safety and good biocompatibility, and are a biocompatible medium, and are called as physiological excipient.
Chinese patent CN114869848A discloses a butylphthalide micelle composition, which may be injection or freeze-dried powder for injection, and the raw materials include butylphthalide, phospholipid, cholic acid or its salt, stabilizer and organic solvent. In the patent, butylphthalide, phospholipid or cholic acid/bile salt are dissolved in an organic solvent, and are evaporated in a rotary way to form a loose film, and the loose film is dissolved in a stabilizer solution to obtain a clear solution, and the clear solution is freeze-dried after the volume is fixed. Dissolving butylphthalide, phospholipid or cholic acid/bile salt in organic solvent or mixed solvent of organic solvent and water for injection, lyophilizing, and dissolving lyophilized block with stabilizer solution; although the use of other surfactants such as cyclodextrin is avoided and the clinical safety is improved to some extent, the production safety and recycling of the organic solvent still have problems when the patent method uses an organic solvent.
The Chinese patent CN107970208B discloses a butylphthalide injection and a preparation method thereof, wherein the butylphthalide injection comprises butylphthalide or derivatives thereof, a surfactant and water for injection. The application has the advantages that the dosage of the surfactant is large, and the stability of the injection can be maintained only by adding the stabilizer.
Therefore, the butylphthalide injection in the prior art still has the problems that the safety is influenced by an organic solvent, the kidney is damaged by excessive use of a surfactant such as cyclodextrin, and the butylphthalide injection can be maintained stable for a long time only by adding components such as a stabilizer into the injection, and the influence of the formula of each component in the butylphthalide injection on the quality, stability and efficacy of the injection is not clear, so that the problems are needed to be solved.
Disclosure of Invention
Aiming at the problems existing in the prior art, the application provides a butylphthalide injection and a preparation method thereof, wherein the butylphthalide injection comprises butylphthalide, cholate, phospholipid and water for injection; the concentration of the butylphthalide in the injection is 2.5-10mg/mL, and butylphthalide, cholate and phospholipid are mixed under the condition of certain concentration and mass ratio to prepare the butylphthalide injection of clear solution; the preparation process is simple, the method is suitable for industrial production, the obtained sample has stable quality, high encapsulation efficiency, high safety and good stability, and the clinical medication requirement is met.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows:
in one aspect, the application provides an injection of butylphthalide, comprising the following components: butylphthalide, cholate, phospholipid and water; the molar ratio of the phospholipid to the cholic acid is 0.3-1.2:1.
Preferably, the mass fraction of the butylphthalide in the injection is 0.025% -1%.
Preferably, the mass fraction of the cholic acid in the injection is 0.546% -5.88%.
Preferably, the mass fraction of the phospholipid in the injection is 0.756% -10.67%.
Further preferably, the butylphthalide injection comprises the following components in percentage by mass: 0.5-1% butylphthalide, 4.933-5.918% cholate, 3.51-8.00% phospholipid and the balance water.
Still more preferably, the butylphthalide injection comprises the following components in percentage by mass: 0.5 percent of butylphthalide, 4.933 to 5.918 percent of cholate, 7 to 7.56 percent of phospholipid and the balance of water.
Preferably, the molar ratio of phospholipid to cholic acid is 0.5-0.96:1.
Further preferably, the molar ratio of phospholipid to cholic acid is 0.85:1.
Preferably, the cholate is at least one selected from sodium glycocholate, sodium glycodeoxycholate and sodium taurocholate.
Preferably, the cholate can be a common commercial product or a self-prepared product; the preparation method of the cholate comprises the following steps: mixing cholic acid with sodium hydroxide solution, and stirring.
Further preferably, the method for preparing cholate comprises the steps of: mixing cholic acid with sodium hydroxide solution, heating at 50-65deg.C, and stirring at 200-600 rpm.
Still more preferably, the concentration of the sodium hydroxide solution is 6-50%; the reaction ratio of cholic acid to sodium hydroxide has no significant effect on the technical effect, and the cholic acid reacts with sodium hydroxide in a ratio of about 1:1.
