CN101612119B - Cucurbitacin solid lipid nanoparticle preparation and preparation method thereof - Google Patents
Cucurbitacin solid lipid nanoparticle preparation and preparation method thereof Download PDFInfo
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- CN101612119B CN101612119B CN2009100655233A CN200910065523A CN101612119B CN 101612119 B CN101612119 B CN 101612119B CN 2009100655233 A CN2009100655233 A CN 2009100655233A CN 200910065523 A CN200910065523 A CN 200910065523A CN 101612119 B CN101612119 B CN 101612119B
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Abstract
The invention aims at providing a cucurbitacin solid lipid nanoparticle preparation and a preparation method thereof, which can effectively solve the problems of poor stability and low quality in the prior art. The technical scheme provided by the invention is that: in the preparation, the weight ratio of cucurbitacin, lipid material and surface active agent is 0.001-30:0.01-99:0.01-50, and the sum of the cucurbitacin, the lipid material and the surface active agent accounts for 0.1-40% of the total weight of the raw materials of the nanoparticle preparation. The preparation method is as follows: heating and melting the lipid material, the surface active agent and the cucurbitacin in dark place, fully and evenly stirring; adding water for dispersing to nanoscale; filtering and cooling in the melting state. The invention has scientific and simple composition, scientific compatibility, reasonable dosage, convenient use and fine stability. The invention integrates the advantages of high physical stability and low drug leakage of polymer nanoparticles with low toxicity and capability of large-scale production of liposome and emulsion, which is an innovation in cucurbitacin solid lipid nanoparticle preparation and has enormous economical and social benefits.
Description
One, technical field
The present invention relates to medicine, particularly a kind of cucurbitacin solid lipid nanoparticle preparation and preparation method thereof.
Two, background technology
Cucurbitacine (cucurbitacins) composition is a class tetracyclic triterpenoid that extracts from plant, basic hydrocarbon backbone is that 19-loses carbon-9 Beta-methyl-10 α-lanostene-5, so far kind surplus having found 40, most widely used with Cucurbitacin B (Cucurbitacin B), E, also have cucurbitacin A, D, I etc. in addition.Multiple biological activitys such as this constituents has antitumor, anti-chemocarcinogenesis, protects the liver, human body immunity improving power, majority is present in the cucurbitaceous plant, in high plants such as Cruciferae, Scrophulariaceae, Begoniaceae, Elaeocarpaceae and some macro fungis, discovery (Yang Kai is arranged also, Zheng Gang. the Advance on Pharmacological Activities of Cucurbitacine. International Journal of Triditional Chinese Medicine, 2006,28 (1): 27-29).
From cucurbitaceous plant Fructus Melo (Cucumis melo L.) Pedicellus Melo, extract the cucurbitacin raw material medicine (Cucurbitacine) that makes at present and obtained China's pharmaceutical production permission.Muskmelon pedicel is a kind of Chinese medicine, is the active drug of treatment jaundice from ancient times to the present, again because of its can be emetic, eliminating the phlegm is used for sputum dyspepsia card.Begin someone and study its antitumor action along with the establishment of cucurbitacin chemical constitution the sixties in 20th century.From muskmelon pedicel, isolate compositions such as Cucurbitacin B, E the beginning of the seventies, and carried out pharmacological researches such as antitumor, anti-hepatitis.The pharmacological action of having reported has: cell toxicant and antitumaous effect; Anti-chemical carcinogenesis; Protect the liver, anti-hepatitis, suppress the effect of hepatic fibroplasia; Improve immunologic function; Promote gastrointestinal motility in addition in addition, increase capillary permeability and contraceptive efficacy etc.(Ji Hong. cucurbitacin and pharmaceutical research thereof. foreign medical science Chinese medicine fascicle, 1996,18 (6): 13-14; Liu Yingju, Liu Wenqing. the pharmacology of cucurbitacin and clinical practice. Chinese herbal medicine, 1992,23 (11): 605-608.)
