CN118453673A - Method for preparing brucea javanica oil composition and application thereof - Google Patents
Method for preparing brucea javanica oil composition and application thereof Download PDFInfo
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- CN118453673A CN118453673A CN202410655507.4A CN202410655507A CN118453673A CN 118453673 A CN118453673 A CN 118453673A CN 202410655507 A CN202410655507 A CN 202410655507A CN 118453673 A CN118453673 A CN 118453673A
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- brucea javanica
- javanica oil
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- 235000010889 Rhus javanica Nutrition 0.000 title claims abstract description 187
- 239000000203 mixture Substances 0.000 title claims abstract description 74
- 241001533159 Brucea javanica Species 0.000 title claims abstract 26
- 238000000034 method Methods 0.000 title abstract description 31
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 60
- 239000009969 fructus bruceae Substances 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims description 40
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 25
- 239000008347 soybean phospholipid Substances 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
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- 239000002775 capsule Substances 0.000 claims description 2
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- 239000000843 powder Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
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- 208000004852 Lung Injury Diseases 0.000 claims 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
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- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 206010039083 rhinitis Diseases 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- 206010018910 Haemolysis Diseases 0.000 abstract description 82
- 230000008588 hemolysis Effects 0.000 abstract description 82
- 229940083466 soybean lecithin Drugs 0.000 abstract description 47
- 210000003743 erythrocyte Anatomy 0.000 abstract description 25
- 230000002776 aggregation Effects 0.000 abstract description 22
- 238000004220 aggregation Methods 0.000 abstract description 19
- 238000002156 mixing Methods 0.000 abstract description 14
- 244000097577 Rhus javanica Species 0.000 description 161
- 239000000839 emulsion Substances 0.000 description 128
- 238000002347 injection Methods 0.000 description 125
- 239000007924 injection Substances 0.000 description 125
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 230000015271 coagulation Effects 0.000 description 13
- 238000005345 coagulation Methods 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
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- 238000002474 experimental method Methods 0.000 description 7
- 238000005189 flocculation Methods 0.000 description 7
- 230000016615 flocculation Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 6
- 244000046052 Phaseolus vulgaris Species 0.000 description 5
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 5
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- 239000011780 sodium chloride Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 229940067606 lecithin Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 3
- 238000005054 agglomeration Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
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- 239000000706 filtrate Substances 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000158621 Brucea Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 230000008859 change Effects 0.000 description 1
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- 239000007857 degradation product Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical class Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
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Abstract
The invention provides a method for preparing a brucea javanica oil composition and application thereof, wherein the method for preparing the brucea javanica oil composition comprises the following steps: mixing refined soybean lecithin with pH value of 7.0-8.0 with oleum fructus Bruceae. The pH value of the brucea javanica oil composition prepared by the method is 6.2-7.9 within 24 months, namely the pH value of the brucea javanica oil composition has small fluctuation within 24 months, the quality stability and the product safety are obviously improved, and hemolysis or erythrocyte aggregation can not be caused.
Description
The invention relates to a division application of a parent application with the application number 202111467497.4, the application date of the parent application is 2021, 12 and 03, and the name of the parent application is a method for preparing a brucea javanica oil composition and application of the brucea javanica oil composition.
Technical Field
The invention relates to the technical field of medicines, in particular to a method for preparing a brucea javanica oil composition and application thereof, and more particularly relates to the brucea javanica oil composition, a method for preparing the brucea javanica oil composition and a pharmaceutical composition.
Background
Hemolysis (Hemolysis) refers to the rupture of red blood cells, the escape of hemoglobin is called erythrolysis, abbreviated as hemolysis. The isotonic solution of human plasma is 0.9% NaCl solution, and red blood cells are broken and hemoglobin escapes in less than 0.45% NaCl solution due to water infiltration and swelling of red blood cells. In humans, hemolysis can be caused by hemolytic bacteria or certain snake venom invasion, antigen-antibody reaction (e.g., blood with poor blood transfusion), various mechanical injuries, defects in erythrocytes (membrane, enzyme), certain drugs, etc.
For some Chinese medicinal injection, due to the fact that the injection contains hemolysis components (such as saponin) or physical, chemical and biological reasons, hemolysis can be generated after direct injection into blood vessels; some injections contain impurities and other components, so that local injection can cause swelling pain, blood cell aggregation can be generated after the injection is injected into blood vessels, and adverse reactions such as blood circulation dysfunction and the like are caused; in addition, because of the complex components of the Chinese medicinal preparation, there is also immune hemolysis caused by immune reaction.
The brucea javanica oil emulsion injection is prepared by extracting brucea javanica oil with petroleum ether, mixing with soybean lecithin and glycerol, and mixing with water for injection. The specific preparation method refers to the preparation method of the brucea javanica oil emulsion injection described in a fourteenth book of Chinese medicinal prescription preparation WS 3-B-2739-97: namely, 15g of refined soybean lecithin and 25ml of warm glycerin are taken and mixed with a certain mass of water for injection, and then the mixture is transferred into a high-speed tissue masher, and is stirred twice at 8000 revolutions per minute for 5 minutes for 2 minutes for the first time, so that the mixture is uniformly dispersed. Adding warm refined oleum fructus Bruceae 100ml, stirring for 3 times and 2 min each time to obtain primary emulsion, adding injectable water to 1000ml, homogenizing in high pressure homogenizing machine (40 MPa) for three times, filtering, collecting filtrate, packaging, and sterilizing.