Further preferably, the cholate has a pH of 5.4-5.8; and still more preferably 5.48 to 5.68.
Preferably, the phospholipid is selected from at least one of soybean phospholipid, lecithin and hydrogenated phospholipid.
In the application, the water is water for injection.
In the application, the injection is undiluted, diluted by adding glucose injection or diluted by water for injection.
In another aspect, the present application provides a method for preparing the injection of butylphthalide, comprising the steps of:
(1) Mixing cholate solution with phospholipid and butylphthalide, and stirring to obtain a mixture system;
(2) The mixture system is kept warm and stands or continuously stirred according to the viscous state to prepare a mixture A;
(3) Mixing the mixture A with part of water, and stirring to obtain a mixture B;
(4) And (3) fixing the volume of the mixture B, filtering, and filling to obtain the butylphthalide injection.
Preferably, in step (1), the cholate solution has a pH of 5.4-5.8.
Further preferably, the cholate solution has a pH of 5.48-5.68.
Preferably, in the step (1), the stirring temperature is 25-70 ℃, the stirring rotating speed is 200-600rpm, and the stirring time is 10-20min.
Preferably, in step (2), the viscous state is divided into a mixture system which is in a viscous state or in a solution state; when the mixture is in a sticky state, keeping the temperature at 50-65 ℃ and standing for 1-12h; when the solution is in a solution state, the temperature is kept and stirring is continued for 3 to 21 hours.
Preferably, in the step (3), the mixture A and part of water are mixed, the mixing is carried out in batches, the number of batches is 1-3, the volume of the mixture B is 75-85% of the total volume of the injection finished product of butylphthalide, and the operation temperature of the step (3) is 25-90 ℃.
Further preferably, the mixture A is firstly mixed with part of water and stirred into a solution state, and stirring is continued for 1-16h; then mixing the mixture with the rest water until the volume of the mixture B is 75-85% of the total volume of the finished injection product of butylphthalide, and adjusting the pH value of the mixture B to 4.5-6.5; the rotation speed of the continuous stirring is 200-1200rpm.
Still more preferably, the substance for adjusting the pH of the mixture B is at least one selected from a sodium hydroxide solution and a hydrochloric acid solution.
Preferably, in step (4), the filtration is through a 0.2 μm pes filter.
After filling, the application can carry out terminal sterilization, and the sterilization is maintained for 10-20min at 110-130 ℃.
In the step (3) of the application, before the mixture B is mixed with the rest of water until the volume of the mixture B is 75-85% of the total volume of the finished injection product of butylphthalide, if a large amount of foam exists, standing and defoaming are needed.
In the application, the specification of the filling is 2.5-100 mL/branch.
In the present application, the injection may be an undiluted injection, an injection diluted with glucose injection, or an injection diluted with water for injection.
Compared with the prior art, the application has the following beneficial effects:
1. the injection of butylphthalide prepared by the application does not use cyclodextrin and other synthetic surfactants, and does not add stabilizer components, and does not add organic solvent in the process of preparing the injection; the application can prepare the injection of butylphthalide with stable property, stable grain diameter, high quality, low cost and high safety performance by using water for injection, which is easy to be diluted by the common diluent in the field and does not influence the quality of the injection.
2. According to the injection of butylphthalide, the stability of the injection is improved and the demulsification phenomenon is reduced under the action of a certain concentration and mass ratio of butylphthalide, cholate and phospholipid; meanwhile, cholic acid and phospholipid in cholate are synergistic in a certain molar ratio, so that the solubility and stability of the injection are improved, and meanwhile, the bioavailability and the encapsulation rate of the medicine are improved.
3. The injection of butylphthalide of the application has high content and can be split-packed into small-volume preparations, thereby meeting the clinical administration requirement; meanwhile, the injection disclosed by the application is simple in preparation process, and the stability of the injection is further improved by utilizing multiple dissolution and stirring; the preparation method provided by the application has strong operability and is beneficial to industrialization.
