CN114073675A - Propofol mixed micelle and preparation method thereof - Google Patents
Propofol mixed micelle and preparation method thereof Download PDFInfo
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- CN114073675A CN114073675A CN202010794025.9A CN202010794025A CN114073675A CN 114073675 A CN114073675 A CN 114073675A CN 202010794025 A CN202010794025 A CN 202010794025A CN 114073675 A CN114073675 A CN 114073675A
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- propofol
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- polyethylene glycol
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- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 92
- 229960004134 propofol Drugs 0.000 title claims abstract description 92
- 239000000693 micelle Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229920001304 Solutol HS 15 Polymers 0.000 claims abstract description 29
- 229920001223 polyethylene glycol Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002202 Polyethylene glycol Chemical class 0.000 claims abstract description 14
- 150000002334 glycols Chemical class 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- -1 polyethylene Polymers 0.000 claims abstract description 11
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 11
- 239000004698 Polyethylene Substances 0.000 claims abstract description 9
- 229920000573 polyethylene Polymers 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 6
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940072106 hydroxystearate Drugs 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 14
- 239000002504 physiological saline solution Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 238000005303 weighing Methods 0.000 claims description 11
- 238000003760 magnetic stirring Methods 0.000 claims description 10
- 230000003204 osmotic effect Effects 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 11
- 239000006185 dispersion Substances 0.000 abstract description 9
- 239000012071 phase Substances 0.000 abstract description 9
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 abstract 1
- 239000010408 film Substances 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000007924 injection Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 238000009472 formulation Methods 0.000 description 9
- 206010018910 Haemolysis Diseases 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 230000008588 hemolysis Effects 0.000 description 7
- 239000002960 lipid emulsion Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000036407 pain Effects 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000001965 increasing effect Effects 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 235000012424 soybean oil Nutrition 0.000 description 3
- 239000003549 soybean oil Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 108010007979 Glycocholic Acid Proteins 0.000 description 2
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 2
- 229940099347 glycocholic acid Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- ALWNROUGZXQZCX-UHFFFAOYSA-N [Ca].C=C Chemical group [Ca].C=C ALWNROUGZXQZCX-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000003022 colostrum Anatomy 0.000 description 1
- 235000021277 colostrum Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
Images
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Anesthesiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a propofol mixed micelle and a preparation method thereof, wherein the propofol mixed micelle comprises propofol, polyethylene glycol derivatives and other pharmaceutically acceptable auxiliary materials, and the polyethylene glycol derivatives are one or two of polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) or polyethylene glycol-15 hydroxystearate (Solutol HS 15). The invention adopts a film dispersion method, the propofol and the polyethylene glycol derivative are dissolved by an organic phase, the organic solvent is removed by rotary evaporation, and the drug-carrying micelle is obtained by film passing after the water phase is hydrated.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a propofol mixed micelle and a preparation method thereof.
Background
Propofol (Propofol, Prop) is a commonly used clinical intravenous anesthetic, has the characteristics of quick response and short action time, and is commonly used for inducing and maintaining anesthesia. Propofol is highly hydrophobic, and the initially marketed preparation is an injection solubilized with polyoxyethylene castor oil (Cremophor EL) micelles, but is rapidly withdrawn from the market due to allergic reactions caused by the polyoxyethylene castor oil and injection pain of the preparation. At present, the O/W type fat emulsion injection is used, the clinical application concentration is 10mg/ml, soybean oil is used as an oil phase, phospholipid is used as an emulsifier, and glycerol is used as an osmotic pressure regulator, so that the problem that propofol is difficult to dissolve in water is solved, and the pain incidence rate is reduced. However, domestic clinical studies show that the incidence of pain caused by injection of the fat emulsion injection is still as high as 40%. Because the fat emulsion is a thermodynamically unstable system and is not heat-resistant and frozen, the requirement on the storage temperature is high. Therefore, a novel injection preparation which can improve the solubility and stability of propofol and reduce injection pain is urgently needed to meet clinical requirements.
CN200710188561.9 discloses a compound propofol injection containing analgesic and a preparation method thereof, and although the injection has the dual effects of anesthesia and analgesia, the prescription introduces additional analgesic drugs, thereby further increasing the adverse reaction and medication risk of patients.
CN200710017685.0 discloses a long-circulating fat emulsion propofol preparation, propofol, vegetable oil, lecithin, polyethylene glycol phospholipid, oleic acid, vitamin E and the like are prepared into fat emulsion, the obtained preparation can inhibit the removal of in-vivo medicines and improve the curative effect of the medicines, but the components are complex, the preparation process is complicated, and the propofol stability is reduced due to the heating in the preparation method.