The cucurbitacin sheet that with the Cucurbitacine is feedstock production is one of preparation that is used for the treatment of clinically chronic persistent hepatitis and primary hepatocarcinoma.Aspect the treatment chronic hepatitis, through Shanghai, the clinical research of ground 13 tame hospitals such as Beijing, Chongqing shows that the effective percentage of cucurbitacin sheet is 75.2%, obvious effective rate is 44.6%.This medicine can obviously improve the common sympton of chronic hepatitis, but transaminase lowering, reduce the red matter of gallbladder, do not cause after the drug withdrawal that the transaminase bounces, albumen inversion and hyperglobulinemia also there is tangible role of correcting, can also improve patient's non-specific cell immunocompetence, no obvious toxic-side effects (Hu'nan Inst. of Plarmaceutical Industry. the muskmelon pedicel extract is in harmony and is treated chronic hepatitis example clinical effectiveness, Chinese herbal medicine, 1982,12 (10) 26-28.) aspect the treatment primary hepatocarcinoma, treatment to 169 routine Patients with Primary shows that this medicine is improving patient's clinical symptoms, alleviate liver pain, dwindle the tumor body, prolong life cycle, aspect such as regain one's strength all is better than contrasting the chemotherapeutic 5-fluorouracil.Through the treatment later six months above survival rate be 66.6%, the annual rate of depositing is 29%, the biennial rate of depositing is that survival rate is 4.3% more than 29%, three year, total effective rate is 69%, wherein obvious effective rate is 29%.Be suitable for various phase hepatocarcinoma, but II phase curative effect is better than the III phase, simple type, atherosclerotic type be better than inflammatory type (Cui Xingyi. the one cucurbitacin technical expertise conference of treatment hepatocarcinoma new drug is held in Changsha. Chinese herbal medicine, 1985,15 (4): 34).
'Hulusu ' demonstrates stronger lethal effect to multiple cancerous cell in therapeutic dose, myeloid element and liver and kidney cells are not had obvious influence, also have protect the liver, effect such as enhancing human body immunity power.At present, constantly have other pharmacological actions to be found, its clinical practice potentiality and economic worth are higher.The cucurbitacin dosage form of having gone on the market is mainly tablet.Although tablet has advantages such as easy to use, because cucurbitacin is strong liposoluble constituent, dissolution rate is slower in body fluid, and fluctuation is bigger, is difficult to guarantee the stable of therapeutic effect, in addition, conventional tablet can't satisfy dysphagia patients or needs quick acting patient's requirement.Therefore, exploring the research of cucurbitacin novel formulation carries out, mainly comprise the cucurbitacin polylactic acid nano particle, the polylactic-co-glycolic acid nanosphere, drop pill, liposome and injection Cucurbitacin B self-emulsifying microemulsion drug delivery system etc., the preparation research that wherein with the polylactic acid is preparing carriers is more common in periodical, the preparation and the medicine carrying process of cucurbitacin-polylactic acid nano particle have been studied as Zhang Jifen etc., found that the pharmaceutical preparation of failing to obtain high envelop rate with the sedimentation method, about 70% cucurbitacin forms new nucleus gradually, be present in the medium with microcrystalline form, finally obtaining existing nanoparticle has the suspendible system (Zhang Jifen of crystallite again, Hou Shixiang, Liu Huilian, Deng. the preparation of cucurbitacin-polylactic acid nano particle and medicine carrying process study. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2005,30 (6): 436-439.).Li Chaoying etc. studies show that, the physical and chemical stability of cucurbitacin polylactic acid nanoparticle colloid solution is poor, should not make the liquid type injection, and its lyophilized injection room temperature placement had good stability in 3 months, and therefore its lyophilized injection of preparation has certain feasibility (Li Chaoying, Hou Shixiang under suitable prescription and process conditions, sun is kept burning day and night, Deng. the research of cucurbitacin nanoparticle lyophilized injection. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2001,26 (5): 315-317.).Yang Kai etc. have prepared Cucurbitacine polylactic acid nano microgranule and have been used for oral cancer Cervical Lymph Node Metastasis patient, the result shows that mean diameter is that the preparation of 85nm has good targeting to its metastasis, can reach and improve drug level and the purpose of prolong drug persistent period in the metastasis, reduced the toxic and side effects (Yang Kai of medicine simultaneously, Wen Yuming, Li Longjiang, Deng. the development of the lympha targeted Cucurbitacine polylactic acid nano of neck microgranule lyophilized formulations. West China stomatology magazine, 2001,19 (6): 345-349).Employing solvent evaporation methods such as wangdan flower bud prepare Cucurbitacin B polylactic-co-glycolic acid nanosphere, and the nanosphere suspension is 1 month energy kept stable of 4 ℃ of preservations in refrigerator, the long-term then instability of placing; Nanosphere dried frozen aquatic products room temperature was placed 3 months, its pH value, particle size distribution, envelop rate and drug loading have no significant change (wangdan flower bud, Chen Dawei, Guo Tao etc., the preparation of injection Cucurbitacin B polylactic-co-glycolic acid nanosphere. Shenyang Pharmaceutical University's journal, 2006,23 (6) 335-339).Li Mo etc. have studied the formulation optimization (Li Mo of injection Cucurbitacin B self-emulsifying microemulsion drug delivery system, Zhao Xiuli, Chen Dawei, etc. the formulation optimization of injection Cucurbitacin B self-emulsifying microemulsion drug delivery system. Shenyang Pharmaceutical University's journal, 2008,25 (1): 15-19).
Applied for that at present also disclosed cucurbitacin patent has 28, preparation patent wherein, comprise " cucurbitacin cyclodextrin clathrate and preparation thereof; application number 02153647.3 ", " nano medicine ' Hulusu ' and preparation method thereof; application number 01103658.3 ", " cucurbitacin liposome prescription and preparation thereof; application number 02144633.4 ", " but a kind of cucurbitacin Emulsion and preparation method of filtration sterilization; application number 200510046583.2 ", " containing proteic cucurbitacin nano preparation and preparation method and purposes, application number 200610091449.9 ", " stable type cucurbitacin liquid formula and preparation thereof; application number 200710011513.2 ", " cucurbitacin liquid type prescription and preparation thereof, application number 200410021536.8 " etc.
Still there is not the patent application of cucurbitacin solid lipid nanoparticle (SLN) at present, SLN is a kind of novel microgranule drug administration carrier, because adopting the solid lipid compatible with organism physiology is the basic framework material,, be suitable as very much the carrier of cucurbitacin therefore to fat-soluble high entrapment efficiency height.It is solid-state that the SLN particle at room temperature is usually, both possessed polymer nanoparticle physical stability height, the slow advantage of drug leakage, and the toxicity that has had liposome, Emulsion again concurrently is low, advantage that can large-scale production, is a kind of extremely promising novel drug-supplying system.Up to now, have only one piece of relevant said preparation bibliographical information (pay refined, the research of injection cucurbitacin solid lipid nanoparticle.Shenyang: Shenyang Pharmaceutical University's Master's thesis, 2004).Concrete prescription and the preparation method put down in writing in this paper are: take by weighing lecithin and the 200mg poloxamer 188 of 300mg, heating makes in the water for injection that is dissolved in 20mL, constitutes water.Take by weighing the glyceryl monostearate of 200mg, be heated to (75 scholar 2) and ℃ make moltenly, the cucurbitacin of 10mg is distributed in the fusion glyceryl monostearate of stirring, constitute oil phase.Water is heated to identical temperature, injects the oil phase that stirs, constant temperature stirs, and makes colostrum.While hot colostrum is carried out ultrasonic redispersion (ultrasonic time 6min, ultrasonic power is set at 400w for ultrasonic 5s, 5s intermittently), put coldly naturally, promptly get the suspension of cucurbitacin SLN.At last need be by 0.22 micron microporous filter membrane, to reach the purpose of degerming.But, said preparation exists obviously not enough, mainly is the less stable of made cucurbitacin solid lipid nanoparticle liquid preparation, at room temperature stores only promptly to occur phenomenons such as particle diameter obviously increases, the increasing of outward appearance turbidity in 2 months, of poor quality, there is not application value.Said preparation prepares with emulsifying-ultrasonic method, but not screening proper supplementary material and prescription, and the large usage quantity of surfactant, is 2.5 times of lipid, research on preparation technology is not deep enough in addition, and is influential to its stability as adding method of surfactant etc. yet.Therefore, its improvement and innovate imperative.