Drawings
FIG. 1 is a graph showing the particle size distribution of a butylphthalide injection according to example 1 of the present application;
FIG. 2 is a graph showing the particle size distribution of butylphthalide injection according to example 2 of the present application;
FIG. 3 is a graph showing the particle size distribution of the injection solution of butylphthalide in example 3 of the present application;
FIG. 4 is a graph showing the particle size distribution of the injection solution of butylphthalide of example 4 of the present application;
FIG. 5 is a graph showing the particle size distribution of the injection solution of butylphthalide of example 5 of the present application;
FIG. 6 is a graph showing the particle size distribution of the injection solution of butylphthalide 4 of comparative example of the present application;
FIG. 7 is a graph showing the particle size distribution of an intermediate before sterilization of a butylphthalide injection of the present application.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the application and are not intended to limit the application in any way. The following is merely exemplary of the scope of the application as it is claimed and many variations and modifications of the application will be apparent to those skilled in the art in light of the disclosure, which should be considered as falling within the scope of the application as claimed. Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The application is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present application were obtained by conventional commercial means unless otherwise specified. In the application, reagent products of different manufacturers have no significant influence on the effect.
Example 1
The molar ratio of soybean phosphatidylcholine to glycocholic acid was varied to be 0.3:1 (example 1-1), 0.48:1 (example 1-2), 0.5:1 (example 1-3), 0.64:1 (example 1-4), 0.70:1 (example 1-5), 0.70:1 (example 1-6), 0.85:1 (example 1-7), 0.96:1 (example 1-8) and 1.2:1 (example 1-9), respectively.
The composition of the butylphthalide injection (5 mL) and the butylphthalide drug injection product (20 pieces) is specifically shown as follows:
(1) a method for preparing butylphthalide injection when the mole ratio of soybean phosphatidylcholine to glycocholic acid is 0.3:1 (example 1-1), 0.48:1 (example 1-2), 0.5:1 (example 1-3), 0.64:1 (example 1-4) and 0.70:1 (example 1-5), respectively, comprises the steps of:
(1) Weighing sodium hydroxide with a prescription amount, adding a proper amount of water for injection to dissolve, adding glycocholic acid with a prescription amount, and stirring at 200rpm to dissolve to obtain cholate solution;
(2) Weighing soybean phospholipid and butylphthalide with prescription amount, and continuously stirring in the cholate solution for 4 hours to obtain a mixture A;
(3) After the mixture A is kept stand, continuously adding water for injection to about 80% of the total volume, and measuring pH to prepare a mixture B;
(4) Continuously adding water for injection to 100mL, filtering and filling with 0.2 mu m PES filter membrane, and obtaining 5 mL/branch colorless and clear butylphthalide injection;
(5) Sterilizing the injection at 121deg.C for 15min to obtain sterilized butylphthalide injection.
(2) A preparation method of butylphthalide injection when the mole ratio of soybean phosphatidylcholine to glycocholic acid is 0.70:1 (examples 1-6), 0.85:1 (examples 1-7), 0.96:1 (examples 1-8) and 1.2:1 (examples 1-9) respectively comprises the following steps:
(1) Weighing sodium hydroxide with a prescription amount, adding a proper amount of water for injection to dissolve, adding glycocholic acid with a prescription amount, and stirring at 200rpm to dissolve to obtain cholate solution;
(2) Weighing soybean phospholipid and butylphthalide with prescription amount, and continuously stirring in the cholate solution for about 15min to obtain a mixture A;
(3) After the mixture A is kept stand for 4 hours, continuously adding water for injection to about 80% of the total volume, and measuring the pH value to obtain a mixture B;
(4) Continuously adding water for injection to 100mL, filtering and filling with 0.2 mu m PES filter membrane, and obtaining 5 mL/branch colorless and clear butylphthalide injection;
(5) Sterilizing the injection at 121deg.C for 15min to obtain butylphthalide injection.
