CN110339174B - A bilobalide dripping pill and its preparation method - Google Patents
A bilobalide dripping pill and its preparation method Download PDFInfo
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- CN110339174B CN110339174B CN201910614643.8A CN201910614643A CN110339174B CN 110339174 B CN110339174 B CN 110339174B CN 201910614643 A CN201910614643 A CN 201910614643A CN 110339174 B CN110339174 B CN 110339174B
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- ginkgolide
- dripping
- poloxamer
- pill
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- 239000006187 pill Substances 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 title description 66
- 229930184727 ginkgolide Natural products 0.000 claims abstract description 62
- 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 29
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000008347 soybean phospholipid Substances 0.000 claims abstract description 21
- 239000004094 surface-active agent Substances 0.000 claims abstract description 21
- 229920001983 poloxamer Polymers 0.000 claims abstract description 17
- 229960000502 poloxamer Drugs 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 8
- 239000011159 matrix material Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 229920001993 poloxamer 188 Polymers 0.000 claims description 15
- 229940044519 poloxamer 188 Drugs 0.000 claims description 15
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000010298 pulverizing process Methods 0.000 claims description 8
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 7
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 5
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229940008099 dimethicone Drugs 0.000 claims description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 2
- 229940057995 liquid paraffin Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- -1 polyoxyethylene monostearate Polymers 0.000 claims description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960004274 stearic acid Drugs 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 31
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 2
- 229940023488 pill Drugs 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 229940083037 simethicone Drugs 0.000 description 13
- 241000282472 Canis lupus familiaris Species 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 229940083466 soybean lecithin Drugs 0.000 description 10
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- SQOJOAFXDQDRGF-ZMVGXLHTSA-N ginkgolide b Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-ZMVGXLHTSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- FPUXKXIZEIDQKW-MFJLLLFKSA-N ginkgolide A Natural products O=C1[C@H](C)[C@@]2(O)[C@@H](O1)C[C@]13[C@@H]4OC(=O)[C@]21O[C@@H]1OC(=O)[C@H](O)[C@]31[C@@H](C(C)(C)C)C4 FPUXKXIZEIDQKW-MFJLLLFKSA-N 0.000 description 4
- FPUXKXIZEIDQKW-VKMVSBOZSA-N ginkgolide-a Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-VKMVSBOZSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229930063422 Bilobalide A Natural products 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010003541 Platelet Activating Factor Proteins 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000002409 epiglottis Anatomy 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 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 1
- AMOGMTLMADGEOQ-FNZROXQESA-N Ginkgolide C Chemical compound O([C@H]1O2)C(=O)[C@H](O)C31[C@]14[C@@H](O)[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@@H](O)[C@H]3C(C)(C)C AMOGMTLMADGEOQ-FNZROXQESA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000012901 Milli-Q water Substances 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003353 bioavailability assay Methods 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001275 dimeticone Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000009322 erkang Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- AMOGMTLMADGEOQ-DPFZUGDXSA-N ginkgolide C Natural products O=C1[C@@H](C)[C@]2(O)[C@H]([C@H](O)[C@@]34[C@H]5[C@H](O)[C@@H](C(C)(C)C)[C@]63[C@H](O)C(=O)O[C@H]6O[C@@]24C(=O)O5)O1 AMOGMTLMADGEOQ-DPFZUGDXSA-N 0.000 description 1
- FPUXKXIZEIDQKW-MALVTOHRSA-N ginkgolide a Chemical group O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24C13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-MALVTOHRSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000002515 guano Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000012360 testing method 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a ginkgolide dripping pill which is characterized by comprising the following raw and auxiliary materials in parts by weight: 5-20 parts of ginkgolide, 20-40 parts of a matrix and 0.2-5 parts of a surfactant; wherein, the surfactant is preferably selected from soybean phospholipid and/or poloxamer. The invention disperses the raw materials in the substrate to prepare the dripping pill, improves the solubility, the dissolution speed, the absorption rate and the bioavailability of the raw materials, and the ginkgolide preparation has high stability, is not easy to hydrolyze and oxidize and is convenient to use and carry.
