CN100493515C - Nano emulsion containing ginsenoside, preparation method and usage - Google Patents
Nano emulsion containing ginsenoside, preparation method and usage Download PDFInfo
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- CN100493515C CN100493515C CNB2004100643854A CN200410064385A CN100493515C CN 100493515 C CN100493515 C CN 100493515C CN B2004100643854 A CNB2004100643854 A CN B2004100643854A CN 200410064385 A CN200410064385 A CN 200410064385A CN 100493515 C CN100493515 C CN 100493515C
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Abstract
The present invention provides a nano emulsion of containing ginsenoside, preparation method and usage. The emulsion of containing ginsenoside contains ginsenoside, water, oil, isotonic regulator and surfactant, also can contain stabilizing agent. The emulsion according to the invention does not contain organic menstruum and solubilizer having toxic and side effect, thus the emulsion has not irritability and little side effect; and the active ingredient in the nano emulsion oil is relative high, which satisfies high thickness required by clinical efficacy of the drug, meantime the emulsion also can change distribute of saponin in human body to improve the bioavailability of the drug, the ginsenoside in human body can be concentrated at tumour position to improve the restraining effect of the compound to tumour.
Description
Invention field
The present invention relates to a kind of nano-emulsion and its production and use, relate to nano-emulsion that contains protopanoxadiol and its production and use particularly.
Background technology
Protopanoxadiol is ginsenoside's one pack system chemical compound, but because it is a hydrophobicity, therefore prepare a large amount of organic solvent of injection needs or use the solubilizing agent of a large amount of toxic side effects, as (Cremophor-EL) waits surfactant to use the polyoxyethylene castor oil class, such surfactant has sensitization, and a large amount of anaphylactoid incidence rates in back of using are higher, see [Wei Xiaohui, Deng Chinese Journal of Pharmaceuticals 2001,32 (4): 188-192].Given this inventor provides a kind of organic solvent and little protopanoxadiol nano-emulsion of toxic and side effects of not containing.
Summary of the invention
The invention provides the nano-emulsion that contains protopanoxadiol, wherein protopanoxadiol be 20 (R)-protopanoxadiols, 20 (S)-protopanoxadiols or 20 (R, S)-protopanoxadiol.
The invention provides the preparation method of the nano-emulsion of protopanoxadiol.
The invention provides the application of protopanoxadiol nano-emulsion in the medicine of preparation treatment or prophylaxis of tumours.
Nano-emulsion provided by the invention, contain ginsenoside, oil, surfactant, accent isotonic agent and water, wherein ginsenoside: oil: surfactant: transferring the weight ratio of isotonic agent is 1:1-50:1-10:1-10.It can also contain stabilizing agent, can be cholesterol, long-chain alcohol (C14-22), oleic acid, linoleic acid or derivatives thereof, and consumption is 0-200 a times of ginsenoside.
Oil of the present invention is meant biological acceptable material, can be in vegetable oil, animal oil, quintessence oil, mineral oil or the artificial oil one or more.Wherein, vegetable oil is selected among a kind of or several in soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil, Oleum Ricini, Petiolus Trachycarpi oil, Oleum Cocois, Oleum Brassicae campestris, Oleum sesami or the Oleum Gossypii semen; Animal oil is selected from one or more in fish oil, oleic acid, Whale wax oil, single, double, the triglyceride; Quintessence oil is selected from one or more in Fructus Schisandrae oil, Oleum Hippophae, peach kernel oil, almond oil, safflower oil, Oleum Camelliae, Radix Oenotherae erythrosepalae oil, Semen Tritici aestivi germ oil, perilla oil, litsea cubeba oil, Oleum Fructus Bruceae or the Oleum Curcumae; Mineral oil is selected from one or more in aliphatic hydrocarbon, cerul hydrocarbon, aromatic hydrocarbon or the paraffin oil; Artificial oil is selected from one or more in linoleic acid, conjugated linoleic acid, ethyl oleate, castor oil hydrogenated, hydrogenated groundnut, hydrogenated cottonseed oil, Ethyl linoleate, conjugated linoleic acid ethyl ester, self-emulsifying monostearate, suffering/caprin or the glycerol triethyl.Be preferably the Oleum Glycines that is rich in triglyceride according to the physicochemical property of above-mentioned oil phase and to the helpfulness of human body.