The brucea javanica oil emulsion injection is developed by the university of Shenyang medical science Yao Chongshun teaching scientific research team in 1976, and is marketed in 1987, and the anti-tumor traditional Chinese medicine injection for treating lung cancer, brain metastasis of lung cancer and digestive tract tumor is widely trusted by clinical medical staff and patients until now.
Although the brucea javanica oil emulsion injection has good treatment effect, limited by the development of medicine technology during research and development and the common two sides of medicines, the brucea javanica oil emulsion injection also has some adverse reactions which are increasingly highlighted along with the development of social economy and the improvement of the living standard of people, and hemolysis is a quality risk which is difficult to be ignored by the brucea javanica oil emulsion injection.
This is mainly because the brucea javanica oil emulsion injection contains refined soybean phospholipids in addition to the mixed component brucea javanica oil. The refined soybean lecithin is the same as soybean lecithin, and has the main component of Phosphatidylcholine (PC), and also contains a small amount of Phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), lysophosphatidyl and the like, wherein the lysophosphatidyl is a main degradation product of the phosphatidylcholine and has the function of hemolyzing or dissolving cell membranes. Meanwhile, the refined soybean lecithin can be easily hydrolyzed in storage after being prepared into emulsion, and Lysophosphatidylcholine (LPC) is generated, so that the brucea javanica oil emulsion injection liquid has a hemolysis phenomenon in an external hemolysis test, and the brucea javanica oil emulsion injection liquid is indicated to have a relatively high risk of hemolysis in clinical use.
In the preparation process, in order to avoid hemolysis of the brucea javanica oil emulsion injection in clinical use as much as possible, a hemolysis test is carried out in quality control of the product, and the hemolysis test result is judged by formulating corresponding indexes, so that whether the product has hemolysis risk in future clinical use is predicted to a producer, and if the hemolysis test result does not meet the standard specification, the corresponding product is not allowed to flow into the market, thereby reducing the hemolysis risk of the brucea javanica oil emulsion injection in clinical use.
The method for controlling the hemolysis risk of the brucea javanica oil emulsion injection in clinical use is to monitor the quality of the product, and not to improve the quality of the product, so that the condition that the brucea javanica oil emulsion is easy to cause hemolysis in production and storage is not improved at all.
In order to solve the problem, the most basic idea is to solve the hemolysis risk of the brucea javanica oil emulsion injection by improving certain processes or production parameters affecting the hemolysis risk in the production of the brucea javanica oil emulsion injection. However, because the brucea javanica oil emulsion injection is a mixture of multiple components, and the emulsion belongs to a complex preparation, both of which make it very difficult to obtain a qualified and stable product in commercial mass production, the production process and the drug administration for changing the prescription of the preparation can be carefully treated, and a considerable amount of non-clinical and clinical research and funds are generally required to be further invested.
Therefore, on the premise of ensuring that the original production process and the preparation prescription of the brucea javanica oil emulsion injection are not changed, the risk of hemolysis of the brucea javanica oil emulsion injection is reduced, and the method is a main problem for solving the clinical safety of the brucea javanica oil emulsion injection.
Disclosure of Invention
The present application has been made based on the findings and knowledge of the inventors of the following problems:
The brucea javanica oil emulsion injection is mainly prepared from brucea javanica oil and refined soybean lecithin, wherein the refined soybean lecithin is soybean lecithin which is prepared into the injection after treatment, and the refined soybean lecithin is easy to hydrolyze in the storage process after being prepared into emulsion to generate lysophosphatidylcholine, so that the brucea javanica oil emulsion injection has a hemolysis phenomenon in an external hemolysis test, thereby influencing the stability of the brucea javanica oil emulsion injection. Through a great deal of experimental research, the inventor creatively discovers that the pH value of the refined soybean lecithin has an important influence on the stability of the brucea javanica oil emulsion injection, when the pH value of the refined soybean lecithin is within a certain range, the stability of the brucea javanica oil emulsion injection is obviously improved, the fluctuation of the pH value is smaller, and the risks of hemolysis and erythrocyte aggregation in clinical use are obviously reduced.
Thus, in a first aspect of the present invention, the present invention proposes a brucea javanica oil composition. According to an embodiment of the invention, it comprises: refined soybean phospholipid and oleum fructus bruceae, wherein the pH value of the refined soybean phospholipid is 7.0-8.0, the oleum fructus bruceae meets the standard of oleum fructus brucease in fourteenth book of Chinese medicinal prescription preparation WS3-B-2739-97, and the mass volume ratio of the refined soybean phospholipid to the oleum fructus brucea is 3g:20mL. The brucea javanica oil composition provided by the embodiment of the invention has higher stability in 24 months, 18 months and 15 months, lower hemolysis risk and higher safety and quality stability than that of the brucea javanica oil composition with the pH regulated by the pH regulator.