Description
Technical Field
The invention relates to the field of medicines, in particular to a ginkgolide dropping pill and a preparation method thereof.
Background
The ginkgolide belongs to terpenoid, and scientific research shows that the ginkgolide is a natural Platelet Activating Factor (PAF) receptor antagonist and has the effects of expanding coronary vessels, improving cerebral circulation and the like.
In the existing bilobalide preparation, injection preparation and oral tablet are mostly adopted. The ginkgolide is a water-insoluble medicine, and is dispersed in a matrix to prepare the dripping pill, so that the solubility, dissolution speed, absorption rate and bioavailability of the ginkgolide can be improved, and the dripping pill has the advantages of high medicine stability, difficulty in hydrolysis and oxidation, convenience in use and carrying and the like.
Disclosure of Invention
The invention aims to provide a ginkgolide dripping pill and a preparation method thereof.
Specifically, the invention provides a ginkgolide dripping pill which is characterized by comprising the following raw and auxiliary materials in parts by weight: 5-20 parts of ginkgolide, 20-40 parts of matrix and 0.2-5 parts of surfactant.
The bilobalide is selected from monomer or any combination of bilobalide A, bilobalide B, bilobalide C, bilobalide K, etc., or extract containing bilobalide as main ingredient. Preferably, the ginkgolide comprises ginkgolide A, ginkgolide B, ginkgolide C and ginkgolide K, and the total amount of the ginkgolide is 80-99% by mass. More preferably, the ginkgolide is a composition of ginkgolide a and ginkgolide B.
Further, the matrix includes, but is not limited to, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, glyceryl monostearate, polyoxyethylene monostearate, sodium stearate or glycerogelatin, and may be selected from one or more of the above-mentioned matrixes.
Specifically, the surfactant includes, but is not limited to, soybean phospholipid, poloxamer, and can be selected from soybean phospholipid and/or poloxamer.
Further, when the surfactant is selected from soybean phospholipid and poloxamer 188, the weight ratio of the soybean phospholipid to the poloxamer is 10: 1-1: 10, and preferably 2-7: 3-6.
Preferably, the bilobalide is obtained by pulverizing with an ultrafine pulverizer, preferably to a particle size of 2-50 um.
Further, the ginkgolide dropping pill comprises 10-15 parts by weight of ginkgolide, 20-40 parts by weight of a substrate and 0.5-2.5 parts by weight of a surfactant. More preferably 10 parts of ginkgolide, 600025 parts of polyethylene glycol and 0.5 part of surfactant; wherein the surfactant is soybean phospholipid and poloxamer 188.
The invention also provides the application of the soybean phospholipid and/or the poloxamer as the surfactant in preparing the dripping pill preparation. Preferably, the soybean phospholipid and the poloxamer are combined, and the weight ratio of the soybean phospholipid to the poloxamer is 10: 1-1: 10, and more preferably 2-7: 3-6.
The invention also provides a preparation method of the ginkgolide dripping pill, which is characterized by comprising the following steps: mixing a matrix and a surfactant, heating to melt, adding ginkgolides under the condition of heat preservation at 70-95 ℃, stirring to suspend, and then dripping the suspended medicine into condensate at 8-15 ℃ for cooling and forming.
Preferably, the ginkgolide is: pulverizing with a micronizer to obtain fine powder.
Specifically, the condensate is selected from one or more of liquid paraffin, dimeticone and vegetable oil.
The invention also provides a dripping pill which is characterized in that soybean lecithin and/or poloxamer are used as surfactants. The dripping pill is preferably bilobalide dripping pill.
