CN117942303A - Fat emulsion injection and preparation method thereof - Google Patents
Fat emulsion injection and preparation method thereof Download PDFInfo
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- CN117942303A CN117942303A CN202211294475.7A CN202211294475A CN117942303A CN 117942303 A CN117942303 A CN 117942303A CN 202211294475 A CN202211294475 A CN 202211294475A CN 117942303 A CN117942303 A CN 117942303A
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- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
- 239000002960 lipid emulsion Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims abstract description 22
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229920001983 poloxamer Polymers 0.000 claims abstract description 11
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims abstract description 10
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005642 Oleic acid Substances 0.000 claims abstract description 10
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 10
- 229960000502 poloxamer Drugs 0.000 claims abstract description 10
- 239000008215 water for injection Substances 0.000 claims abstract description 6
- 229920001993 poloxamer 188 Polymers 0.000 claims abstract description 5
- 229940044519 poloxamer 188 Drugs 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000000839 emulsion Substances 0.000 claims description 20
- 239000003921 oil Substances 0.000 claims description 20
- 235000019198 oils Nutrition 0.000 claims description 20
- 210000003022 colostrum Anatomy 0.000 claims description 12
- 235000021277 colostrum Nutrition 0.000 claims description 12
- 239000012071 phase Substances 0.000 claims description 12
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 230000001954 sterilising effect Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 239000008159 sesame oil Substances 0.000 claims description 4
- 235000011803 sesame oil Nutrition 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 235000013336 milk Nutrition 0.000 claims description 3
- 239000008267 milk Substances 0.000 claims description 3
- 210000004080 milk Anatomy 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 244000124209 Crocus sativus Species 0.000 claims description 2
- 235000015655 Crocus sativus Nutrition 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000010495 camellia oil Substances 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 239000002385 cottonseed oil Substances 0.000 claims description 2
- 235000012343 cottonseed oil Nutrition 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
- 229940093471 ethyl oleate Drugs 0.000 claims description 2
- 235000021323 fish oil Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 229940042880 natural phospholipid Drugs 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 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 claims description 2
- 229920001992 poloxamer 407 Polymers 0.000 claims description 2
- 229940044476 poloxamer 407 Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004248 saffron Substances 0.000 claims description 2
- 235000013974 saffron Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 238000009826 distribution Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract 3
- 239000012467 final product Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920002635 polyurethane Polymers 0.000 description 3
- 239000004814 polyurethane Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 230000002222 downregulating effect Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
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- 241001656898 Buxus microphylla Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 102000007074 Phospholipase C beta Human genes 0.000 description 1
- 108010047834 Phospholipase C beta Proteins 0.000 description 1
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- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
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- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
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- 102000020233 phosphotransferase Human genes 0.000 description 1
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- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
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- -1 triterpene alkaloid Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a fat emulsion injection and a preparation method thereof. The fat emulsion injection comprises 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-alcohol, oil for injection, phospholipid, poloxamer 188, oleic acid, glycerol and water for injection, wherein each 1L of fat emulsion consists of the following raw materials in weight: 0.6-0.8g of 4, 14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, 100-200g of oil for injection, 10-15g of phospholipid, 3-6g of poloxamer, 0.1-0.5g of oleic acid, 20-25g of glycerol. The fat emulsion provided by the invention has uniform appearance, the average grain diameter is about 200-250 nm, the distribution is narrower, and the quality is stable. In addition, the fat emulsion is free from adding organic solvent in the preparation process, so that the residue of the organic solvent of the final product is avoided, and the safety of the product and the compliance of patients are improved; meanwhile, the application of an organic solvent in the production process is avoided, the production process is simple and feasible, the controllability is high, and the industrial production is easy.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, relates to a pharmaceutical preparation for treating ischemic cerebral apoplexy, and in particular relates to 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-alcohol fat emulsion injection and a preparation method thereof.