Surfactant of the present invention can be amphoteric surfactant, non-ionic surface active agent.Wherein amphoteric surfactant is selected from one or more in fabaceous lecithin, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, serinephosphatide, lipositol, phosphatidic acid, cephalin or the hydrogenated phospholipid; Non-ionic surface active agent is selected from one or more in sucrose-fatty esters (as sucrose ester), spans, Tweens, polyoxyethylene fatty acid ester class (as Myrij Myrij), polyoxyethylene aliphatic alcohol ether class (as Bian Ze Brij), Cetomacrogol class or the poloxamer class (as poloxamer).Through toxicology and physio-chemical study screening, it is preferably in soybean phospholipid, egg yolk lecithin, hydrogenated phospholipid or the polyoxyethylene polyoxypropylene block polymer (poloxamer) one or more.
Accent isotonic agent of the present invention is a glycerol.
Ginsenoside's Emulsion provided by the invention, the content of active component are 0.1～100mg/ml.
Preparation ginsenoside Emulsion generally adopts organic solvent to dissolve the ginsenoside, so not only causes the content of active component in residual organic solvent in the injection but also the oil phase lower, so brings difficulty to clinical application.The inventor provides a kind of preparation method of ginsenoside's Emulsion through a large amount of experimentatioies, and this method does not adopt organic solvent, and has satisfied the needed ginsenoside's oil phase of clinical drug effect high concentration.
The preparation method of ginsenoside's Emulsion provided by the invention is: be dissolved in ginsenoside and surfactant in the oil earlier, can also add stabilizing agent, under heating state (30-90 ℃), be mixed to clear and bright, again with the surfactant that is soluble in the aqueous phase with transfer isotonic agent to be distributed in the water.The oil solution that contains the ginsenoside following of high-speed stirred is added to aqueous phase and forms thick Emulsion.The thick Emulsion of gained is by ultrasonic disintegrator, the further emulsifying of high pressure dispersing emulsification machine, must place stable, epigranular, nontoxic Emulsion.
Protopanoxadiol nano-emulsion provided by the invention does not contain the solubilizing agent of organic solvent and toxic side effect, does not therefore have anaphylaxis, and side effect is little; And the content of active component is higher in the nano-emulsion oil phase provided by the invention, satisfied the required high concentration of clinical drug effect, this Emulsion can also change saponin in the intravital distribution of people simultaneously, improve bioavailability of medicament, the ginsenoside is concentrated in vivo in tumor locus, improve the tumor-inhibiting action of this chemical compound.
The specific embodiment
Preparation example 1: preparation ginsenoside Emulsion
With 0.5g 20 (S) protopanoxadiol, 1.2g egg yolk lecithin, 0.04g oleic acid join in the 10g refined soybean oil, and heating (60-90 ℃) is mixed to clear and brightly, obtains containing ginsenoside 50mg/g oil solution.With 1.2g poloxamer, 2.25g glycerol be dispersed in the water for injection water, under stirring condition, the oil solution that drips the phospholipid that contains the ginsenoside gets oil phase in the water dispersion, makes thick Emulsion, adds water to 100ml.Under the condition of pressure 100Mpa, by the further emulsifying of dispersing emulsification machine, emulsifying can be in 115 ℃ after finishing with resulting thick Emulsion, the 30min sterilization, and packing promptly gets the Emulsion of 5mg/ml.
Preparation example 2: preparation ginsenoside Emulsion
0.5g protopanoxadiol, 2g fabaceous lecithin, 0.5g oleic acid are joined in the 10g refined soybean oil, and heating is mixed to clear and brightly, obtains containing the oil solution of ginsenoside 50mg/g.2.25g glycerol, 1.2g poloxamer be added to be prepared as water in the water for injection.Under stirring condition, the oil solution that drips the phospholipid that contains the ginsenoside is made thick Emulsion in the water dispersion, add water to 100ml.Under the condition of pressure 100Mpa, by the further emulsifying of dispersing emulsification machine, emulsifying can be in 115 ℃ after finishing with resulting thick Emulsion, the 30min sterilization, and packing promptly gets the Emulsion of 5mg/ml.