Three, summary of the invention
At above-mentioned situation, for overcoming the prior art defective, the present invention's purpose just provides a kind of cucurbitacin solid lipid nanoparticle preparation and preparation method thereof, can effectively solve poor stability, ropy problem, the technical scheme of its solution is, said preparation is by cucurbitacin, matrix material and surfactant are counted with weight ratio: 0.001-30: 0.01-99: 0.01-50 (that is: cucurbitacin: matrix material: surfactant=0.001-30: 0.01-99: 0.01-50), cucurbitacin, matrix material and surfactant sum are the 0.1-40% of nano particle preparations raw material gross weight; Its basic preparation method is with matrix material, surfactant and cucurbitacin lucifuge heating and melting and abundant mixing, adds water and is dispersed to nanoscale, keeps filtering under the molten condition and cooling, and its basic step is:
1) preparation of pastille phase: be higher than the temperature of lipid fusing point more than 10 ℃, with matrix material and surfactant heating and melting, adding the cucurbitacin rapid mixing stirs, standby, or be higher than the temperature of lipid fusing point more than 10 ℃, earlier with the matrix material heating and melting, again surfactant is mixed the back with cucurbitacin and mix with fused matrix material fast, standby (sometimes surfactant is added water and does not add the fat phase, its add reach addition mutually and determine) by concrete prescription;
2) preparation of water: pastille other composition beyond mutually adds in the bigger solvent of entry or polarity and is mixed into water in will writing out a prescription;
3) particle disperses: be higher than under the lipid melting temperature condition, with water join pastille mutually in, with preliminary mixing such as magnetic stirring apparatus, stirring dispersion machine or Glass rod, adopt in ultrasonic cell disruptor, microjet, high pressure dispersing emulsification machine, shearing high speed dispersor, the colloid mill etc. one or several to operate again preparation further is dispersed to nanometer particle, or the employing ultrasonic method, pastille directly is dispersed to nanoscale after mutually mixed with water.
4) filter: scattered preparation is pressed through the microporous filter membrane that the aperture is 0.1-0.8 μ m under heat-retaining condition.
5) store: lucifuge is placed under room temperature (18-25 ℃, the as follows) condition of sealing back.
Wherein said cucurbitacin solid lipid nanoparticle preparation comprise with made cucurbitacin solid lipid nanoparticle be raw material further preparation have the drug forms such as injection, mixture, soft capsule, ointment, gel, suppository, spray, nasal drop, drop pill of therapeutical effect.
The weight ratio of cucurbitacin, matrix material and surfactant is preferably: 0.01-10: 50-80: 20-50, and cucurbitacin, matrix material and surfactant sum are the 0.1-10% of nano particle preparations raw material gross weight;
Said cucurbitacin includes cucurbitacine chemical compounds such as cucurbitacin effective part extract, cucurbitacin monomer and composition thereof, Cucurbitacine, Cucurbitacin B, cucurbatacin E;
Said matrix material contains list, two or triglyceride, fatty acid, aliphatic alcohol, the wax class, the mixture of one or more in the lipids such as cholesterol, as stearic acid, octadecanol, glyceryl tristearate, Palmic acid, myristic acid, glyceryl monostearate, glyceryl palmitostearate (Precirol ATO5), Glyceryl Behenate (compritol 888 ATO), hexadecylic acid etc., wherein, with list, two or the lipid mixture of triglyceride be that lipid is best, its best mixed weight ratio is a glyceryl monostearate: glyceryl palmitostearate/Glyceryl Behenate=2～4: 6～8, and preferably 2: 8～4: 6.
Said surfactant comprises pharmaceutically useful various surfactants and composition thereof, as one or more the mixture in poloxamer, lecithin, polyoxyethylene ether (35) Oleum Ricini (ELP), Brij, tween, the span etc., wherein better with the poloxamer class, as poloxamer 188, poloxamer 407, poloxamer 124, poloxamer 237 and poloxamer 338 etc.