Background
The active ingredient 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-alcohol is a triterpene alkaloid and is an active ingredient extracted from Chinese herbal medicine Buxus microphylla. The melting point is 219-222 ℃, the water-soluble polyurethane emulsion is easy to dissolve in chloroform, the water-soluble polyurethane emulsion is dissolved in methanol or ethanol, and the water-soluble polyurethane emulsion is only 0.06mg/mL. The molecular formula is C 26H46N2 O, and the structure is as follows:
1,4, 14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol of formula
The compound of formula 1 can inhibit platelet activation and thrombosis by down regulating thromboxane/phospholipase C-beta-3/protein kinase C pathway, thereby preventing and treating ischemic cerebral apoplexy; the protein and damaged organelles which can induce autophagy misfolding of neurons by activating an adenylate activated protein kinase-human serine/threonine kinase signal pathway can inhibit oxidative stress process by downregulating a phosphorylated amino-terminal kinase and Toll-like receptor family signal pathway, and can reduce the release of pro-inflammatory cytokines, thereby reducing cerebral cortex neuron damage caused by ischemic stroke and being beneficial to rehabilitation of ischemic stroke patients.
The solubility of the compound of the formula 1 in water is only 0.06mg/mL, so that no injection exists on the market at present, and the clinical application of the compound of the formula 1 is limited. At present, a traditional Chinese medicine tablet with the compound of the formula 1 as an active ingredient is marketed, but the drug effect of the compound of the formula 1 is influenced due to the low gastrointestinal tract absorption and low oral bioavailability. Therefore, there is a need to provide a novel formulation with high safety, less irritation and stable quality to solve the above problems.
Disclosure of Invention
The invention aims to solve the problem of poor alcoholysis property of 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha; meanwhile, aiming at the risk of toxic and side effects caused by adding a large amount of solubilizers into the existing injection, the fat emulsion injection is provided, and the drug property of the drug is greatly improved on the premise of ensuring the safety of the preparation.
In order to achieve the aim of the invention, the invention provides a fat emulsion injection which comprises active ingredients 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-ring-5 alpha, 9 beta-pregnane-16 alpha-alcohol, oil for injection, phospholipid, poloxamer, oleic acid, glycerol and water for injection.
Preferably, each 1L of fat emulsion consists of the following raw materials by weight: 0.6-0.8g of 4, 14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, 100-200g of oil for injection, 10-15g of phospholipid, 3-6g of poloxamer, 0.1-0.5g of oleic acid, and 20-25g of glycerol.
The oil for injection is selected from peanut oil, soybean oil, sesame oil, saffron oil, tea oil, cotton seed oil, corn oil, fish oil, sesame oil, ethyl oleate or a combination thereof, preferably soybean oil.
The phospholipid is one or more of natural phospholipid or its salt, synthetic phospholipid or its salt, preferably egg yolk lecithin.
Preferably, the phosphatidylcholine content in the phospholipid is 75% or more.
The poloxamers are preferably poloxamer 188 and poloxamer 407, and more preferably poloxamer 188.
In some embodiments, the fat emulsion injection of the compound of formula 1 further comprises a pH adjuster selected from sodium hydroxide, hydrochloric acid, citric acid, phosphoric acid, acetic acid, or any combination thereof.
Preferably, the pH of the fat emulsion injection is 6.5-8.0.
In some embodiments, the fat emulsion injection of the compound of formula 1 further comprises an isotonic regulator selected from the group consisting of glycerol, glucose, propylene glycol, polyethylene glycol, sucrose, inorganic salts, lactose, sorbitol, dextrose, or any combination thereof.
The invention also provides a preparation method of the fat emulsion injection, which is used for preparing the fat emulsion injection of the compound of the formula 1 according to any one of the technical schemes, and is characterized by comprising the following steps:
(1) Preparing an oil phase: the prescribed amounts of 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, oil for injection and phospholipid were mixed homogeneously.
(2) Preparing an aqueous phase: the prescribed amounts of poloxamer, oleic acid, glycerin are dissolved in a quantity of water for injection.
(3) Preparing colostrum: slowly adding the water phase into the oil phase, and dispersing to form colostrum.
(4) Adjusting the pH: the pH of the colostrum is adjusted using a pH adjuster.
(5) Preparing final emulsion: homogenizing the colostrum with a high-pressure homogenizer to obtain final emulsion.