CN200710169846.8 discloses a micro-emulsion composition of propofol, which contains propofol, Solutol HS 15, oil for injection, phospholipid and other water-soluble components. Although the hemolytic effect of propofol is improved to a certain extent, the preparation process is complex and tedious, and heating is required, so that the structure of propofol which is sensitive to temperature is changed, the content of impurities is increased, and the risk of medication is increased.
CN201110320553.1 discloses a propofol medium-long chain fat emulsion, which comprises propofol, soybean oil, medium-chain triglyceride, glycerol, lecithin, sodium bicarbonate, oleic acid and water for injection. The process is prepared by heating, and can cause the structure of propofol to be changed and the stability to be reduced.
In the prior art, the free drug concentration of the prepared propofol fat emulsion is too high, the preparation process is complex and heating is needed, so that the stability of propofol is reduced, the compliance of patients is reduced, and the medication risk is increased.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a propofol mixed micelle which is simple in components, safe and effective, and a preparation method thereof. According to the invention, the amphiphilic polymer polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) and polyethylene glycol-15 hydroxystearate (Solutol HS 15) are combined for use, so that an excellent propofol micelle preparation is prepared, the solubility of propofol is effectively improved, few free drugs are used, the entrapment rate is high, the pain of patients is effectively relieved, the compliance is improved, the preparation process is simple, and the production is easy.
The invention provides a propofol mixed micelle, which comprises propofol and polyethylene glycol derivatives, wherein the polyethylene glycol derivatives are one or two of polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) or polyethylene glycol-15 hydroxystearate (Solutol HS 15),
the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-50mg/ml
Solutol HS 15 0-250mg/ml。
In the invention, the polyethylene glycol derivative is the combination of PEG-DSPE and Solutol HS 15.
In the invention, the PEG-DSPE is PEG with the PEG molecular weight of 20002000-DSPE。
In the invention, the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-20mg/ml
Solutol HS 15 0.5-100mg/ml。
In the invention, the propofol mixed micelle is isotonic with blood plasma.
In the invention, pharmaceutically acceptable auxiliary materials are added into the propofol mixed micelle.
In the invention, the pharmaceutically acceptable other auxiliary materials are osmotic pressure regulators.
In the present invention, the osmotic pressure regulator is physiological saline.
The invention provides a preparation method of a propofol mixed micelle, which comprises the following specific steps: weighing propofol and polyethylene glycol derivatives, adding an organic solvent for dissolving and mixing, carrying out rotary evaporation on the organic solvent to form a layer of film, adding an aqueous phase for vortex, carrying out magnetic stirring, and then filtering the film to obtain the propofol mixed micelle.
Preferably, the propofol, the polyethylene glycol derivative PEG-DSPE and/or the Solutol HS 15 are weighed firstly, the organic solvent methanol is added for dissolving and mixing, the organic solvent methanol is evaporated in a rotating mode to form a layer of film, the physiological saline is added for vortex, the film passes through a 0.45-micrometer filter membrane after magnetic stirring, and the propofol mixed micelle is obtained.
Preferably, at the temperature of 40 ℃, the Solutol HS 15 is melted, the propofol, the polyethylene glycol-distearoyl phosphatidyl ethanolamine and the melted Solutol HS 15 are weighed, an organic solvent methanol is added for dissolving and mixing, the organic solvent methanol is evaporated in a rotating way to form a layer of film, physiological saline is added for vortex for 3-5min, the mixture is stirred by magnetic force for 0.5-1h and then is filtered by a 0.45 mu m filter membrane, and the propofol micelle is obtained.
Compared with the prior art, the invention has the following beneficial effects:
(1) the solubility of propofol is effectively improved; (2) the free drug concentration of propofol is reduced, and the patient compliance is improved;
(3) the hemolysis percentage of propofol is reduced, and the medication safety is improved; (4) the preparation process is simple, heating is not needed, and the stability of the propofol is improved.
Drawings
FIG. 1 is a graph of the particle size distribution of propofol micelles from example 1.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 2
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 3
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000-DSPE, Solutol HS 15, adding methanol to dissolve and mix, adopting film dispersion method, rotary evaporating methanol to form a layerAnd (3) adding 5ml of physiological saline into the film, vortexing for 5min, magnetically stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 4
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 3min, performing magnetic stirring for 0.5h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 5
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 6
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000-DSPE, Solutol HS 15, adding chloroform for dissolving and mixing, performing thin film dispersion method, performing rotary evaporation on methanol to form a thin film, adding 5ml of normal saline, and performing vortexAnd (5) magnetically stirring for 1h, and filtering with a 0.45-micron filter membrane to obtain the mixed micelle.