The invention has the following advantages:
1. the bilobalide preparation has high stability, is not easy to hydrolyze and oxidize, and is convenient to use and carry;
2. adding a surfactant in the preparation process of the dripping pill, detecting various indexes of the dripping pill according to a method of Chinese pharmacopoeia 2015, and finding that after the surfactant is added, the dissolution time is faster and faster, and the in-vitro dissolution rate at 45min can reach more than 90%;
3. in the experimental process, when the surfactant is selected from the mixture of soybean phospholipid and poloxamer, indexes such as dissolution time limit, dissolution rate and the like are obviously improved, and the stability is greatly improved, so that the auxiliary material combination can be used for preparing the dropping pill;
4. compared with the common crushing and sieving, the raw materials in the invention can improve the bioavailability of the dripping pill and shorten the dissolution time after being crushed by an ultrafine crusher.
Detailed Description
As mentioned above, the present invention aims at providing a ginkgolide dripping pill and a preparation method thereof. The following will specifically describe the contents of the experimental examples.
If the specific conditions are not indicated, the method is carried out according to the conventional conditions or the conditions suggested by manufacturers, and the used raw material medicines or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.
It is particularly pointed out that the present invention is described in more detail below by means of specific embodiments in order to be able to better understand the solution of the invention and the advantages of its various aspects. The present invention is not limited by the following examples, and specific embodiments may be determined according to the technical solutions and practical situations of the present invention.
Preparation of ginkgolide drop pills
1 apparatus and reagent
1.1 apparatus
DWJ-2000S5-D type multifunctional dripping pill machine (cigarette Tai Kangdaler medicine Co., Ltd.) -cigarette Tai Baiyaotai Chinese medicine science and technology development Co., Ltd.)
DWJL-2000 pill centrifuge (tobacco platform Baiyaotai Chinese medicine science and technology development Co., Ltd.)
HWS26 type electric constant temperature water bath (Shanghai-Hengshi Co., Ltd.)
PL60001-L electronic balance (Mettler Torledo apparatus (Shanghai Co., Ltd))
JB300-SH type digital display constant speed strong electric mixer (made by Shanghai Biao brand model factory)
Model J-50 ultrafine grinder (TECNOLOGIA MECCANAICA S.r.l.)
1.2 reagent
Bilobalide starting material (prepared according to the method of example one of CN107915742A, batch No. 190101)
Polyethylene glycol 6000 (Hunan Er kang pharmaceutical Co., Ltd., F1807034)
Polyethylene glycol 4000 (Hunan Erkang pharmaceutical Co., Ltd., F1807033)
Dimethicone (Jiangxi alpha high-tech pharmaceutical Co., Ltd., F1807049)
Glyceryl monostearate (Tianjin city Feng boat chemical reagent Co., Ltd., analytical purity)
Poloxamer 188 (Beijing Phoenix ceremony Shang Shu Limited liability company)
Soya bean lecithin (pharmaceutical adjuvant, oral grade, Jiangsu tendril's biotechnology limited)
1.3 dropping pill machine parameters
Oil bath temperature: 80-85 DEG C
Temperature of the chassis: 80-85 DEG C
Pipe orifice temperature: 30 to 35 DEG C
Condensation temperature: 12-15 deg.C
2 study of adjuvant screening
2.1 preparation of ginkgolides
The ultrafine grinder is mounted, a power supply is turned on, the feeding speed is set to be 1100r/h, the Venturi pressure is 0.72bar, the annular pressure is 27bar, after the parameters reach set values, materials are added, grinding is started, the particle size range is about 2-50 microns, and the ground medicinal powder is collected by a material bag for later use.