Prescription of the present invention is simple, the compatibility science, consumption is reasonable, quality is good, and is easy to use, good stability, particularly as novel microgranule drug administration carrier, because adopting the solid lipid compatible with organism physiology is the basic framework material, therefore to fat-soluble high entrapment efficiency height, as the carrier of cucurbitacin with other carriers of consideration such as liposome, Emulsion, polymer nanoparticle etc. to its envelop rate may be low problem.It is solid-state that the SLN particle at room temperature is usually, both possessed polymer nanoparticle physical stability height, the slow advantage of drug leakage, the problem that the toxicity that has had liposome, Emulsion again concurrently is low, can large-scale production is the innovation on the cucurbitacin solid lipid nanoparticle preparation, and economic and social benefit is huge.
Four, the specific embodiment
Below in conjunction with embodiment the specific embodiment of the present invention is elaborated.
The raw material that relates among the embodiment wherein: Cucurbitacine (Tianjin Inst. of Materia Medica pharmaceutcal corporation, Ltd); Glyceryl monostearate (Changsha chemical reagent factory, chemical pure); Glyceryl palmitostearate (Precirol ATO5, GATTEFOSSE, France); Hexadecylic acid (Tianjin recovery fine chemistry institute); Stearic acid (the reagent company limited is learned in triumphant Tonghua, Tianjin); Poloxamer 188 (Lutrol F68, BASF, Germany); Poloxamer 407 (Lutrol F127, BASF, Germany); Glyceryl Behenate (Compritol 888 ATO, GATTEFOSSE, France); Polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, German BASF); Soybean lecithin (SPC, Shanghai Taiwei Pharmaceutical Co., Ltd.), Tween 80 (Haidian, Beijing fellow member of an association or organization's Fine Chemical Works).
Machinery: JY92-2D ultrasonic cell disruptor (NingBo XinZhi Biology Science Co., Ltd); Ultrathermostat (Shanghai test apparatus factory); T18 type high speed dispersor (ULTRA TURRAX IKA); M-110L type high pressure microjet nano-dispersed instrument (U.S. MFIC company) Nano-ZS90 laser particle size analyzer (Britain Ma Erwen company); Z323K High speed refrigerated centrifuge (German Hermle company).
Embodiment 1
The present invention is by Cucurbitacine 0.003g in force, glyceryl palmitostearate 0.35g, glyceryl monostearate 0.15g, poloxamer 1880.25g, ultra-pure water 10ml makes, wherein, precision takes by weighing each composition, with glyceryl palmitostearate, glyceryl monostearate and poloxamer 188 are behind heating and melting under 90 ℃ of temperature, add Cucurbitacine, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 75 ℃, add the 10ml ultra-pure water, with ultrasonic cell disruptor ultrasonic 18 times in the condition of ultrasonic power 400W, each ultrasonic 10S (10 seconds), interval 10S (stopped 10 seconds between promptly each, carry out ultrasonic next time again), ultrasonic dispersion liquid is afterwards drawn in insulation (75 ℃) afterwards, cross 0.22 μ m microporous filter membrane while hot, filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly gets the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under room temperature (18-25 ℃, the as follows) condition.
