CN103494820A - Nimodipine/ligustrazine double-load PLGA nanoparticles and preparation method thereof - Google Patents
Nimodipine/ligustrazine double-load PLGA nanoparticles and preparation method thereof Download PDFInfo
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Abstract
The invention relates to nimodipine/ligustrazine double-load PLGA nanoparticles which are prepared through a method comprising the steps that: nimodipine, ligustrazine phosphate and a polylactic acid-glycolic acid copolymer are precisely weight according to a mass ratio of 1:5-20:40-60; the materials are dissolved into acetone, such that an organic phase is obtained; a PVA water solution with a mass concentration of 0.5-1.0% is adopted as an aqueous phase; under stirring, the organic phase is slowly dropped into the aqueous phase; when dropping is finished, the mixture is continued to be stirred for 2-4h under a constant temperature of 40-50 DEG C, such that the organic solvent is volatilized; centrifugation is carried out; a sediment is washed 2-3 timed by using distilled water, and is lyophilized, such that the nimodipine/ligustrazine double-loading PLGA nanoparticles are obtained. According to the invention, PLGA is adopted as a carrier material, and P-gp inhibitors TMP and NMD are applied in combination, such that NMD/TMP-PLGA-NPs are prepared. Therefore, defects of short drug half-life, easy generation of cytotoxicity, and the like of simple combination are avoided, a P-gp efflux effect is inhibited, and NMD distribution to tissues is promoted. Therefore, the nanoparticles have certain advantages over single-load nanoparticles.
Description
(1) technical field
The present invention relates to two medicine carrying PLGA nanoparticles (NMD/TMP-PLGA-NPs) of a kind of nimodipine/ligustrazine and preparation method thereof.
(2) background technology
Nimodipine (Nimodipine, NMD) is a class dihydropyridine calcium ion antagonist, by blood flow treatment cerebrovascular disease in expansion brain small artery and raising brain.But the NMD water solublity is poor, commercially available NMD injection mainly, by the dissolve with ethanol medicine, has certain zest; The NMD oral formulations biological half-life of clinical use is short, and first-pass effect is strong, and bioavailability only has 5%～13%; Simultaneously, NMD is as P-glycoprotein(P-gp) substrate, be subject to the upper P-gp of blood brain barrier (blood-brain barrier, BBB) and efflux function influence, cause in its brain concentration lower, limited its therapeutic effect when cerebrovascular disease shows effect.Ligustrazine (Tetramethylpyrazine, TMP) is a class pyrazine Alkaloid, and its pharmacological action is mainly reflected in and improves blood supply and protection ischemic tissue.Research shows, TMP can lower the expression of P-gp, and in restrictive cell, the P-gp substrate effluxes; And the atpase activity that can suppress P-gp, thereby the function of inhibition P-gp increases blood-brain barrier permeability, is conducive to medicine and enters cerebral tissue.Therefore TMP and NMD are share, be expected to improve concentration in the NMD brain, but NMD and TMP simply share and still exist drug half-life short, problem that must frequent drug administration, and in short-term, the TMP excessive concentration may cause NMD excessive concentration in brain, normal cell or tissue is produced to toxicity.
(3) summary of the invention
The present invention seeks to the deficiency existed for solving in prior art when NMD and TMP simply share, two medicine carrying PLGA nanoparticles of a kind of nimodipine/ligustrazine and preparation method thereof are provided.
The two medicine carrying PLGA nanoparticles of a kind of nimodipine/ligustrazine, make by the following method: precision takes nimodipine (NMD), ligustrazine phosphate (TMP) and the Poly(D,L-lactide-co-glycolide (PLGA) that mass ratio is 1:5～20:40～60, be dissolved in acetone, as organic facies; The PVA aqueous solution of mass concentration 0.5～1.0% is as water; Under agitation organic facies is slowly splashed in water, drip to finish, 40～50 ℃ of constant temperature continue to stir 2～4h, fling to organic solvent, centrifugal, and lyophilizing after distilled water wash 2～3 times for precipitation, obtain the two medicine carrying PLGA nanoparticles of described nimodipine/ligustrazine.Described PLGA molecular weight, between 10000～50000Da, is preferably 20000Da, and described PVA molecular weight, between 10000～50000Da, is preferably 13000～23000Da.
Preferably, described nimodipine, ligustrazine phosphate and poly lactic-co-glycolic acid mass ratio are 1:10:50.
Nanoparticle (nanoparticles, NPs) is a kind of new drug carrier, has the advantages such as slow release medicine, reduction toxic and side effects.The present invention is stated from the common bag of NMD and TMP in NPs and can delays drug release, avoids the strong first pass effect of hepar of NMD, reduces because of the excessive cell or tissue toxicity caused of TMP concentration in short-term, when effectively bringing into play the drug combination advantage, is overcoming its deficiency.