2.2 screening of adjuvants
Example 1: placing 100g of polyethylene glycol 6000 into a 250ml small beaker, placing the beaker in a water bath at 80-90 ℃, heating and melting, slowly adding 40g of ginkgolides, uniformly stirring, transferring the mixture into a dropping tank of a pill dropping machine, adjusting a dropping valve to drop, dropping into 12-15 ℃ simethicone, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
Example 2: putting 100g of polyethylene glycol 4000 into a small beaker, adding 2g of poloxamer 188, heating and melting in a water bath at 80-90 ℃, slowly adding 40g of ginkgolides, uniformly stirring, transferring into a dropping pot of a dropping pill machine, adjusting a dropping valve for dropping, dropping into 12-15 ℃ simethicone, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
Example 3: putting 100g of polyethylene glycol 6000 into a small beaker, adding 2g of poloxamer 188, heating and melting in a water bath at 80-90 ℃, slowly adding 40g of ginkgolides, uniformly stirring, transferring into a dropping pot of a dropping pill machine, adjusting a dropping valve for dropping, dropping into 12-15 ℃ simethicone, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
Example 4: putting 100g of glyceryl monostearate into a small beaker, adding 2g of soybean lecithin, heating and melting in a water bath at 80-90 ℃, slowly adding 40g of ginkgolide, uniformly stirring, transferring into a dropping pot of a dropping pill machine, adjusting a dropping valve for dropping, dropping into 12-15 ℃ simethicone, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the product.
Example 5: putting 100g of polyethylene glycol 6000 into a small beaker, adding 2g of soybean lecithin, heating and melting in a water bath at 80-90 ℃, slowly adding 40g of ginkgolides, uniformly stirring, transferring into a dropping pot of a dropping pill machine, adjusting a dropping valve for dropping, dropping into 12-15 ℃ simethicone, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the product.
Example 6: putting 100g of polyethylene glycol 6000 into a small beaker, adding 0.6g of poloxamer 188 and 1.4g of soybean lecithin, heating and melting in a water bath at 80-90 ℃, slowly adding 40g of ginkgolide, stirring uniformly, transferring to a dripping tank of a pill dropping machine, adjusting a dripping valve to drip, dripping into 12-15 ℃ of simethicone, collecting dripping pills, centrifuging at 1200r/min for 10min, and airing at room temperature to obtain the product.
Example 7: putting 100g of polyethylene glycol 4000 into a small beaker, adding 0.6g of poloxamer 188 and 1.4g of soybean lecithin, heating and melting in a water bath at 80-90 ℃, slowly adding 40g of ginkgolide, uniformly stirring, transferring to a dripping tank of a pill dropping machine, adjusting a dripping valve to perform dripping, dripping into dimethyl silicone oil at 12-15 ℃, collecting dripping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the product.
According to the requirements of the pill preparation items in the appendix of 2015 year edition of Chinese pharmacopoeia, the samples are checked, and the checking items are respectively appearance (white to yellowish-white semitransparent pills), pill roundness (scoring from 0 to 10, 10 being the most round and 0 being the least round), pill tailing condition (scoring from 0 to 10, 10 being the best and 0 being the worst), dissolution time limit (min), and in-vitro dissolution rate 45min (X is 75.0%) indexes. The results are shown in Table 1.
TABLE 1 evaluation results of quality of dropping pills
The experimental results are as follows: after the surfactant is added, the dissolution time is faster and faster, and the in vitro dissolution rate can reach more than 90% within 45min, especially the in vitro dissolution rate of the dropping pill prepared according to the embodiment 6 or 7 reaches 97% within 45min, which is the optimal preparation prescription.
2.3 accelerated test
The dropping pills are prepared according to the method of the above embodiment and are put into an accelerating and stabilizing box (the temperature is 40 ℃ plus or minus 2 ℃, the relative humidity is 75 percent plus or minus 5 percent), and the quality conditions of 1, 2, 3 and 6 months are observed.
TABLE 2 accelerated 1 month stability study
TABLE 3 accelerated 2 month stability study
TABLE 4 accelerated 3 month stability study
TABLE 5 accelerated 6 month stability study
The in vitro dissolution rate and the dissolution time limit of the dripping pills prepared according to the preparation formulas of the embodiments 1 to 7 of the invention are changed and show a reduction trend under the same conditions through accelerated experiments, while the in vitro dissolution rate and the dissolution time limit of the dripping pills prepared according to the preparation formulas of the embodiments 6 or 7 of the invention are not obviously changed under the same conditions through accelerated experiments, which shows that the ginkgolide dripping pills have good stability. Therefore, it is preferable that poloxamer 188 and soybean phospholipids are added simultaneously as a result of the adjuvants.