Embodiment 2
The present invention also can be by Cucurbitacin B 0.008g, glyceryl palmitostearate 0.5g, glyceryl monostearate 0.2g, poloxamer 4070.3g, lecithin 0.1g, ethanol 2mL, ultra-pure water 8ml makes, wherein, precision takes by weighing each composition, with glyceryl palmitostearate, glyceryl monostearate and poloxamer 407 are behind heating and melting under 90 ℃ of temperature, add Cucurbitacin B, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 70 ℃, add 2mL ethanol and 8ml ultra-pure water, with ultrasonic cell disruptor ultrasonic 36 times in the condition of ultrasonic power 400W, each ultrasonic 5S, interval 5S, ultrasonic dispersion liquid is afterwards drawn in insulation (70 ℃) afterwards, crosses 0.22 μ m microporous filter membrane while hot, and filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
Embodiment 3
The present invention also can be by cucurbatacin E 0.05g, Glyceryl Behenate 0.3g, glyceryl monostearate 0.2g, poloxamer 1880.2g, polyoxyethylene ether (35) Oleum Ricini 0.3g, ultra-pure water 20ml makes, wherein, precision takes by weighing each composition, with Glyceryl Behenate, glyceryl monostearate and poloxamer 188 are behind heating and melting under 95 ℃ of temperature, add cucurbatacin E, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 80 ℃, add the 20ml ultra-pure water, with ultrasonic cell disruptor ultrasonic 18 times in the condition of ultrasonic power 600W, each ultrasonic 10S, interval 10S, ultrasonic dispersion liquid is afterwards drawn in insulation (80 ℃) afterwards, crosses 0.22 μ m microporous filter membrane, and filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
Embodiment 4
The present invention is by Cucurbitacine 0.005g, Glyceryl Behenate 0.35g, glyceryl monostearate 0.15g, poloxamer 1880.25g and ultra-pure water 10ml make, wherein, precision takes by weighing each composition, with Glyceryl Behenate, glyceryl monostearate and poloxamer 188 are behind heating and melting under 95 ℃ of temperature, add Cucurbitacine, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 80 ℃, add the 10ml ultra-pure water, with ultrasonic cell disruptor ultrasonic 16 times in the condition of ultrasonic power 500W, each ultrasonic 5S, interval 5S, ultrasonic dispersion liquid is afterwards drawn in insulation afterwards, crosses 0.22 μ m microporous filter membrane, and filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
Embodiment 5
The present invention also can be by Cucurbitacine 0.008g, Glyceryl Behenate 1.00g, glyceryl monostearate 0.60g, poloxamer 1881.40g, ultra-pure water 40ml makes, wherein, with Glyceryl Behenate, add Cucurbitacine behind glyceryl monostearate and the poloxamer 188 lucifuge heating and meltings, stirring makes it abundant mixing, under 80 ℃ of heat-retaining conditions, carry out following operation: at first add 10ml equality of temperature ultra-pure water in the mixture, replenish 30ml equality of temperature ultra-pure water behind the magnetic agitation 10min, with the rotating speed dispersion 10min of high speed dispersor with 10000r/min, with first dispersion liquid while hot under the setting pressure of 18k with microjet homogenize 10 times repeatedly, homogenize liquid is crossed 0.45 μ m microporous filter membrane, at room temperature cool off and the inflated with nitrogen sealing by fusing after the filtration, promptly.
Embodiment 6
The present invention is by Cucurbitacine 0.012g, Glyceryl Behenate 1.00g, poloxamer 1880.70g, ultra-pure water 40ml makes, wherein, precision takes by weighing each composition, with Glyceryl Behenate and poloxamer 188 behind heating and melting under 95 ℃ of temperature, add Cucurbitacine, stirring makes it abundant mixing, under 80 ℃ of heat-retaining conditions, carry out following operation: at first add 10ml equality of temperature ultra-pure water in the mixture, replenish 30ml equality of temperature ultra-pure water behind the magnetic agitation 10min, with the rotating speed dispersion 10min of high speed dispersor with 9500r/min, with first dispersion liquid while hot under the setting pressure of 18k with microjet homogenize 10 times repeatedly, homogenize liquid is crossed 0.45 μ m microporous filter membrane, at room temperature cool off and the inflated with nitrogen sealing by fusing after the filtration, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
Embodiment 7
The present invention is by Cucurbitacine 0.004g, Glyceryl Behenate 0.50g, poloxamer 1880.35g, ultra-pure water 10ml makes, wherein, precision takes by weighing each composition, with Glyceryl Behenate, poloxamer 188 is behind lucifuge heating and melting under 95 ℃ of temperature, add Cucurbitacine, stirring makes it abundant mixing, carry out following operation under 80 ℃ of heat-retaining conditions: at first add 6ml equality of temperature ultra-pure water in the mixture, behind magnetic agitation 8min, replenish the same warm water of 4ml, with the rotating speed dispersion 10min of high speed dispersor with 21500r/min, dispersion liquid is drawn in insulation (80 ℃) afterwards, cross 0.45 μ m microporous filter membrane, filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly gets the cucurbitacin solid lipid nanoparticle preparation, and lucifuge is placed under the room temperature condition.