Preparation example 3: preparation ginsenoside Emulsion
0.5g 20 (R) protopanoxadiol, 3.0g egg yolk lecithin, 0.1g oleic acid are joined in the refining Oleum Glycines of 10g, be mixed to clear and brightly, obtain containing ginsenoside 20mg/g oil solution.2.25g glycerol is added in the water for injection, under stirring condition, slowly drips and contain ginsenoside's egg yolk lecithin, oleic oil solution in dispersion, make thick Emulsion, add water to 100ml.With resulting thick Emulsion under pressure 100Mpa, by the further emulsifying of dispersing emulsification machine, can be after the emulsifying in 115 ℃, 30min sterilization, packing promptly gets the Emulsion of 5mg/ml.
Preparation example 4: preparation ginsenoside Emulsion
With 1.0g 20 (S) protopanoxadiol, 2.0g egg yolk lecithin, 0.06g oleic acid join in the refining Oleum Glycines of 10g, and heating is mixed to clear and brightly, obtains containing ginsenoside 100mg/g oil solution.1.2g poloxamer, 2.25g glycerol are dispersed to must water in the water for injection.Under stirring condition, the oil solution that drips the phospholipid that contains the ginsenoside gets oil phase in the water dispersion, makes thick Emulsion, adds water to 100ml.Under the condition of pressure 100Mpa, by the further emulsifying of dispersing emulsification machine, emulsifying can be in 115 ℃ after finishing with resulting thick Emulsion, the 30min sterilization, and packing promptly gets the Emulsion of 10mg/ml.
Test example 1 ginsenoside 20 (S) protopanoxadiol Emulsion and the inhibitory action of injection to growing in S180 sarcoma, H22 hepatocarcinoma and the U14 cervix uteri corpus carcinosus
Experiment material: Emulsion: ginsenoside 20 (S) protopanoxadiol Emulsion is by preparation example 1 method preparation, face with preceding with the glucose for injection solution dilution to respective concentration.Kunming mouse, 18～22g, the male and female dual-purpose, Shandong Province's natural drug Engineering Technical Research Centre animal center provides, the quality certification number: Shandong kinoplaszm word 20010603.Mice S180 sarcoma, H22 hepatocarcinoma and U14 cervical cancer be available from institute of materia medica, Chinese Academy of Medical Sciences Beijing pharmacological room, in the preservation of going down to posterity of Kunming mouse ascites.
Get the go down to posterity good S180 tumor of all growth conditions, H22 hepatocarcinoma or the U14 mice of going down to posterity, get ascites after, add the long-pending injection normal saline dilution of triploid, be inoculated in 50 Kunming mouse oxters, every 0.2ml.Inoculate second day and be divided into 5 groups at random by body weight, be respectively model control group, positive drug group (cyclophosphamide 60mg/kg connects second day single-dose after the tumor), ginsenoside 20 (S) protopanoxadiol Emulsion height (80mg/kg), in (20mg/kg), low (4mg/kg) dosage group.Each organizes mouse tail vein administration (model group is given the equivalent normal saline), once a day, and successive administration 10 days.After the last administration, put to death animal in 24 hours, weigh, strip tumor tissue and weigh, calculate tumour inhibiting rate.
The inhibiting influence of table 1 20 (S) protopanoxadiol Emulsion and injection to growing in S180 sarcoma, H22 adenocarcinoma and the U14 cervix uteri corpus carcinosus
Each administration group tumor is heavy to be compared with model group: P
*＜0.05; P
*＜0.01.
The result shows that 20 (S) protopanoxadiol Emulsion and aqueous injection energy dose dependent ground between 4～80mg/kg suppresses the growth of S180 sarcoma, H22 hepatocarcinoma and U14 cervical cancer, and the highest tumour inhibiting rate can reach 62.1%, 57.4% and 68.8%.
Experimental example 2 20 (S) protopanoxadiol Emulsion is to the influence of ESC ehrlich ascites carcinoma survival time of mice:
Experiment material: Emulsion: ginsenoside 20 (S) protopanoxadiol Emulsion is by preparation example 1 method preparation, face with preceding with the glucose for injection solution dilution to respective concentration.Kunming mouse, 18～22g, the male and female dual-purpose, Shandong Province's natural drug Engineering Technical Research Centre animal center provides, the quality certification number: Shandong kinoplaszm word 20010603.Mice ehrlich carcinoma (ESC) is available from institute of materia medica, Chinese Academy of Medical Sciences Beijing pharmacological room, in the preservation of going down to posterity of Kunming mouse ascites.