3 screening study of preparation method
Example 8: pulverizing bilobalide with pulverizer (sieving with 120 mesh sieve); placing 6000120 g of polyethylene glycol, 1.2g of poloxamer and 0.6g of soybean lecithin in a water bath at 80-90 ℃, heating and melting, slowly adding 40g of ginkgolides, uniformly stirring, transferring into a dripping tank of a pill dropping machine, adjusting a dripping valve for dripping, dripping into 12-15 ℃ simethicone, collecting dripping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the product.
Example 9: pulverizing bilobalide with micronizer (feeding speed of 1000r/h, Venturi pressure of 0.72bar, and ring pressure of 27bar) to particle size of 2-50 um; placing 6000120 g of polyethylene glycol, 1.2g of poloxamer and 0.6g of soybean lecithin in a water bath at 80-90 ℃, heating and melting, slowly adding 40g of ginkgolides, uniformly stirring, transferring into a dripping tank of a pill dropping machine, adjusting a dripping valve for dripping, dripping into 12-15 ℃ simethicone, collecting dripping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the product. The dissolution rates and bioavailability of examples 8 to 9 were examined.
3.1 determination of dissolution time and dissolution
TABLE 6 study results of dissolution time limit and in vitro dissolution rate of drop pills
3.2 relative bioavailability assay
3.2.1 instruments and reagents
3.2.1.1 Experimental instruments
LC-30AD high performance liquid chromatograph (Shimadzu corporation, Japan), AB API4000+Mass spectrometer, ESI ion source (AB corporation, usa), HSC-24A nitrogen blower (guano ltd, nj); ultra-low temperature refrigerators (hail); XW-80A model micro vortex mixer (Shanghai West Analyzer Co., Ltd.); high speed centrifuges (eppendorf) of the Centrifuge 5424 type; an electronic balance model XS205DU (mettler-toledo instruments ltd); Milli-Q water purifier (Shanghai Mi Ribo Co., Ltd.).
3.2.1.2 reagents and reagents
The bilobalide dripping pill is provided by Jiangsu Kangyuan pharmaceutical industry GmbH, wherein bilobalide dripping pill T1(example 8, containing GA 3.0mg and GB 6.0mg), Bilobalide dripping pill T2(example 9, containing GA 2.9mg, GB 5.6mg), ginkgolide A (batch: 110862-201612, purity 97.4%), ginkgolide B (batch: 110863-201611, purity 95.6%).
3.2.2 Experimental animals
Healthy beagle dogs, 6 males, weighing 12-13kg, and certified code SXCK (Su) 20130001.
3.2.3 Experimental methods
3.2.3.1 dosing regimens and sample Collection
6 healthy adult beagle dogs are randomly divided into 2 groups, fasted for more than 12 hours before the experiment, no water is forbidden, and fed uniformly after 4 hours of administration. Self-contrast 1 time, random cross oral administration of ginkgolide dripping pill T1Ginkgolide dripping pill T28 pills each, total 80 mg. Before experiment, extracting blank blood before administration, directly plugging bilobalide dripping pill into epiglottis, allowing dog to swallow automatically and inject 40mL of clear water, taking 0.5-1mL of forelimb venous blood respectively in 5min, 10min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h and 24h, EDTA anticoagulating, placing in ice bath, standing at 4 deg.C within 2 hr at 4800 r.min-1Centrifuging for 10min, collecting upper layer plasma, and freezing at-70 deg.C for storage. Two-by-two cross dosing after one week. The dosing cycle was as follows:
TABLE 7 dosing cycle
3.2.3.2 pretreatment of biological samples
Taking 50 mu L of beagle plasma sample, adding 10 mu L of 6mol/L hydrochloric acid solution, fully oscillating, uniformly mixing, standing for 45min, adding 5 mu L of internal standard solution, adding 1mL of ethyl acetate for extraction, fully oscillating, centrifuging at 12000rpm for 10min, taking 800 mu L of supernatant, volatilizing, re-dissolving with 200 mu L of 70% methanol solution, centrifuging at 14000rpm for 10min, taking the supernatant for sample injection analysis.