According to an embodiment of the present invention, the above brucea javanica oil composition may further include at least one of the following additional technical features:
According to an embodiment of the present invention, the pH of the oleum fructus bruceae composition is 6.2-7.9 within 24 months. The pH regulator can be used for regulating the pH of the brucea javanica oil emulsion injection and delaying the occurrence of hemolysis of the brucea javanica oil emulsion injection, but the hemolysis risk of the brucea javanica oil emulsion injection can not be fundamentally overcome, and the hemolysis phenomenon occurs at the 15 th month. The brucea javanica oil composition provided by the embodiment of the invention can still maintain higher pH within 24 months, the fluctuation of the pH within 24 months is within the range of 6.2-7.9, the fluctuation is small, the stability of the brucea javanica oil composition is obviously improved, the risk of hemolysis or erythrocyte aggregation during clinical application is reduced, the safety is still good within 24 months, and the safety and the quality stability are obviously higher than those of the brucea javanica oil composition with the pH regulated by the pH regulator.
According to an embodiment of the present invention, the pH of the oleum fructus bruceae composition is 6.2-7.9 within 18 months. The pH regulator can be used for regulating the pH of the brucea javanica oil emulsion injection and delaying the occurrence of hemolysis of the brucea javanica oil emulsion injection, but the hemolysis risk of the brucea javanica oil emulsion injection can not be fundamentally overcome, and the hemolysis phenomenon occurs at the 15 th month. According to the brucea javanica oil composition provided by the embodiment of the invention, the higher pH can be maintained within 18 months, the fluctuation of the pH within 18 months is within the range of 6.2-7.9, the fluctuation is small, the stability of the brucea javanica oil composition is obviously improved, the risk of hemolysis or erythrocyte aggregation during clinical application is reduced, and the good safety is still maintained within 18 months.
According to an embodiment of the present invention, the pH of the oleum fructus bruceae composition is 6.2-7.9 within 15 months. The pH regulator can regulate the pH of the brucea javanica oil emulsion injection, delay the occurrence of hemolysis of the brucea javanica oil emulsion injection, but still can not fundamentally overcome the hemolysis risk of the brucea javanica oil emulsion injection, and the hemolysis phenomenon occurs at the 15 th month. According to the brucea javanica oil composition provided by the embodiment of the invention, the higher pH can still be maintained within 15 months, the fluctuation of the pH within 15 months is within the range of 6.2-7.9, the fluctuation is small, the stability of the brucea javanica oil composition is obviously improved, the risk of hemolysis or erythrocyte aggregation during clinical application is reduced, and the product still maintains good safety within 15 months.
According to an embodiment of the present invention, the pH of the oleum fructus bruceae composition is 6.2-7.9 within 12 months. According to the brucea javanica oil composition provided by the embodiment of the invention, the higher pH can still be maintained within 12 months, the fluctuation of the pH within 12 months is within the range of 6.2-7.9, the fluctuation is small, the stability of the brucea javanica oil composition is obviously improved, the risk of hemolysis or erythrocyte aggregation during clinical application is reduced, and the product still maintains good safety within 12 months.
According to an embodiment of the present invention, the pH of the oleum fructus bruceae composition is 6.2-7.9 within 6 months. According to the brucea javanica oil composition disclosed by the embodiment of the invention, the higher pH can still be kept within the period of 6 months, the fluctuation of the pH within the period of 6 months is within the range of 6.2-7.9, the fluctuation is small, the stability of the brucea javanica oil composition is obviously improved, and the risk of hemolysis or erythrocyte aggregation is reduced.
According to the embodiment of the invention, the brucea javanica oil composition is brucea javanica oil emulsion injection.
According to an embodiment of the present invention, the oleum fructus bruceae composition further comprises glycerol.
According to an embodiment of the present invention, the volume ratio of the glycerol to the oleum fructus bruceae is 1:4.
According to the embodiment of the invention, the pH value of the brucea javanica oil emulsion injection is 6.8-7.9. When the preparation of the brucea javanica oil emulsion injection is finished, namely the initial pH value is in the range of 6.8-7.9, the pH value fluctuation of the brucea javanica oil emulsion injection is smaller within 24 months, the higher pH value can be maintained, the stability is obviously improved, and the risk of hemolysis or erythrocyte aggregation is lower in clinical application.
According to the embodiment of the invention, the pH value of the brucea javanica oil emulsion injection is 6.8-7.8. When the preparation of the brucea javanica oil emulsion injection is finished, namely the initial pH value is in the range of 6.8-7.8, the pH value fluctuation of the brucea javanica oil emulsion injection is very small within 24 months, the higher pH value can be maintained, the stability is obviously improved, and the risk of hemolysis or erythrocyte aggregation is low in clinical application.