Embodiment 8
The present invention is by Cucurbitacine 0.004g, hexadecylic acid 0.05g, stearic acid 0.05g, glyceryl monostearate 0.40g, poloxamer 4070.35g, polyoxyethylene ether (35) Oleum Ricini 0.1g, ultra-pure water 10ml makes, wherein, precision takes by weighing each composition, with hexadecylic acid, stearic acid, glyceryl monostearate and poloxamer 407, polyoxyethylene ether (35) Oleum Ricini is behind lucifuge heating and melting under 95 ℃ of temperature, add Cucurbitacine, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 80 ℃, add the 10ml ultra-pure water, with ultrasonic cell disruptor ultrasonic 18 times in the condition of ultrasonic power 400W, each ultrasonic 10S, interval 10S, ultrasonic dispersion liquid is afterwards drawn in insulation (80 ℃) afterwards, crosses 0.22 μ m microporous filter membrane, and filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
Embodiment 9
The present invention is by calabash BE 0.004g, glyceryl tristearate 0.005g, glyceryl palmitostearate 0.25g, glyceryl monostearate 0.20g, poloxamer 1880.20g, Tween 80 0.05g, ultra-pure water 10ml makes, wherein, precision takes by weighing each composition, with glyceryl tristearate, glyceryl palmitostearate, glyceryl monostearate and poloxamer 188 are behind lucifuge heating and melting under 90 ℃ of temperature, add Cucurbitacine, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 75 ℃, the 10ml ultra-pure water that adds dissolving recipe quantity Tween 80, with ultrasonic cell disruptor ultrasonic 36 times in the condition of ultrasonic power 500W, each ultrasonic 5S, interval 5S, ultrasonic dispersion liquid is afterwards drawn in insulation (75 ℃) afterwards, crosses 0.22 μ m microporous filter membrane, and filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
Product of the present invention after measured and the test, its envelop rate height, steady quality, concrete condition is as follows:
Preparation characterizing method and result
(1) characterizing method
1 assay adopts the HPLC method to measure the content of preparation
Get 40 μ l SLN sample to be measured and place the 5ml measuring bottle, add the dissolving of 0.5ml methanol and 1.0ml dichloromethane, use methanol constant volume, cross organic microporous filter membrane of 0.45 μ m, get filtrate 20 μ l sample introductions and measure, record record chromatogram and peak area.With income value substitution standard curve, calculate the Cucurbitacin B content among the cucurbitacin SLN.
Chromatographic column: Hypersil BDS C
18(4.6 * 250mm, 5 μ m); Mobile phase: acetonitrile-0.06moll
-1KH
2PO
4(45: 55); Flow velocity: 1.0ml/min; Ultraviolet detection wavelength: 233nm; Column temperature: room temperature; Sample size: 20 μ g/ml;
2 particle diameters and zeta current potential
Precision is measured the SLN preparation of 400 μ L, with 50 times of ultra-pure water dilutions, average the mensuration of particle diameter and zeta current potential by nanometer current potential particle size analyzer, sample cell is selected DTS1060-Disposable ZetaCell for use, temperature is made as 25 ℃, obtains 3 equal particle size values of Z and 3 zeta potential values.
3. envelop rate
Adopt centrifugal-ultrafiltration to measure the envelop rate of cucurbitacin solid lipid nanoparticle.The earlier centrifugal free drug precipitation that pipettes, ultrafiltration obtains the mode of free drug solution again, adopts the HPLC method to measure, and both are the free drug total amount at the dose sum.
Envelop rate (%)=(free drug precipitation capacity+free drug solution amount)/medicine total amount specifically sees Table 2.
(2) characterization result
The preliminarily stabilised examination result (n=3) of each embodiment particle diameter of table 1
Annotate PDI: the polydispersity coefficient of particle size distribution
As seen from the above table, preserved 4 months under each preparation room temperature lucifuge condition, its particle diameter and distribution are compared at the beginning with preparation significant change are not all taken place, and illustrate that preparation has better physical stability, do not have the particle accumulation phenomenon to take place between probation.