Get the milky ascites of inoculation ESC ascites mice after 7 days, add the long-pending normal saline dilution of triploid, under aseptic condition, give 80 Kunming mouse lumbar injection 0.2ml (about 5,000,000 cells), the inoculation back is divided into 8 groups next day at random, be respectively model control group, positive drug group (cyclophosphamide 60mg/kg connects second day single-dose after the tumor), 20 (S) protopanoxadiol Emulsion height (80mg/kg), in (20mg/kg), low (4mg/kg) dosage group.Each organizes mouse tail vein administration (model group is given the equivalent normal saline), once a day, and administration 10 days.Observe the mice survival condition after the drug withdrawal, the record death time, calculate increase in life span by the existence natural law.
Table 4 20 (S) protopanoxadiol Emulsion and aqueous injection are to the influence of ESC ehrlich ascites carcinoma survival time of mice
Compare with model group: P
*＜0.01.
The result shows, ginsenoside 20 (S) protopanoxadiol Emulsion all can obviously prolong the life span of ESC ehrlich ascites carcinoma mice at 20～80mg/kg, and administration group life cycle and model level relatively have significant difference.
Claims (6)
1. the Emulsion that contains protopanoxadiol is characterized by and contains protopanoxadiol, Oleum Glycines, surfactant, G ﹠ W, wherein
Protopanoxadiol: Oleum Glycines: surfactant: the weight ratio of glycerol is 1:1-50:1-10:1-10.
2. Emulsion according to claim 1, protopanoxadiol be 20 (R)-protopanoxadiols, 20 (S)-protopanoxadiols or 20 (R, S)-protopanoxadiol.
3. Emulsion according to claim 1 and 2, surfactant are one or more in soybean phospholipid, egg yolk lecithin, hydrogenated phospholipid or the polyoxyethylene-polyoxypropylene block polymer.
4. Emulsion according to claim 1, it also contains stabilizing agent, and stabilizing agent is long-chain alcohol, oleic acid, the linoleic acid of cholesterol, C14-22, and its consumption is 0-200 a times of protopanoxadiol.
5. Emulsion according to claim 4, stabilizing agent is an oleic acid.
6. the preparation method of the arbitrary described Emulsion of claim 1-5: protopanoxadiol, surfactant are joined in the Oleum Glycines, also
Can add stabilizing agent, under 30-90 ℃ heating condition, be mixed to clear and bright, again with the surfactant that is soluble in the aqueous phase and
Glycerol is distributed in the water, and the oil solution that will contain protopanoxadiol under high-speed stirred is added to aqueous phase and forms thick Emulsion, and is logical again
Cross ultrasonic disintegrator, the further emulsifying of high pressure dispersing emulsification machine, promptly.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1957927B (en) * | 2005-11-03 | 2010-06-02 | 中国人民解放军军事医学科学院毒物药物研究所 | Fat micro sphere preparation of triterpenoid saponin and derivative, and fabricating method |
| CN100391468C (en) * | 2006-02-27 | 2008-06-04 | 杭州创新中药标准化研究所有限公司 | Protopanaxadiol lyophilized agent and its preparing method |
| CN102178714B (en) * | 2011-04-26 | 2012-07-25 | 中国药科大学 | Preparation for improving oral adsorption of panax notoginsenosides and preparation method thereof |
| CN110037296A (en) * | 2019-04-24 | 2019-07-23 | 吉林大学 | A kind of preparation method of lactalbumin base ginsenoside nanoemulsions |
| KR102102098B1 (en) * | 2019-06-26 | 2020-04-17 | 주식회사 코스모네이처 | A composition of emulsion preconcentrate comprising protopaxadiol |
| CN114425038B (en) * | 2022-01-27 | 2023-03-10 | 沈阳信康药物研究有限公司 | 20 (S) -PPD liposome emulsion complex oral administration preparation and preparation method and application thereof |
| CN114831935B (en) * | 2022-05-18 | 2023-04-07 | 沈阳信康药物研究有限公司 | Sterile 20 (S) -PPD oral liquid preparation capable of being administrated by nasal feeding and preparation method and application thereof |
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Effective date of registration: 20170608 Address after: 264670, No. 15, pioneering Road, hi tech Zone, Shandong, Yantai Patentee after: Shandong Luye Pharma Co., Ltd. Address before: 264003 Laishan, Shandong Province Bao Road, No. 9 District, No. Patentee before: Luye Natural Medicinal Research Developing Co., Ltd., Shandong Prov. |
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