3.2.3.3 conditions of analysis
Chromatographic conditions are as follows:
a chromatographic column: agilent Eclipse Plus C18 (3.0X 50mm, 1.8 μm); mobile phase: methanol-0.1% formic acid water; column temperature: 40 ℃; flow rate: 0.6 mL/min; sample introduction amount: 3 mu L of the solution; gradient elution conditions are shown in table 8:
TABLE 8 chromatographic elution conditions
Conditions of Mass Spectrometry
An electrospray ion source (ESI) is selected, and source parameters are set as follows: spray Voltage (IonSpray Voltage/IS) -4500V; auxiliary Gas 1(Ion Source Gas 1/GS 1, N2)40 Arb; auxiliary Gas 2(Ion Source Gas 2/GS 2, N2)60 Arb; auxiliary gas heating Temperature (Temperature/TEM)500 ℃; air Curtain Gas (Curtain Gas/CUR)20 Arb; 8Pa of Collision Gas (Collision Gas/CAD, N2); the scanning mode is multiple ion reaction monitoring (MRM); a negative ion mode; the ion pairs, Collision voltage (Collision Energy/CE) and Declustering voltage (Declustering Potential/DP) of the compounds tested are shown in Table 9.
TABLE 9 ginkgolide A, B and IS Mass Spectrometry parameters
3.2.4 data analysis
The data processing is automatically calculated by AB Sciex Multi Quant 2.1 software, and the pharmacokinetic parameters of the index components under each administration condition are statistically analyzed by adopting DAS 3.2.8 pharmacokinetic software and a non-compartmental model.
3.2.5 results of the experiment
3.2.5.1 the blood concentration of GA and GB in beagle after administration of ginkgolide dripping pill
The average blood concentration data of total bilobalide A, B measured after administration of bilobalide dripping pills to beagle dogs by gavage are shown in tables 10-11.
TABLE 10 pharmaceutical concentration of ginkgolide A in plasma (ng/mL) after gavage administration of different batches of ginkgolide dropping pills to beagle dogs (n ═ 6)
Note: N.D. means less than the lower limit of quantitation
TABLE 11 drug concentration of ginkgolide B in plasma (ng/mL) (n ═ 6) following gavage administration of different batches of ginkgolide drops to beagle dogs
Note: N.D. means less than the lower limit of quantitation
3.2.5.2 pharmacokinetic parameters and relative bioavailability of GA and GB of ginkgolide dripping pills in different batches after administration of beagle dog
The pharmacokinetic parameters of GA and GB in acidified plasma of each administration group were statistically analyzed using the DAS 3.2.8 pharmacokinetic software in a non-compartmental model, and the relative bioavailability of different batches of ginkgolides was calculated, as shown in table 12.
TABLE 12 pharmacokinetic parameters and relative bioavailability of different batches of bilobalide drops after administration in beagle dogs (n ═ 6)
As a result: compared with example 8, the preparation of example 9 has a certain degree of increase in the in vivo absorption of GA and GB after oral administration to beagle dogs, which is about 1.3-1.7 times higher.
As can be seen from the above results, the dissolution time limit of example 9 is shortened and the bioavailability is improved, therefore, it is preferable that the ginkgolides be added to the melted base material, poloxamer 188 and soybean phospholipids after being micronized, and then the mixture is stirred uniformly to prepare the dropping pill.