According to the embodiment of the invention, the pH value of the brucea javanica oil emulsion injection is 7.1-7.8. When the preparation of the brucea javanica oil emulsion injection is finished, namely the initial pH value is in the range of 7.1-7.8, the pH value fluctuation of the brucea javanica oil emulsion injection is very small within 24 months, the higher pH value can be maintained, the stability is remarkably improved, and the risk of hemolysis or erythrocyte aggregation is low in clinical application.
According to the embodiment of the invention, the content of oleic acid in the brucea javanica oil emulsion injection is 9-12%. The brucea javanica oil emulsion injection obtained according to the embodiment of the invention is detected according to the standard of traditional Chinese medicine formulation fourteenth volume WS3-B-2739-97, and other projects are in accordance with standard regulations except for pH value.
In a second aspect of the present invention, the present invention provides a method for preparing the brucea javanica oil composition of the first aspect. According to an embodiment of the invention, it comprises: mixing refined soybean lecithin with pH value of 7.0-8.0 with oleum fructus Bruceae. The pH regulator can be used for regulating the pH of the brucea javanica oil emulsion injection and delaying the occurrence of hemolysis of the brucea javanica oil emulsion injection, but the risk of hemolysis of the brucea javanica oil emulsion injection can not be fundamentally overcome, and the hemolysis occurs at 15 th month after production. Through a great deal of experimental researches, the inventor summarizes that the pH value of the refined soybean lecithin has an important influence on the stability of the brucea javanica oil composition, the pH value of the brucea javanica oil composition obtained by mixing the refined soybean lecithin with the brucea javanica oil, wherein the pH value of the brucea javanica oil composition is 6.2-7.9 within 15 months, 18 months and 24 months, the fluctuation is small, the stability is obviously improved, the stability is still kept good within 24 months, and the safety and the quality stability are obviously higher than those of the brucea javanica oil composition with the pH regulated by a pH regulator.
According to an embodiment of the present invention, the above method may further include at least one of the following additional technical features:
According to the embodiment of the invention, the mass volume ratio of the soybean phospholipid to the brucea javanica oil is 3g:20mL.
According to the embodiment of the invention, the oleum fructus bruceae meets the oleum fructus bruceae standard of the fourteenth book WS3-B-2739-97 of Chinese medicine prescription preparation;
According to an embodiment of the present invention, further comprising mixing with glycerin.
According to the embodiment of the invention, 3g of refined soybean lecithin, glycerol and brucea javanica oil with the pH value of 7.0-8.0: 5mL: a mixing treatment was carried out at a ratio of 20 mL.
In a third aspect of the present invention, the present invention provides a brucea javanica oil composition. According to an embodiment of the present invention, the oleum fructus bruceae composition is obtained by the method of the second aspect. Through a great deal of experimental study, the inventor summarizes that the pH value of the refined soybean lecithin has an important influence on the stability of the brucea javanica oil composition, and according to the method of the second aspect, the pH value of the brucea javanica oil composition obtained by mixing the refined soybean lecithin with the pH value of 7.0-8.0 with the brucea javanica oil is 6.2-7.9 within 15 months, 18 months and 24 months, the fluctuation is small, the stability is obviously improved, good safety is still maintained within 24 months, and the safety and the quality stability are obviously higher than those of the brucea javanica oil composition regulated by a pH regulator.
In a fourth aspect of the invention, the invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the oleum fructus bruceae composition of the first or third aspect. The pharmaceutical composition provided by the embodiment of the invention has the advantages of smaller pH fluctuation, lower risk of causing hemolysis or erythrocyte aggregation, and higher stability and safety.
According to an embodiment of the present invention, the above pharmaceutical composition may further include at least one of the following additional technical features:
According to an embodiment of the present invention, the pharmaceutical composition further comprises: pharmaceutically acceptable adjuvants including at least one of stabilizers, wetting agents, emulsifiers, binders, isotonic agents.
According to an embodiment of the present invention, the pharmaceutical composition is in at least one of a tablet, a granule, a powder, a capsule, a solution, a suspension, a lyophilized preparation.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative of the invention and is not to be construed as limiting the invention.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the present invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise.
The pH value of the intravenous transfusion preparation is required to be equal to or close to that of blood, and generally should be between 4 and 9, and when the pH value of the brucea javanica oil emulsion injection is too low, the brucea javanica oil emulsion injection cannot be used for intravenous transfusion. The pH value of the brucea javanica oil emulsion injection is lower, when the early preparation production technology and the medicinal material planting technology are undeveloped, the pH value of the preparation of the brucea javanica oil emulsion injection is between 4 and 5 after the brucea javanica oil emulsion injection is placed for a period of time, and the pH value of the current brucea javanica oil emulsion injection is between 5 and 5.5 along with the improvement of the brucea javanica medicinal material production technology and the improvement of the brucea javanica oil production technology. In production practice, the inventors found that even though the pH of the brucea javanica oil emulsion injection is already at the pH recommended for intravenous infusion preparations, there is a risk of hemolysis during long-term placement of the drug.