The invention still further relates to the method for the two medicine carrying PLGA nanoparticles of the described nimodipine/ligustrazine of preparation, described method comprises: precision takes nimodipine, ligustrazine phosphate and the Poly(D,L-lactide-co-glycolide that mass ratio is 1:5～20:40～60, be dissolved in proper amount of acetone, as organic facies; The PVA aqueous solution of mass concentration 0.5～1.0% is as water; Stirring (500～800rmin
-1) under organic facies is slowly splashed in water, drip to finish, 40～50 ℃ of constant temperature continue to stir 2～4h(500～800rmin
-1), fling to organic solvent, 10000～15000rmin
-1centrifugal 20～30min, get lyophilizing after distilled water wash 2～3 times for precipitation, obtains the two medicine carrying PLGA nanoparticles of described nimodipine/ligustrazine.
Preferably, the ratio of described nimodipine, ligustrazine phosphate and poly lactic-co-glycolic acid consumption is 1:10:50.
Preferably, described acetone consumption is 2～10mL/mg nimodipine, and the water volume is 5～20 times of organic facies volume.
Beneficial effect of the present invention is mainly reflected in: the present invention be take PLGA as carrier material, P-gp inhibitor TMP and NMD use in conjunction have been prepared to NMD/TMP-PLGA-NPs, short at the drug half-life of avoiding simply share existence, easily suppressed P-gp when producing the deficiencies such as cytotoxicity and effluxed effect, promoted the distribution of NMD to tissue, with single drug-carrying nanometer particle, compared and there is some superiority.
(4) accompanying drawing explanation
Fig. 1 is NMD/TMP-PLGA-NPs transmission electron microscope photo (* 60000);
Fig. 2 is the NMD/TMP-PLGA-NPs particle size distribution;
Fig. 3 is the NMD/TMP-PLGA-NPs Zeta potential;
Fig. 4 is NMD, TMP tablets in vitro curve (n=3);
Fig. 5 is blank rat plasma (A), and blank rat plasma adds NMD standard solution (B), rat plasma sample (C) high-efficient liquid phase chromatogram after tail intravenously administrable NMD/TMP-PLGA-NPs;
Fig. 6 is curve during medicine after rat tail vein administration NMD suspension, NMD/TMP suspension, NMD-PLGA-NPs and NMD/TMP-PLGA-NPs.
(5) specific embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1:
1. instrument and material
1.1 instrument
UV-1700 ultraviolet spectrophotometer (Japanese Shimadzu company); Agilent1200 high performance liquid chromatograph (U.S. Anjelen Sci. & Tech. Inc); 380ZLS laser granulometry (U.S. Nico mp company); JEM-1200EX transmission electron microscope (Japanese JEOL company); Labconc o freezer dryer (U.S. Labconco company); Mill-Q Superpure water machine (U.S. Millpore company); KQ5200DE type numerical control ultrasonic cleaner (Kunshan Ultrasonic Instruments Co., Ltd.); TGL-16B high speed tabletop centrifuge (Anting Scientific Instrument Factory, Shanghai); CP225D electronic balance (Beijing Sai Duolisi scientific instrument company limited); Nitrogen purging instrument (Hangzhou Ao Sheng Instrument Ltd.); Bag filter (upper sea green bird development in science and technology company limited, Mw=14000Da); HZ-9212S water-bath constant temperature oscillator (Taicang, Jiangsu Hua Lida experimental facilities company).
1.2 medicine and reagent
Nimodipine (Hubei Heng Shuo pharmaceutcal corporation, Ltd, purity > 98%, lot number 20100302); Nimodipine reference substance (Chinese food drug assay institute, lot number 100270-200002); Ligustrazine phosphate (Nantong flies space bio tech ltd, purity > 95%, lot number 20110215); Ligustrazine phosphate reference substance (Chinese food drug assay institute, lot number 110817-201008); Poly(D,L-lactide-co-glycolide (Mount Tai, Jinan handle of the Big Dipper biological engineering company limited, Mw=20000Da); Polyvinyl alcohol (U.S. Sigma company, Mw=13000～23000Da, lot number 10918AE); Methanol (chromatographically pure, U.S. Honeywell Burdick& Jackson company, lot number 10071753); Other reagent are domestic analytical pure.
1.3 laboratory animal
Clean level SD rat, male and female dual-purpose, body weight (220 ± 10) g(Zhejiang University of Traditional Chinese Medicine Experimental Animal Center, (quality certification number: SCXK Zhejiang 2008-0036)); All zooperies are all carried out according to Zhejiang University's animal feeding and guide for use.
2. method
2.1 the preparation of nanoparticle
Adopt the emulsified solvent sedimentation method to prepare nanoparticle: precision takes 1.0mg NMD, 10mg TMP and 50mg PLGA is dissolved in 3mL acetone, as organic facies; 0.75%PVA aqueous solution 36mL is as water.At 800rmin
-1with No. 5 syringe needles, organic facies is slowly splashed in water under mixing speed, drip and finish, 40 ℃ of constant temperature continue 800rmin
-1stir 3h, obtain the NMD/TMP-PLGA-NPs suspension, fling to organic solvent, ultracentrifugation (13000rmin
-1) 30min, precipitation obtains NMD/TMP-PLGA-NPs with lyophilizing after distilled water wash 3 times.
NMD-PLGA-NPs(nimodipine medicine carrying PLGA nanoparticle) preparation method is except not adding TMP all same NMD/TMP-PLGA-NPs.