(with embodiment 1 is example, n=3) for table 2 comprehensive stability and envelop rate result of the test
| Holding time | Content % | Particle diameter (Z is equal) | PDI (polydispersity coefficient) | The zeta current potential | Envelop rate % |
| Preparation at the beginning | 100 | 118.4±1.5 | 0.23±0.03 | -20.37±1.17 | 97±2.5 |
| 1 month | 101±0.5 | 119.5±2.0 | 0.24±0.05 | -18.88±2.35 | 98±3.7 |
| 3 months | 98±2.6 | 116.1±2.6 | 0.25±0.03 | -19.65±2.29 | 97±4.0 |
| 6 months | 99％±1.6 | 118.7±1.8 | 0.23±0.06 | -18.65±3.12 | 96±2.8 |
As seen from the above table, preparation was at 6 months storage period, and every index does not all have significant change, and this explanation said preparation not only has better physical stability, also has better chemical stability.
Claims (2)
1. cucurbitacin solid lipid nanoparticle preparation, it is characterized in that, by Cucurbitacine 0.004g, hexadecylic acid 0.05g, stearic acid 0.05g, glyceryl monostearate 0.40g, poloxamer 4070.35g, polyoxyethylene ether (35) Oleum Ricini 0.1g, ultra-pure water 10ml makes, wherein, with hexadecylic acid, stearic acid, glyceryl monostearate and poloxamer 407, polyoxyethylene ether (35) Oleum Ricini is behind lucifuge heating and melting under 95 ℃ of temperature, add Cucurbitacine, with the quick stirring and evenly mixing of Glass rod, putting the refrigerator frozen coating makes it to solidify, the mixture that will solidify is transferred in the ultraphonic pipe of tool thermal insulation casing again, ultrasonic temperature is 80 ℃, add the 10ml ultra-pure water, usefulness ultrasonic cell disruptor ultrasonic 18 times, each ultrasonic 10S in the condition of ultrasonic power 400W, interval 10S, 80 ℃ of insulations afterwards, draw ultrasonic dispersion liquid afterwards, cross 0.22 μ m microporous filter membrane, filtrate is at room temperature cooled off and the inflated with nitrogen sealing by fusing, promptly get the cucurbitacin solid lipid nanoparticle preparation, lucifuge is placed under the room temperature condition.
2. cucurbitacin solid lipid nanoparticle preparation, it is characterized in that, by Cucurbitacine 0.012g, Glyceryl Behenate 1.00g, poloxamer 1880.70g, ultra-pure water 40ml makes, with Glyceryl Behenate and poloxamer 188 behind heating and melting under 95 ℃ of temperature, add Cucurbitacine, stirring makes it abundant mixing, under 80 ℃ of heat-retaining conditions, carry out following operation: at first add 10ml equality of temperature ultra-pure water in the mixture, replenish 30ml equality of temperature ultra-pure water behind the magnetic agitation 10min, with the rotating speed dispersion 10min of high speed dispersor with 9500r/min, with first dispersion liquid while hot under the setting pressure of 18k with microjet homogenize 10 times repeatedly, homogenize liquid is crossed 0.45 μ m microporous filter membrane, at room temperature cool off and the inflated with nitrogen sealing by fusing after the filtration, lucifuge is placed under the room temperature condition.
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| CN103735555B (en) * | 2013-12-27 | 2015-06-10 | 德立唯（北京）生物科技有限公司 | Cucurbitacin medicinal composition and pharmaceutical application thereof |
| CN109589367A (en) * | 2018-11-22 | 2019-04-09 | 福建中医药大学 | A kind of vine tea general flavone solid lipid nano granule and preparation method |
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| CN105456200A (en) * | 2015-12-08 | 2016-04-06 | 郑州大学 | Preparation method and application of nanoparticle microsphere for improving oral bioavailability of poorly soluble drugs |
| CN105456200B (en) * | 2015-12-08 | 2018-08-21 | 郑州大学 | A kind of preparation method and application for the nano mciroball improving insoluble drug oral administration biaavailability |
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