In response to this problem, scientists have proposed a solution to the problem, wherein adjusting the pH of intravenous solutions to a suitable range is a commonly practiced approach. For the brucea javanica oil emulsion injection, the pH regulator is often alkaline substances such as NaOH, but because the brucea javanica oil contains multiple components and has complex active ingredients, the pH of the brucea javanica oil emulsion injection is regulated by using chemical substances such as NaOH for blind purposes, which may change the composition of the brucea javanica oil emulsion, so that the subsequent research to be paid is more and inapplicable.
The brucea javanica oil emulsion injection is detected according to the standard of the fourteenth book of Chinese medicinal prescription preparation WS3-B-2739-97, and other indexes except the pH value meet the standard regulation, wherein the refined soybean lecithin should meet the quality standard of the refined soybean lecithin in the fourteenth book of Chinese medicinal prescription preparation WS3-B-2739-97, and the indexes which are not mentioned should meet the standard recorded in soybean lecithin (for injection) in the fourth edition of Chinese pharmacopoeia 2020. On the basis of meeting the standard, the inventor surprisingly finds that when the pH value of the refined soybean lecithin is higher, the prepared brucea javanica oil emulsion injection is not easy to have a hemolysis risk, and meanwhile, the quality of the whole brucea javanica oil emulsion injection is not unstable and the hemolysis risk is enhanced along with the extension of the standing time.
After a great deal of experimental study, the inventor further discovers that the pH value of the refined bean lecithin used by the brucea javanica oil emulsion injection is less than 7, and the pH value is usually between 7.0 and 8.0 when the pH value of the refined bean lecithin is, the prepared brucea javanica oil emulsion injection product keeps stable, and along with the extension of the standing time, the hemolysis risk is still lower, and the product quality is stable.
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not limiting in any way.
Example 1 preparation of purified soybean phospholipids of different pH
1. Crude extraction of soybean phospholipids
Weighing soybean condensed phospholipid, adding acetone according to the mass-volume ratio of 1:2-1:10, stirring and mixing uniformly, filtering to remove supernatant fluid, and drying precipitate to obtain acetone insoluble substances. Adding 95% ethanol with the mass volume ratio of 1:10-1:50 to the soybean concentrated phospholipid into the acetone insoluble substance, stirring and mixing uniformly, performing suction filtration to obtain an ethanol solution and an ethanol insoluble substance, collecting the ethanol solution, adding ethanol with the same amount as the first adding amount into the ethanol insoluble substance, stirring and mixing uniformly, performing suction filtration, collecting the obtained ethanol solution again, adding ethanol with the amount reduced by half compared with the first adding amount into the ethanol insoluble substance, stirring and mixing uniformly mechanically, performing suction filtration, collecting the obtained ethanol solution, and combining the ethanol solutions obtained by the three suction filtration to obtain the soybean phospholipid extract.
2. Refined soybean lecithin
Adding the soybean phospholipid extract obtained in the step 1 to silica gel column chromatography, and using petroleum ether: ethanol: eluting by using a water (about 1:1:0.1-1:1:1) mixed solvent as an eluent, collecting and combining all soybean phospholipid sections with the pH value meeting the requirement to obtain a soybean phospholipid qualified section combined liquid, adjusting the pH value of the combined liquid, evaporating the combined liquid solvent, directly purifying by using an aluminum oxide column, and eluting by using 95% ethanol as the eluent. All eluents were collected and the solvent was evaporated to dryness to obtain purified soybean phospholipids, and the pH values of the purified soybean phospholipids obtained in this example are shown in table 1.
3. Purified soybean phospholipid pH detection
The pH value of the refined soybean lecithin obtained in the step 2 is measured according to the following method: the preparation method comprises the steps of treating according to the quality standard of refined soybean lecithin specified in the fourteenth book WS3-B-2739-97 of Chinese medicine prescription preparation, taking 1g of refined soybean lecithin, grinding uniformly (about 10 minutes), measuring according to the pH value measuring method of the general rule 0631 in the fourth edition of Chinese pharmacopoeia 2020, and measuring the pH value of the solution by using a pH meter (acidometer). The pH of the aqueous solution is typically measured using a glass electrode as the indicator electrode and a saturated calomel electrode as the reference electrode. pH meters (acidometers) should be regularly subjected to metering tests and meet national regulations. Before measurement, the following standard buffer correction instruments are adopted, and various standard buffer correction instruments which are issued by the national standard substance management department and mark that the pH value is accurate to 0.01pH unit can also be used. The pH was measured by the method according to the instructions of the apparatus. The pH values of the purified soybean phospholipids obtained in this example are shown in table 1.