4. Specific preparation examples
Preparation example 1: pulverizing bilobalide with micronizer (feeding speed of 1200r/h, Venturi pressure of 0.60bar, and ring pressure of 20 bar); taking polyethylene glycol 600080 g, poloxamer 1.4g and soybean lecithin 1.4g, placing in a water bath at 80-90 ℃, heating for melting, slowly adding 20g of ginkgolides, stirring uniformly, transferring into a dripping tank of a pill dropping machine, adjusting a dripping valve for dripping, dripping into simethicone at 12-15 ℃, collecting dripping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
Preparation example 2: pulverizing bilobalide with micronizer (feeding speed 1500r/h, Venturi pressure 0.66bar, and ring pressure 24 bar); heating and melting 400060 g of polyethylene glycol, 1.5g of poloxamer and 1.2g of soybean phospholipid in a water bath at 80-90 ℃, slowly adding 40g of ginkgolides, uniformly stirring, transferring into a dripping tank of a pill dropping machine, adjusting a dripping valve for dripping, dripping into 12-15 ℃ simethicone, collecting dripping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
Preparation example 3: micronizing bilobalide (feeding speed of 1000r/h, Venturi pressure of 0.70bar, and ring pressure of 25 bar); placing 600090 g of polyethylene glycol, 2.0g of poloxamer and 1.0g of soybean lecithin in a water bath at 80-90 ℃, heating and melting, slowly adding 15g of ginkgolides, uniformly stirring, transferring into a dripping tank of a pill dropping machine, adjusting a dripping valve for dripping, dripping into 12-15 ℃ simethicone, collecting dripping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the product.
Preparation example 4: micronizing bilobalide (feeding speed of 1000r/h, Venturi pressure of 0.70bar, and ring pressure of 25 bar); taking polyethylene glycol 600080 g, poloxamer 2g and soybean lecithin 0.2g, placing in a water bath at 80-90 ℃, heating and melting, slowly adding 10g of ginkgolides, uniformly stirring, transferring into a dropping pot of a pill dropping machine, adjusting a dropping valve for dropping, dropping into simethicone at 12-15 ℃, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
Preparation example 5: pulverizing bilobalide with micronizer (feeding speed 1500r/h, Venturi pressure 0.66bar, and ring pressure 24 bar); heating and melting 400080 g of polyethylene glycol, 0.2g of poloxamer and 2g of soybean phospholipid in a water bath at 80-90 ℃, slowly adding 30g of ginkgolides, uniformly stirring, transferring into a dropping pot of a dropping pill machine, adjusting a dropping valve for dropping, dropping into 12-15 ℃ simethicone, collecting dropping pills, centrifuging at 1200r/min for 10min, and drying at room temperature to obtain the traditional Chinese medicine composition.
4.1 dissolution time limit and in vitro dissolution Studies
The dissolution time and in vitro dissolution rates of preparation examples 1 to 5 were examined by referring to example 8.
TABLE 13 dissolution time limit and in vitro dissolution results
4.2 relative bioavailability study
4.2.1 reagent
Bilobalide dripping pill T1Example 8 containing GA 3.0mg and GB 6.0mg
Bilobalide dripping pill T2Preparation example 1 containing GA 2.9mg and GB 5.6mg
Bilobalide dripping pill T3Preparation example 2 containing GA 2.9mg and GB 6.1mg
Bilobalide dripping pill T4Preparation example 3 containing GA 3.0mg and GB 6.1mg
Bilobalide dripping pill T5Preparation example 4 containing GA 3.1mg and GB 5.9mg
Bilobalide dripping pill T6(preparation example 5, containing GA 2.8mg and GB 6.0 mg).
4.2.2 Experimental methods
6 healthy adult beagle dogs are numbered 1, 2, 3, 4, 5 and 6 respectively, and are fasted for more than 12 hours before the experiment without water prohibition and fed uniformly after being administered for 4 hours. Pharmacokinetic studies were performed on the 6 tested drugs using a 6 x 6 latin design, with 8 pills per formulation for a total of 80 mg. Before experiment, extracting blank blood before administration, directly plugging bilobalide dripping pill into epiglottis, allowing dog to swallow automatically and inject 40mL of clear water, taking 0.5-1mL of forelimb venous blood respectively in 5min, 10min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h and 24h, EDTA anticoagulating, placing in ice bath, standing at 4 deg.C within 2 hr at 4800 r.min-1Centrifuging for 10min to collect upper layer plasma, and freezing at-70 deg.C for storage. The dosing cycle was as follows:
TABLE 14 dosing cycle table
4.2.3 analytical methods 3.2.3.3
4.2.4 relative bioavailability results
The DAS 3.2.8 pharmacokinetic software was used to statistically analyze the GA and GB pharmacokinetic parameters in plasma of each administration group in a non-atrioventricular model, and to calculate the relative bioavailability of different batches of bilobalide, as shown in table 15.