Example 7
1) Propofol mixed micelle formulation:
concentration of the components
Propofol 1mg/ml
PEG2000-DSPE 20mg/ml
2) The preparation process comprises the following steps:
weighing prescription dose of propofol and PEG2000And (3) adding chloroform into the DSPE to dissolve and mix, performing rotary evaporation on methanol by adopting a film dispersion method to form a layer of film, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 8
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000-DSPE and Solutol HS 15, adding chloroform for dissolving and mixing, performing rotary evaporation on methanol by adopting a film dispersion method to form a layer of film, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Comparative example 1:
1) prescription:
2) the preparation process comprises the following steps:
heating soybean oil, lecithin, sodium oleate and PEG2000-DSPE of the prescription amount to 75 ℃ under the protection of nitrogen, stirring for 10min to fully dissolve the added auxiliary materials, adding propofol and vitamin E of the prescription amount, dissolving uniformly, taking 800ml of water for injection, adding glycerol, adding oil solution containing the medicine into glycerol aqueous solution under the condition of shearing and stirring under the protection of nitrogen to prepare colostrum, adjusting the total amount to 1000ml, homogenizing for 5-8 times under high pressure, adjusting the pH value to 7.0-8.0 and filtering.
Comparative example 2:
1) prescription
2) The preparation process comprises the following steps:
dissolving lecithin in MCT (methyl cellulose acetate) at 65 ℃ in a water bath, adding Solutol HS 15 and propofol, and uniformly stirring to obtain an oil phase; dispersing glycocholic acid, calcium ethylene diamine tetracetate and glycerol in about 60ml of water, and adjusting the pH to 7 by using a sodium hydroxide solution to change the glycocholic acid into sodium glycocholate to obtain a water phase; adding the water phase into the oil phase under stirring at about 60 deg.C, stirring to obtain microemulsion, filtering, and adding water to 100 ml.
Verification example 1:
1. particle size analysis
The formulation solutions obtained in examples 1 to 8 and comparative examples 1 to 2 were measured for dynamic light scattering particle diameter, polydispersity index (PDI) by a particle size analyzer.
TABLE 1 particle size and polydispersity index for examples and comparative examples
| Examples | Particle size (nm) | Polydispersity index (PDI) |
| Example 1 | 29.9 | 0.166 |
| Example 2 | 33.42 | 0.201 |
| Example 3 | 21.08 | 0.193 |
| Example 4 | 13.55 | 0.110 |
| Example 5 | 15.96 | 0.151 |
| Example 6 | 12.57 | 0.199 |
| Example 7 | 28.13 | 0.199 |
| Example 8 | 25.24 | 0.242 |
| Comparative example 1 | 189.65 | 0.389 |
| Comparative example 2 | 11.52 | 0.358 |
The mixed micelle prepared by the method has smaller particle size, PDI (polymer induced degradation) less than 0.3, is uniformly dispersed, and is obviously superior to the prior art.
2. Free drug detection
The propofol mixed micelles obtained in examples 1-8 were collected and 400. mu.L of the propofol mixed micelles were loaded into an ultrafiltration centrifuge tube (3K, Millipore), ultracentrifuged at 3000rpm for 20min, and the lower aqueous phase was analyzed by HPLC using a chromatographic column, Eclipse Plus C185. mu.m, 4.6X250 mm; the mobile phase is phosphoric acid water solution (A) with pH 2 and acetonitrile (B); the detection wavelength is 270 nm; the sample volume is 20 mu L; the flow rate is 1 ml/min; gradient elution.
TABLE 2 gradient elution method
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 50 | 50 |
| 6 | 30 | 70 |
| 13 | 30 | 70 |
| 14 | 50 | 50 |
| 16 | 50 | 50 |
TABLE 3 results of measurement of free concentration in examples 1 to 8 and comparative examples 1 to 2
The micelle free drug concentration obtained by the invention is lower, compared with the prior art, the micelle free drug concentration is reduced by at least 68.1%, the pain degree of a patient during injection can be obviously reduced, and the compliance of the patient is effectively improved.