Table 1:
Example 2 preparation of brucea javanica oil emulsion injection with different pH values
1. Preparation of brucea javanica oil injection
In this embodiment, the brucea javanica oil obtained by extracting brucea javanica with petroleum ether, the refined bean phospholipids with different pH values obtained in step 2, glycerin with the same batch number and a certain amount of water for injection are mixed to prepare the brucea javanica oil emulsion injection, and the specific preparation method refers to the preparation method of the brucea javanica oil emulsion injection described in the fourteenth book of Chinese medicine formulation WS 3-B-2739-97: 15g of refined soybean lecithin and 25ml of warm glycerin are taken and mixed with a certain mass of water for injection, and then the mixture is transferred into a high-speed tissue masher, and stirred twice at 8000 revolutions per minute for 5 minutes for 2 minutes to uniformly disperse the mixture. Adding warm refined oleum fructus Bruceae 100ml, stirring for 3 times and 2 minutes each time to obtain primary emulsion, adding injectable water to 1000ml, homogenizing in high pressure homogenizing machine (40 MPa) for three times, filtering, collecting filtrate, packaging, and sterilizing to obtain oleum fructus Bruceae injection.
2. PH detection of brucea javanica oil injection
Determination method of pH value of brucea javanica oil emulsion injection referring to the detection method of pH of refined soybean phospholipid in step 3 of example 1, pH of brucea javanica oil emulsion injection is shown in table 2.
Table 2:
example 3 determination of haemolysis and coagulation of brucea javanica oil emulsion injection
In vitro hemolysis and coagulation experiments are carried out on brucea javanica oil emulsion injection with different pH values obtained in the example 2 respectively in 0 month, 6 months, 12 months, 15 months and 18 months. The in vitro hemolysis and coagulation experiment is determined by adopting an in vitro method recorded in general rule 1148 of the fourth edition of Chinese pharmacopoeia 2020, and the specific experiment operation is as follows:
The method is a method for mixing a certain amount of sample (brucea javanica oil emulsion injection) with 2% rabbit erythrocyte suspension, and observing whether the sample has an influence on the erythrocyte state after a certain period of incubation.
1. Preparation of 2% erythrocyte suspension
Healthy rabbit blood was taken and placed in an conical flask containing glass beads and shaken for 10 minutes, or the blood was agitated with a glass rod to remove fibrinogen and to form defibrinated blood. Defibrinated blood was mixed with 0.9% sodium chloride solution according to 1:10, shaking up, centrifuging for 15 minutes at 1000-1500 rpm, removing supernatant, washing the precipitated red blood cells with 0.9% sodium chloride solution for 2-3 times according to the method until the supernatant does not appear red. The resulting erythrocytes were made into a 2% suspension with 0.9% sodium chloride solution for the test.
2. Preparation of test solutions
Taking 5 clean glass test tubes, numbering, wherein the tubes 1 and 2 are sample tubes, the tube 3 is a negative control tube, the tube 4 is a positive control tube, and the tube 5 is a sample control tube. 2% erythrocyte suspension, 0.9% sodium chloride solution and purified water were added in this order according to the values shown in Table 3, and after mixing, the mixture was immediately placed in an incubator at 37.+ -. 0.5 ℃ for incubation. After 3 hours, hemolysis and coagulation reactions were observed. (note: no hemolysis and no aggregation +: hemolysis and aggregation).
Table 3:
3. method for judging hemolysis or hemagglutination
If the solution in the test tube is in clear red, the bottom of the tube has no cell residue or a small amount of red blood cell residue, which indicates that hemolysis occurs; if the red blood cells are totally submerged, the supernatant is colorless and clear, or the supernatant is colored and clear, but the visible observation of the tube 1, the tube 2 and the tube 5 has no obvious difference, the no hemolysis is shown. If one of the tubes 1 or 2 had hemolysis, the experiment was repeated for that lot.
If there is a brownish red or reddish brown flocculent precipitate in the solution, the solution is gently inverted for 3 times and still not dispersed, which indicates that the possible aggregation of red blood cells occurs, and the solution should be further observed under a microscope, for example, the aggregation of red blood cells is visible as aggregation.
When the negative control tube has no hemolysis and coagulation, the positive control tube has hemolysis, if the solution in the 2 sample tubes has no hemolysis and coagulation within 3 hours, the sample is judged to be in accordance with the regulation; if the solution of 1 sample tube is hemolyzed and/or coagulated within 3 hours, 4 sample tubes should be set for retest, and the solution of the sample tube is not hemolyzed and/or coagulated within 3 hours, otherwise, the samples are determined to be not in compliance with the regulations, and the results of in vitro hemolysis and coagulation experiments of the brucea javanica oil emulsion injection with different PH values at the time of 0 month, 6 months, 12 months, 15 months, 18 months and 24 months are shown in tables 4-6.
4. And visually observing the appearance of each sample according to time nodes of 0 month, 6 months, 12 months, 15 months, 18 months and 24 months, and judging whether emulsion is unstable such as layering, flocculation and the like.
Table 4: the pH values of all time nodes of the brucea javanica oil emulsion injection with different initial pH values
Table 5: haemolysis and agglomeration conditions of brucea javanica oil emulsion injection with different initial pH values at all time nodes
Table 6: appearance conditions of various time nodes of brucea javanica oil emulsion injection with different initial pH values
Note that: in Table 6, "normal" means meeting the requirement of the brucea javanica oil emulsion injection in the fourteenth book of Chinese medicinal prescription preparation WS3-B-2739-97 on the character "the product is milky white even emulsion".