(6) Filling and sterilizing: and (5) filling, sealing and sterilizing the final emulsion to obtain a finished product.
The more preferred preparation method of the invention comprises the following steps:
(1) Preparing an oil phase: the preparation method comprises uniformly mixing 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, injectable oil and egg yolk lecithin, mechanically stirring at 60-75deg.C for 10-20min, and introducing nitrogen for protection.
(2) Preparing an aqueous phase: dissolving poloxamer, oleic acid and glycerol in a certain amount of injectable water, mechanically stirring for 10-20min until adjuvants are dissolved, and then placing at 60-75deg.C for heat preservation.
(3) Preparing colostrum: slowly adding the water phase into the oil phase, dispersing and stirring at 1000rpm under nitrogen condition for 10-20min to form colostrum.
(4) Adjusting the pH: the pH value of the colostrum is regulated to 6.5-8.0 by using a pH regulator.
(5) Preparing final emulsion: homogenizing the primary emulsion with a high pressure homogenizer for 1-5 times under 1000-1500bar to obtain final emulsion.
(6) Filling and sterilizing: and (3) filling and sealing the final milk, and sterilizing at 121 ℃ for 8-12min to obtain a finished product.
The invention has the technical effects that:
(1) The 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-alcohol fat emulsion injection provided by the invention greatly improves the drug property of the drug on the premise of ensuring the safety of the preparation;
(2) The preparation method of the 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-alcohol fat emulsion injection provided by the invention is convenient to operate, high in controllability, suitable for industrial mass production and high in stability.
Detailed description of the preferred embodiments
The following will provide a clear and complete description of the technical solutions of various embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to fall within the scope of the invention.
Example 1:
4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol fat emulsion injection, which comprises the following components:
The preparation method comprises the following steps:
The preparation method comprises the steps of uniformly mixing 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, oil for injection and egg yolk lecithin according to the prescription amount, mechanically stirring for 20min at 70 ℃, and simultaneously introducing nitrogen for protection. Dissolving poloxamer, oleic acid and glycerol in a certain amount of water for injection, mechanically stirring for 15min until the auxiliary materials are dissolved, and then placing at 70 ℃ for heat preservation. Slowly adding the water phase into the oil phase, dispersing and stirring at 1000rpm under nitrogen condition for 15min to form colostrum. Homogenizing the primary emulsion with a high pressure homogenizer for 3 times under 1000bar to obtain final emulsion. And (5) filling and sealing the final milk, and sterilizing for 8min at 121 ℃ to obtain a finished product.
Example 2:
4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol fat emulsion injection, which comprises the following components:
the preparation method comprises the following steps: as in example 1.
Example 3:
4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol fat emulsion injection, which comprises the following components:
the preparation method comprises the following steps: as in example 1.
Comparative example 1:
the amount of the oil phase in example 1 was adjusted to 20%, and the other steps were the same as in example 1.
Comparative example 2:
The poloxamer 188 dosage in example 1 was adjusted to 0% with the remainder being as in example 1.
Comparative example 3:
the high pressure homogenizing conditions in example 1 were adjusted to 800bar/3 times, the remainder being the same as in example 1.
Experimental example 1:
Emulsion quality evaluation experiment
The particle size and distribution, zeta potential, pH value and content of the fat emulsion injection sample were determined according to the samples prepared in the examples. The results were as follows:
Table 1 quality study of 4, 14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol fat emulsion injection
| Sample of | Traits (3) | PH value of | Zeta potential (mV) | Average particle diameter | PDI |
| Example 1 | White emulsion | 7.38 | -24.66 | 231.19 | 0.119 |
| Example 2 | White emulsion | 7.43 | -23.93 | 241.59 | 0.074 |
| Example 3 | White emulsion | 7.32 | -21.23 | 237.85 | 0.136 |
| Comparative example 1 | Yellow emulsion | 6.92 | -24.34 | 286.31 | 0.101 |
| Comparative example 2 | Yellow emulsion | 7.12 | -18.24 | 361.65 | 0.180 |
| Comparative example 3 | White emulsion | 7.04 | -22.54 | 251.59 | 0.326 |
The results show that 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol fat emulsion injection prepared by the embodiment of the invention has good effects on the aspects of average particle size, uniformity of particle size distribution, charge stability and the like, and the effects are basically similar. Whereas the samples of comparative examples 1 and 2 exhibited yellow color in character, and had a larger particle diameter, and the PDI of comparative example 3 was larger, showing an unstable tendency. Therefore, the prescription and the preparation method of the fat emulsion injection are reasonable and reliable.