Example 2
Unlike examples 1 to 7, the temperature in step (1) was 25℃at ordinary temperature. The remainder were the same as in examples 1-7.
The prepared butylphthalide injection before and after sterilization is clear and stable injection.
Example 3
The amounts of water for injection in step (1) were changed to 6mL (example 3-1), 12mL (example 3-2), 26mL (example 3-3), 40mL (example 3-4) and 50mL (example 3-5), respectively.
Butylphthalide injection (5 mL), butylphthalide drug injection product (20 pieces) are composed of:
the remaining parameters and preparation methods of example 3-1 are the same as those of example 1-7, example 3-2, example 3-3, example 3-4, example 3-5, example 3-6, and example 1-1.
Example 4
The stirring time in step (2) of the preparation method was changed to 1h (example 4-1), 3h (example 4-2), 4h (example 4-3), 6h (example 4-4) and 21h (example 4-5), respectively, and the remaining parameters and preparation method were the same as in example 1-1. The prepared butylphthalide injection is clear and stable injection.
Butylphthalide injection (5 mL), butylphthalide drug injection product (20 pieces) are composed of:
example 5
The prescribed amounts of butylphthalide in step (2) were changed to 0.25mg/mL (example 5-1), 2.5mg/mL (example 5-2), 5mg/mL (example 5-3) and 10mg/mL (example 5-4), respectively.
The preparation method of the butylphthalide injection comprises the following steps:
the steps of the preparation methods of examples 5-2, 5-3 and 5-4 are the same as those of examples 1-7;
in the preparation method of example 5-1, the mixture B in the step (4) is continuously added with water for injection, the volume is fixed to 1000mL, a 0.2 mu m PES filter membrane is filtered and filled, 10 mL/branch is colorless and clear, and the rest steps are the same as those in examples 1-7.
Example 6
The pH in step (3) was changed to 4.5 (example 6-1), 5.0 (example 6-2), 5.5 (example 6-3), 6.0 (example 6-4) and 6.5 (example 6-5), respectively, and the remaining parameters and preparation methods were the same as in examples 1-7.
The prepared butylphthalide injection before and after sterilization is clear and stable injection.
Comparative example 1
The molar ratio of soybean phosphatidylcholine to glycocholic acid is respectively glycocholic acid single auxiliary material (comparative example 1-1), 0.2:1 (comparative example 1-2) and 1.5:1 (comparative example 1-3).
Butylphthalide injection (5 mL), butylphthalide drug injection product (20 pieces) is composed of:
when the mole ratio of the soybean phosphatidylcholine to the glycocholic acid is respectively the single auxiliary material of the glycocholic acid (comparative example 1-1) and 0.2:1 (comparative example 1-2), the preparation method steps are the same as those of example 1-1;
the procedure was as in examples 1-7, when the molar ratio of soybean phosphatidylcholine to glycocholic acid was 1.5:1 (comparative examples 1-3), respectively.
Comparative example 2 differs from examples 1 to 7 in the drug concentration of butylphthalide, the mass fraction of each component, and the molar ratio of soybean phospholipid to glycocholic acid, specifically:
the preparation method and other parameters of the butylphthalide injection are the same as those of examples 1-7.
Comparative example 3
Butylphthalide injection (5 mL), butylphthalide drug injection product (20 pieces) is composed of:
component (A) Weight g Mass fraction of the components, percent
Sodium hydroxide 0.116 0.116
Glycocholic acid 1.388 1.388
Soybean lecithin 3.496 3.496
Butylphthalide 0.5 0.5
Total proportion of auxiliary materials 4.884 4.884
Water for injection Make up to 100mL Allowance of
Among the components, the concentration of butylphthalide is 5mg/mL (mass fraction is 0.5%), and the molar ratio of soybean phospholipid to glycocholic acid is 0.8:1; the mass ratio of the glycocholic acid to the butylphthalide is 2.776:1.