As shown in Table 6, when the pH value of the soybean lecithin is higher than 7.0, the pH value of the prepared brucea javanica oil emulsion injection is not reduced after being reduced to a certain degree along with the extension of the standing time, and the prepared brucea javanica oil emulsion injection can pass through a hemolysis and coagulation experiment. However, when the pH value of the soybean lecithin is higher than 8.0, the appearance of the prepared brucea javanica oil emulsion injection does not meet the property requirements of the brucea javanica oil emulsion injection in traditional Chinese medicine formulation fourteenth book WS 3-B-2739-97.
Example 4 stability test of brucea javanica oil emulsion injection
In this example, soybean phospholipids were purified by the preparation method described in example 1 and the pH values thereof were examined, and the pH values of the obtained purified soybean phospholipids are shown in table 9; preparing brucea javanica oil emulsion injection according to the method of the embodiment 2, wherein 3 repeated experiments are set for each group of refined soybean phospholipids with different pH values, namely 3 batches of brucea javanica oil emulsion injection which are prepared in parallel from the same batch of refined soybean phospholipids with batch numbers of 180910-1, 180910-2 and 180910-3 are prepared in parallel, and the pH values of the brucea javanica oil emulsion injection are shown in table 10; in vitro hemolysis and aggregation conditions of the brucea javanica oil emulsion injection in different time periods are detected for all batches according to the method described in the example 3; and visually observing the appearance of each sample to judge whether the emulsion is unstable such as layering, flocculation and the like. The detailed results are shown in tables 7 to 11.
Table 7:
| Refined soybean phospholipid batch | PH value of |
| Refined soybean lecithin b1 | 5.8 |
| Refined soybean lecithin b2 | 6.0 |
| Refined soybean lecithin b3 | 6.2 |
| Refined soybean lecithin b4 | 6.5 |
| Refined soybean lecithin b5 | 6.7 |
| Refined soybean lecithin b6 | 7.0 |
| Refined soybean lecithin b7 | 7.2 |
| Refined soybean lecithin b8 | 7.5 |
| Refined soybean lecithin b9 | 7.8 |
| Refined soybean lecithin b10 | 8.0 |
| Refined soybean lecithin b11 | 8.5 |
| Refined soybean lecithin b12 | 9.0 |
Table 8:
table 9: the pH values of all time nodes of the brucea javanica oil emulsion injection with different initial pH values
Table 10: haemolysis and agglomeration conditions of brucea javanica oil emulsion injection with different initial pH values at all time nodes
Table 11: appearance conditions of various time nodes of brucea javanica oil emulsion injection with different initial pH values
As can be seen from the experimental results in tables 7 to 11, when the pH value of the refined soybean lecithin is more than 7, the pH value of the brucea javanica oil emulsion injection tends to be a stable value in the long-term standing process, and meanwhile, the phenomena of hemolysis, coagulation and layering or flocculation do not occur. However, when the pH value of the refined soybean lecithin is too large or more than 8, the pH value of the brucea javanica oil emulsion injection tends to be a stable value in the long-term standing process, and meanwhile, the phenomenon of hemolysis and coagulation does not occur, but the quality of the refined soybean lecithin is unstable due to the limitation of the preparation process of the refined soybean lecithin, the phenomenon of layering or flocculation occurs, and the product with the appearance conforming to the quality standard of the brucea javanica oil emulsion injection is difficult to prepare.
Example 5 Effect of pH regulator on hemolysis and aggregation of brucea javanica oil emulsion injection
1. Preparation of brucea javanica oil emulsion injection without adding pH regulator and key index determination
The brucea javanica oil emulsion injection was prepared according to the prescription and preparation method of the brucea javanica oil emulsion injection in example 2, and refined soybean lecithin was commercially available (lot number 1712291, shenyang Tianfeng biopharmaceutical limited). 3 batches of brucea javanica oil emulsion injection were prepared in parallel, and the batch numbers of the 3 batches of brucea javanica oil emulsion injection and the pH value after preparation (0 th month) are shown in Table 12.
A commercially available purified soybean lecithin (lot 1712291, shenyang Tianfeng biopharmaceutical Co., ltd.) was tested according to the pH test method described in example 1, and its pH was 5.4. Brucea javanica oil injection added with common refined soybean phospholipids was tested for in vitro hemolysis and coagulation for various time periods according to the method described in example 3. And visually observing the appearance of each sample to judge whether the emulsion is unstable such as layering, flocculation and the like. Specific experimental results are shown in tables 12-14, the brucea javanica oil emulsion injection without the pH regulator has a hemolysis phenomenon at the 12 th month and has a layering phenomenon at the 24 th month, namely the brucea javanica oil emulsion injection without the pH regulator has a short effective period, has a large hemolysis risk after being used, and has high safety and high quality stability.