Experimental example 2:
stability study
Influence factor stability test: the indices of example 1 were measured under conditions of high temperature of 40℃and light of 4500.+ -. 500Lux for 5 days, 10 days and 30 days, and the results were as follows:
TABLE 2 results of high temperature test
TABLE 3 results of illumination tests
Accelerated stability test: the measurements of the indexes of example 1 were carried out for 6 months at a temperature of 30.+ -. 2 ℃ and a relative humidity of 65%.+ -. 5%, and the results were as follows:
TABLE 4 accelerated test results
Long-term stability test: the measurements of the indexes of example 1 were carried out for 12 months at a temperature of 5.+ -. 3 ℃ and the results were as follows:
TABLE 5 long-term test results
The experimental results show that 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol fat emulsion injection of the invention maintains good physical and chemical properties under various experimental conditions, which shows that the stability is good.
Claims (10)
1. A fat emulsion injection and a preparation method thereof are characterized in that the fat emulsion injection comprises 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-alcohol, oil for injection, phospholipid, poloxamer, oleic acid, glycerol and water for injection.
2. The fat emulsion injection according to claim 1, wherein each 1L of fat emulsion consists of the following raw materials by weight: 0.6-0.8g of 4, 14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, 100-200g of oil for injection, 10-15g of phospholipid, 3-6g of poloxamer, 0.1-0.5g of oleic acid, and 20-25g of glycerol.
3. The fat emulsion injection according to claim 1, wherein the oil for injection is selected from one or more of peanut oil, soybean oil, sesame oil, saffron oil, tea oil, cotton seed oil, corn oil, fish oil, sesame oil, and ethyl oleate.
4. The fat emulsion injection according to claim 1, wherein the phospholipid is one or more of natural phospholipid or a salt thereof, synthetic phospholipid or a salt thereof.
5. The fat emulsion injection according to claim 1, wherein the content of phosphatidylcholine contained in the phospholipid is 75% or more.
6. The fat emulsion injection according to claim 1, wherein the poloxamer is poloxamer 188 and/or poloxamer 407.
7. The fat emulsion injection according to claim 1, further comprising a pH adjuster selected from sodium hydroxide, hydrochloric acid, citric acid, phosphoric acid, acetic acid, or any combination thereof.
8. The fat emulsion injection according to claim 1, wherein: the pH of the fat emulsion injection is 6.5-8.0.
9. The fat emulsion injection according to claim 1, wherein: the fat emulsion injection further comprises an isotonic regulator selected from glycerol, glucose, propylene glycol, polyethylene glycol, sucrose, inorganic salts, lactose, sorbitol, dextrose, or any combination thereof.
10. The method for preparing the fat emulsion injection as claimed in any one of claims 1 to 9, comprising the steps of:
(1) Preparing an oil phase: the prescribed amounts of 4,4,14-trimethyl-3 beta, 20 alpha-bis (methylamino) -9, 19-cyclo-5 alpha, 9 beta-pregnane-16 alpha-ol, oil for injection and phospholipid were mixed homogeneously.
(2) Preparing an aqueous phase: the prescribed amounts of poloxamer, oleic acid, glycerin are dissolved in a quantity of water for injection.
(3) Preparing colostrum: slowly adding the water phase into the oil phase, and dispersing to form colostrum.
(4) Adjusting the pH: the pH of the colostrum is adjusted using a pH adjuster.
(5) Preparing final emulsion: homogenizing the colostrum in step (4) by using a high-pressure homogenizer to obtain final milk.
(6) Filling and sterilizing: and (5) filling, sealing and sterilizing the final emulsion in the step (5) to obtain a finished product.
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