TABLE 15 pharmacokinetic parameters and relative bioavailability studies of GA and GB in plasma of different batches of ginkgolide drops administered to beagle dogs (n ═ 6)
As a result: compared with example 8, the relative bioavailability of other preparations is improved, the relative bioavailability of GA is improved by more than 30%, and the relative bioavailability of GB is improved by more than 50%.
In conclusion, the relative bioavailability of the preparation examples 1-5 is improved compared with that of the preparation example 8, the improvement of the preparation examples 1-3 is more obvious, and the in vitro dissolution degree of each preparation example group is more stable.
4.3 accelerated stability study
3 batches of samples were prepared according to preparation examples 1 to 5, respectively, and their accelerated stability was examined (temperature 40 ℃ C. + -. 2 ℃ C., relative humidity 75%. + -. 5%).
Table 160 month study results
TABLE 17 accelerated 1 month stability study results
TABLE 18 accelerated 2 month stability study results
TABLE 19 accelerated 3 month stability study results
TABLE 20 accelerated 6 month stability study results
The accelerated stability results for 0-6 months show that the preparation examples 1-5 all meet the requirements, and the finished dropping pill products have good quality stability. In the preparation examples 1 to 3, the in vitro dissolution rate and the dissolution time period were not changed basically.
Finally, it should be noted that: it should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the scope of the invention.
Claims (9)
1. A ginkgolide dripping pill is characterized by comprising the following raw and auxiliary materials in parts by weight: 5-20 parts of ginkgolide, 20-40 parts of a matrix and 0.2-5 parts of a surfactant; wherein,
the surfactant is selected from soybean phospholipid and poloxamer 188, and the weight ratio of the soybean phospholipid to the poloxamer 188 is 10: 1-1: 10.
2. The ginkgolide dripping pill of claim 1, wherein said base is selected from one or more of polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, glyceryl monostearate, polyoxyethylene monostearate, sodium stearate, and glycerogelatin.
3. The ginkgolide dripping pill of claim 1, wherein the weight ratio of soybean phospholipid to poloxamer 188 is 2-7: 3-6.
4. The ginkgolide dripping pill of any one of claims 1 to 3, wherein said ginkgolide is prepared by pulverizing said ginkgolide with a micronizer.
5. The ginkgolide dripping pill of claim 4, wherein the particle size of ginkgolide after being pulverized by said ultrafine pulverizer is in the range of 2-50 um.
6. The ginkgolide drop pill of any one of claims 1 to 3, wherein the ginkgolide drop pill comprises 10 to 15 parts of ginkgolide, 20 to 40 parts of matrix, and 0.5 to 2.5 parts of surfactant.
7. The application of soybean phospholipid and poloxamer as surfactants in preparing ginkgolide dripping pill preparations is characterized in that the weight ratio of the soybean phospholipid to the poloxamer 188 is 10: 1-1: 10.
8. The method for preparing ginkgolide dripping pills of any one of claims 1-6, wherein the method comprises: mixing a matrix and a surfactant, heating to melt, adding ginkgolide under the condition of keeping the temperature of 70-95 ℃, stirring to suspend, dropping the suspended medicine into a condensate of 8-15 ℃, and cooling and forming, wherein the surfactant is selected from soybean phospholipid and poloxamer 188, and the weight ratio of the soybean phospholipid to the poloxamer 188 is 10: 1-1: 10.
9. The method according to claim 8, wherein the condensate is selected from one or more of liquid paraffin, dimethicone and vegetable oil.
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