Table 12: PH value of each time node of brucea javanica oil emulsion injection without PH regulator
Table 13: haemolysis and coagulation conditions of each time node of brucea javanica oil emulsion injection without pH regulator
Table 14: appearance condition of each time node of brucea javanica oil emulsion injection without pH regulator
2. Preparation of brucea javanica oil emulsion injection added with pH regulator and key index determination
The preparation of the brucea javanica oil emulsion injection added with the pH regulator was carried out according to the prescription and the preparation method of the brucea javanica oil emulsion injection in example 2, the refined bean lecithin was prepared by using commercially available refined bean lecithin (batch No. 1712291, shenyang Tianfeng biological pharmaceutical Co., ltd.), meanwhile, in the preparation method, 100ml of warm refined brucea javanica oil was added, stirring was carried out for 3 times each for 2 minutes to obtain a primary emulsion, 10% sodium hydroxide solution was added to the primary emulsion after' the primary emulsion was added, the pH value was adjusted to 6.0 or 8.0, water for injection was added to 1000ml, stirring was carried out for 3 times each for 2 minutes to obtain the primary emulsion, water for injection was added to 1000ml, and then the solution was homogenized in a high-pressure emulsion machine (40 MPa) for three times, filtered, filled and sterilized to obtain the brucea javanica oil injection added with the pH regulator. 3 batches of brucea javanica oil emulsion injection are prepared in parallel.
Brucea javanica oil injection with added pH regulator was tested for in vitro hemolysis and coagulation for various time periods according to the method described in example 3. And visually observing the appearance of each sample to judge whether the emulsion is unstable such as layering, flocculation and the like. Specific experimental results are shown in tables 15-17, the brucea javanica oil emulsion injection added with different pH regulators does not have the phenomenon of unstable emulsion such as layering and flocculation within 24 months, but has the condition of in-vitro hemolysis at 15 months after production, namely the condition of in-vitro hemolysis of the brucea javanica oil emulsion injection is delayed to a certain extent after the pH of the brucea javanica oil emulsion injection is regulated by adding the pH regulator, but the risk of hemolysis still exists after 15 months.
Table 15: the pH values of all time nodes of the brucea javanica oil emulsion injection with different initial pH values
Table 16: haemolysis and agglomeration conditions of brucea javanica oil emulsion injection with different initial pH values at all time nodes
Table 17: appearance conditions of various time nodes of brucea javanica oil emulsion injection with different initial pH values
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (7)
1. The brucea javanica oil composition is characterized in that the initial pH value of the brucea javanica oil composition is 6.1-7.9;
Preferably, the initial pH value of the brucea javanica oil composition is 6.6-7.9;
preferably, the initial pH value of the brucea javanica oil composition is 7.1-7.9;
Preferably, the initial pH value of the brucea javanica oil composition is 7.3-7.8.
2. The brucea javanica oil composition is characterized in that the pH of the brucea javanica oil composition is 6.1-7.7 at any time within 6 months;
preferably, the pH of the brucea javanica oil composition is 6.5-7.7 at any time within 6 months;
Preferably, the pH of the brucea javanica oil composition is 7.1-7.7 at any time within 6 months;
Preferably, the pH of the brucea javanica oil composition is 7.3-7.7 at any time within 6 months.
3. The brucea javanica oil composition is characterized in that the pH of the brucea javanica oil composition is 6.1-7.7 at any time within 12 months;
Preferably, the pH of the brucea javanica oil composition is 6.5-7.7 at any time within 12 months;
Preferably, the pH of the brucea javanica oil composition is 6.8-7.1 at any time within 12 months.
4. The brucea javanica oil composition of any one of claims 1-3, wherein the brucea javanica oil composition is free of pH modifiers.
5.A pharmaceutical composition comprising the oleum fructus bruceae composition of any one of claims 1-4;
Preferably, the pharmaceutical composition further comprises: pharmaceutically acceptable adjuvants including at least one of stabilizers, wetting agents, emulsifiers, binders, isotonic agents;
preferably, the pharmaceutical composition is in at least one of a tablet, granule, powder, capsule, solution, suspension, lyophilized formulation.
6. Brucea javanica oil composition according to any one of claims 1-4 or pharmaceutical composition according to claim 5, characterized by comprising: refined soybean phospholipid and brucea javanica oil, wherein the mass-volume ratio (g: mL) of the refined soybean phospholipid to the brucea javanica oil is 3:20, a step of;
preferably, the brucea javanica oil composition or the pharmaceutical composition further comprises glycerol;
optionally, the volume ratio of the glycerol to the brucea javanica oil is 1:4.
7. Use of the oleum fructus bruceae composition of any one of claims 1-4 or the pharmaceutical composition of any one of claims 5-6 in the preparation of a medicament for preventing or treating cancer, viral infection, canker sore, rhinitis, pharyngitis, lung injury diseases.
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| CN101129419A (en) * | 2006-08-22 | 2008-02-27 | 浙江九旭药业有限公司 | Emulsified pharmaceutical composition containing oleum fructus bruceae and processes for producing same |
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