The preparation method of the butylphthalide injection comprises the following steps:
(1) Weighing the prescription amount of sodium hydroxide into a three-necked flask, adding 5mL of water for injection to dissolve, adding the prescription amount of glycocholic acid, heating at 60 ℃, and mechanically stirring at about 200rpm to dissolve to obtain cholate solution, wherein the pH value of the solution is 5.66;
(2) Weighing soybean phospholipid and butylphthalide with prescription amount, and stirring in the cholate solution for 40min to obtain a mixture A;
(3) Mixture a was left to stand overnight, still in the form of a viscous emulsion; 12mL of water for injection was added and stirring was continued at 60℃for 5h, still in the form of a viscous emulsion after standing.
Comparative example 4
Mannitol is added, specifically: butylphthalide injection (5 mL), butylphthalide drug injection product (20 pieces) is composed of:
among the above components, butylphthalide drug concentration is 5.0mg/mL (mass fraction is 0.5%).
The preparation method of the butylphthalide injection comprises the following steps:
(1) Same as in examples 1-7;
(2) Weighing soybean phospholipid, butylphthalide and mannitol with prescription amounts, and continuously stirring at 200rpm in the cholate solution in the step (1) for 4 hours to prepare a mixture A;
(3) - (4) the same as in examples 1 to 7.
The prepared butylphthalide injection before and after sterilization is clear and stable injection.
Test 1 particle size distribution
Detecting particle size before and after sterilization of the prepared butylphthalide injection by using a Markov ZETASIZER PRO nanometer particle size analyzer, and setting detection parameters:
Material:Polystyrene latex(RI:1.59，Absorption:0.01)；
Dispersant:water(Temperature:25℃，RI：1.330)；
Cell Name:DTS0012。
the particle size distribution of the butylphthalide injection is shown in the following table 1.
TABLE 1
As can be seen from the above table 1, the butylphthalide injection of the present application has small particle size change before and after sterilization, and the butylphthalide injection has high temperature resistance and stability. In table 1, peak1 represents the first Peak; peak2 represents the second Peak; peak3 represents the third Peak. When the mole ratio of soybean phospholipid to glycocholic acid is 0.20:1, the butylphthalide injection is turbid, and the particle size cannot be detected; when the molar ratio of soybean phospholipid to glycocholic acid is 1.5:1, the butylphthalide injection is turbid, and the particle size cannot be detected.
The results of the particle size distribution detection of the butylphthalide injection of example 3 are shown in Table 2 below, and when the amount of water for injection in step (1) is 60mL (60% by volume of total), the butylphthalide injection is cloudy and cannot be detected.
TABLE 2
The particle size distribution of the butylphthalide injection of example 4 is shown in Table 3 below.
TABLE 3 Table 3
The particle size distribution of the butylphthalide injection of example 5 is shown in Table 4 below.
TABLE 4 Table 4
Drawing particle size distribution diagrams of butylphthalide injection solutions of examples and comparative examples, wherein the particle size distribution diagram of the butylphthalide injection solution of example 1 is shown in figure 1; example 2 the particle size distribution of butylphthalide injection is shown in figure 2; example 3 particle size distribution of butylphthalide injection is shown in figure 3; example 4 particle size distribution of butylphthalide injection is shown in figure 4; example 5 particle size distribution of butylphthalide injection is shown in figure 5; the particle size distribution diagram of the butylphthalide injection of comparative example 4 is shown in fig. 6; FIG. 7 is a graph showing the particle size distribution of an intermediate before sterilization of a butylphthalide injection of the present application.
The injection prepared in comparative example was an emulsion or a turbid liquid, and a stable solution was not formed, so it was not necessary to examine the particle size and stability of the injection.
Test 2 dilution stability test
The butylphthalide injection of the examples and the comparative examples were diluted 20 times with 0.9% sodium chloride injection, respectively; the diluted solution was diluted 20 times with 5% glucose injection, and after 9 hours, the appearance stability was observed, and the detection results are shown in table 5:
TABLE 5
As can be seen from the above Table 5, the injection of butylphthalide of the present application maintains high particle size stability after 20-fold dilution with 5% glucose injection.