3. Encapsulation efficiency test
The propofol mixed micelle obtained in the embodiments 1 to 8 adopts the liquid phase method to detect the propofol concentration, 100 mu L of the obtained micelle solution is taken, 900 mu L of acetonitrile is added for demulsification, the propofol concentration is detected by HPLC, and the encapsulating rate of the propofol is calculated according to the following formula.
Wherein: cGeneral assemblyAs the total propofol concentration in the micelle, CFree formIs the free concentration of propofol in the micelles.
TABLE 4 results of encapsulation efficiency measurements of examples 1-8
| Examples | Encapsulation efficiency (%) |
| Example 1 | 76.9 |
| Example 2 | 69.9 |
| Example 3 | 53.9 |
| Example 4 | 70.3 |
| Example 5 | 87.6 |
| Example 6 | 82.6 |
| Example 7 | 60.9 |
| Example 8 | 67.36 |
4. Hemolysis test
5ml of blood is taken from an SD rat, the SD rat is centrifuged at 3000rpm for 10min to remove blood plasma, red blood cells are left to be precipitated, 10 times of physiological saline is added, the centrifugation step is repeated for three times, the supernatant is clear and colorless, and the red blood cell precipitate is prepared into 2 percent suspension by the physiological saline for standby. Adding 800 μ l of the preparations obtained in examples 1-8 into an EP tube, adding 200 μ l of erythrocyte suspension, shaking uniformly, placing in 37 ℃ and slowly shaking for 2h, centrifuging the incubated tube solution at 3000rpm for 10min, taking the supernatant, transferring the supernatant into a 96-well plate, reading the OD value of each tube solution by a microplate reader, wherein the selected wavelength is 545nm, the positive control is distilled water, and the negative control is physiological saline. Percent hemolysis was calculated using the following equation.
Hemolysis ratio (%) - (ODt-ODnc)/(ODpc-ODnc) x 100%
ODt- -absorbance in test tubes;
ODnc — absorbance of negative tubes;
ODpc-positive absorbance.
TABLE 5 hemolysis results of examples 1 to 8
| Examples | Percent hemolysis (%) |
| Example 1 | 4.37 |
| Example 2 | 3.15 |
| Example 3 | 3.84 |
| Example 4 | 5.19 |
| Example 5 | 2.61 |
| Example 6 | 9.34 |
| Example 7 | 7.51 |
| Example 8 | 12.9 |
The hemolysis percentage of the embodiments 1 to 8 of the invention is less than 15 percent, which is obviously superior to the prior art and effectively improves the safety.
Claims (10)
1. A propofol mixed micelle, which is characterized in that: the composition of the compound comprises propofol and polyethylene glycol derivatives, wherein the polyethylene glycol derivatives are one or two of polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) or polyethylene glycol-15 hydroxystearate (Solutol HS 15),
the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-50mg/ml
Solutol HS 15 0-250mg/ml。
2. Propofol mixed micelle according to claim 1, wherein: the polyethylene glycol derivative is the combination of PEG-DSPE and SolutolHS 15.
3. Propofol mixed micelle according to claim 1, wherein: the PEG-DSPE is PEG with PEG molecular weight of 20002000-DSPE。
4. Propofol mixed micelle according to claim 1, wherein: the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-20mg/ml
Solutol HS 15 0.5-100mg/ml。
5. Propofol mixed micelle according to claim 1, wherein: the propofol mixed micelles are isotonic with plasma.
6. Propofol mixed micelle according to claim 1, wherein: the propofol mixed micelle is added with pharmaceutically acceptable auxiliary materials.
7. Propofol mixed micelle according to claim 6, characterized in that: the pharmaceutically acceptable other auxiliary materials are osmotic pressure regulators.
8. Propofol mixed micelle according to claim 7, wherein: the osmotic pressure regulator is normal saline.
9. A process for the preparation of propofol mixed micelles as claimed in claim 1, wherein: the method comprises the following specific steps: weighing propofol and polyethylene glycol derivatives, adding an organic solvent for dissolving and mixing, carrying out rotary evaporation on the organic solvent to form a layer of film, adding an aqueous phase for vortex, carrying out magnetic stirring, and then filtering the film to obtain the propofol mixed micelle.
10. The method for preparing propofol mixed micelles of claim 9, wherein: weighing propofol, polyethylene glycol derivative PEG-DSPE and/or Solutol HS 15, adding an organic solvent methanol for dissolving and mixing, carrying out rotary evaporation on the organic solvent methanol to form a layer of film, adding physiological saline for vortex, carrying out magnetic stirring, and then, filtering through a 0.45-micrometer filter membrane to obtain the propofol mixed micelle.
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