Summarizing:
1. clarifying the molar ratio of the phosphatidylcholic acid in the range of 0.3-1.2;
2. according to the particle size distribution, the molar ratio of the phospholipid cholic acid is distributed more intensively within the range of 0.7-1.2;
3. according to the result of a dilution test of the 0.9% sodium chloride injection, the injection prepared by a prescription with smaller total auxiliary material amount or smaller mixed micelle amount forming the mole ratio of phospholipid bile salt is preliminarily estimated to be in a clearer state after the 0.9% sodium chloride injection is diluted;
4. according to the particle size distribution of the intermediate and the particle size distribution after sterilization, the particle size distribution before and after sterilization has no obvious difference;
5. clear and transparent injection can be prepared at the preparation temperature of 25-90 ℃ respectively, no obvious difference exists between the particle size distribution of the injection and the prescription, but the injection needs to be prepared overnight at the preparation temperature of 25 ℃ and takes longer time, so that the optimal temperature is 60 ℃;
6. the initial water quantity is 6-50% of the total volume, and clear injection can be prepared;
7. the concentration range of the encapsulated drug is 2.5-10mg/mL;
8. stirring and reacting the raw materials for more than 1h after feeding, so as to prepare clear injection;
9. the addition of mannitol has no obvious effect on the stability of the injection.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present application, and not for limiting the scope of the present application, and that the simple modification and equivalent substitution of the technical solution of the present application can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present application.

Claims (10)

1. An injection of butylphthalide, which is characterized by comprising the following components: butylphthalide, cholate, phospholipid and water; the molar ratio of the phospholipid to the cholic acid is 0.3-1.2:1.
2. The injection according to claim 1, wherein the mass fraction of butylphthalide in the injection is 0.025% -1%.
3. The injection according to claim 1, wherein the mass fraction of cholic acid in the injection is 0.546% -5.88%.
4. An injection according to any one of claims 1 to 3, comprising the following components in mass fraction: 0.5 to 1 percent of butylphthalide, 4.933 to 5.918 percent of cholate, 3.51 to 8.00 percent of phospholipid and the balance of water.
5. The injection according to claim 1, wherein the molar ratio of phospholipid to cholic acid is 0.5-0.96:1.
6. The injection according to claim 1, wherein the cholate is at least one selected from sodium glycocholate, sodium glycodeoxycholate, sodium taurocholate; the phospholipid is at least one selected from soybean phospholipid, lecithin and hydrogenated phospholipid.
7. The method for preparing the injection according to any one of claims 1 to 6, comprising the steps of:
(1) Mixing cholate solution with phospholipid and butylphthalide, and stirring to obtain a mixture system;
(2) The mixture system is kept warm and stands or continuously stirred according to the viscous state to prepare a mixture A;
(3) Mixing the mixture A with part of water, and stirring to obtain a mixture B;
(4) And (3) fixing the volume of the mixture B, filtering and filling to obtain injection of butylphthalide.
8. The method of claim 7, wherein in step (1), the cholate solution has a pH of 5.4-5.8; in the step (1), stirring is carried out at 25-70 ℃ for 10-20min; in the step (2), the viscous state is divided into a mixture system which is in a viscous state or a solution state; when the mixture is in a sticky state, keeping the temperature at 50-65 ℃ and standing for 1-12h; when the solution is in a state, keeping the temperature and continuing stirring for 3-21h; in the step (3), the mixture A is mixed with part of water until the volume of the mixture B is 75-85% of the total volume of the finished injection of butylphthalide, and the operation temperature of the step (3) is 25-90 ℃.
9. The method of claim 8, wherein in step (1), the cholate solution has a pH of 5.48-5.68; in the step (3), the mixture A is firstly mixed with part of water and stirred into a solution state, and stirring is continued for 1-16h; then mixing the mixture with the rest water until the volume of the mixture B is 75-85% of the total volume of the finished injection product of butylphthalide, and adjusting the pH value of the mixture B to 4.5-6.5; the rotation speed of the continuous stirring is 200-1200rpm; in step (4), the filtration is performed through a 0.2 μm PES filter.
10. The injection according to claim 1, wherein the injection is an undiluted injection, an injection diluted with glucose injection, or an injection diluted with water for injection.
CN202311040362.9A 2023-08-16 2023-08-16 Butylphthalide injection and preparation method thereof Pending CN116942604A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311040362.9A CN116942604A (en) 2023-08-16 2023-08-16 Butylphthalide injection and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311040362.9A CN116942604A (en) 2023-08-16 2023-08-16 Butylphthalide injection and preparation method thereof

Publications (1)

Publication Number Publication Date
CN116942604A true CN116942604A (en) 2023-10-27

Family

ID=88458388

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311040362.9A Pending CN116942604A (en) 2023-08-16 2023-08-16 Butylphthalide injection and preparation method thereof

Country Status (1)

Country Link
CN (1) CN116942604A (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112870160A (en) * 2021-02-01 2021-06-01 江苏华阳制药有限公司 Novel fat-soluble vitamin mixed micelle injection and preparation method thereof
CN114869848A (en) * 2022-05-20 2022-08-09 济南大学 Butylphthalide micelle composition and preparation process thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112870160A (en) * 2021-02-01 2021-06-01 江苏华阳制药有限公司 Novel fat-soluble vitamin mixed micelle injection and preparation method thereof
CN114869848A (en) * 2022-05-20 2022-08-09 济南大学 Butylphthalide micelle composition and preparation process thereof

Similar Documents

Publication Publication Date Title
DE69805070T2 (en) ITRACONAZOLE WITH AN IMPROVED SOLUBILITY, A METHOD FOR THE PRODUCTION THEREOF AND A PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION CONTAINING THIS
DE60214012T2 (en) PROCESS FOR PREPARING CRYSTALLINE MEDICINAL PACKAGING BY EXPANSION
AU2010312021B2 (en) A submicron emulsion of paclitaxel using steroid complex as intermediate carrier
CN100415221C (en) Method for preparing curcumin lyophilized liposome
EA006241B1 (en) Amphotericin b aqueous composition
US20130150335A1 (en) Paclitaxel/steroidal complex
CN101612121A (en) The preparation of microemulsion containing paclitaxel method
CN110772482A (en) Emulsion of high proportion emulsifier and preparation method thereof
CN104721155B (en) A kind of temozolomide freeze-dried powder preparation and preparation method thereof
CN101524329A (en) Bicyclo-ethanol submicron emulsion and preparation method thereof
CN113181114B (en) Hesperetin emulsion and preparation method thereof
US20190336922A1 (en) Process for producing a nano resveratrol microemulsion system
CN111643451B (en) Honokiol self-emulsifying microemulsion preparation for injection and preparation method thereof
CN116942604A (en) Butylphthalide injection and preparation method thereof
CN110392567A (en) Fat emulsion and its manufacturing method containing drug
CN111388419A (en) Aprepitant emulsion
CN115501180A (en) Methotrexate fat emulsion injection and preparation method thereof
CN101491495B (en) Salvianolic acid B magnesium injection, preparation method and use thereof
CN109414407A (en) Smectite suspension composition and preparation method thereof
CN104288110B (en) 5alpha-androstane-3beta,5,6beta-triol injection and preparing method thereof
CN107157926B (en) Preparation method of docetaxel injection
CN110548004B (en) Stable butylphthalide high-capacity injection and preparation method thereof
RU2500396C2 (en) Agent showing cardioprotective action, and method for preparing it
CN107789324A (en) A kind of injection De Lasha star meglumines and preparation method thereof
JP4475405B2 (en) Pharmaceutical composition

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20231027