2.2 form, particle diameter and Zeta potential
Get appropriate NMD/TMP-PLGA-NPs lyophilized powder, add water and redissolve for the suspendible drop on copper mesh, blot with filter paper after standing 10min, then drip mass fraction 2.0% Salkowski's solution negative staining 3min on copper mesh, naturally volatilize, by transmission electron microscope observation form photographs; Get the NMD/TMP-PLGA-NPs suspension, after appropriate distilled water diluting, adopt laser granulometry to measure mean diameter, particle size distribution and Zeta potential.
2.3 the mensuration of envelop rate and drug loading
2.3.1 chromatographic condition
NMD chromatographic condition chromatographic column: Thermo Hypersil Gold C
18post (250mm * 4.6mm, 5 μ m); Mobile phase: methanol-water (70:30); Detect wavelength: 238nm; Flow velocity: 1.0mLmin
-1; Column temperature: 35 ℃; Sampling volume: 20 μ L.
TMP chromatographic condition chromatographic column: Thermo Hypersil Gold C
18post (250mm * 4.6mm, 5 μ m); Mobile phase: methanol-water (45:55); Detect wavelength: 280nm; Flow velocity: 1.0mLmin
-1; Column temperature: 35 ℃; Sampling volume: 20 μ L.
2.3.2 linear relationship is investigated
The NMD linear relationship investigates that accurate to take drying under reduced pressure appropriate to the NMD reference substance of constant-quality, puts in the 10mL volumetric flask, and with dissolve with methanol and be diluted to scale, obtaining mass concentration is 0.196mgmL
-1nMD reference substance storing solution.Precision measures storing solution in right amount in the 10mL volumetric flask respectively, with methanol, is diluted to scale, obtains concentration and is respectively 1.96,3.92,9.80,19.60,39.20,58.80 μ gmL
-1serial reference substance solution, measure by " 2.3.1 " lower NMD chromatographic condition, with peak area integrated value (A), mass concentration (C) is carried out to linear regression, obtain regression equation A=146.10C+13.23(r=0.9997), show that NMD is at 1.96～58.80 μ gmL
-1interior peak area and drug level are good linear relationship.
The TMP linear relationship investigates that accurate to take drying under reduced pressure appropriate to the TMP reference substance of constant-quality, puts in the 10mL volumetric flask, and with dissolve with methanol and be diluted to scale, obtaining mass concentration is 0.196mgmL
-1tMP reference substance storing solution.Precision measures storing solution in right amount in the 10mL volumetric flask respectively, with methanol, is diluted to scale, and obtaining concentration is 1.25,2.50,5.00,10.00,12.50,23.00 μ gmL
-1serial reference substance solution, measure by " 2.3.1 " lower TMP chromatographic condition, with peak area integrated value (A), mass concentration (C) is carried out to linear regression, obtain regression equation A=42.587C-13.869(r=0.9999), TMP is at 1.25～46.00 μ gmL
-1interior peak area and drug level are good linear relationship.
2.3.3 envelop rate and drug loading are measured precision and are measured NMD/TMP-PLGA-NPs suspension 1mL, are placed in tool plug centrifuge tube, 13000rmin under room temperature
-1centrifugal 30min, get supernatant 200 μ L in the 10mL volumetric flask, by dilution in acetonitrile, to scale, through 0.22 μ m microporous filter membrane, filters, and gets subsequent filtrate and measure respectively free NMD and TMP content by " 2.3.1 " lower chromatographic condition; Separately get NMD/TMP-PLGA-NPs suspension 200 μ L in the 10mL volumetric flask, with appropriate acetonitrile breakdown of emulsion and be diluted to scale, through 0.22 μ m microporous filter membrane, filter, subsequent filtrate is measured respectively NMD total in NMD/TMP-PLGA-NPs and TMP content by " 2.3.1 " lower chromatographic condition; Calculate respectively envelop rate (EE%) and the drug loading (DL%) of NMD and TMP in NPs by following formula.
EE%＝(W
0–W
1)/W
0×100%
DL%＝(W
0–W
1)/W
t×100%
Wherein, W
0for the total medication amount in NPs; W
1for the free drug amount in NPs; W
t: the gross weight of NPs.
2.4 tablets in vitro research
The PBS solution of choosing containing volume fraction 30% ethanol is release medium (pH7.4), investigates the tablets in vitro behavior of NMD/TMP-PLGA-NPs.Precision takes each 3 parts of the former medicine mixed-powder of appropriate NMD/TMP, NMD/TMP-PLGA-NPs lyophilized powders respectively, be scattered in the 2mL release medium, be placed in the bag filter (Mw=14000Da) of anticipating, after getting rid of bubble, seal, be placed in the 200mL release medium, in (37 ± 0.5) ℃ water bath with thermostatic control vibration (75rmin
-1), respectively at 0.1,0.25,0.5,0.75,1,1.25,1.5,1.75,2,2.5,3,4,5,6,8,12,24h accurately samples 1mL, and add immediately the fresh release medium of equivalent equality of temperature, sample filters through 0.22 μ m microporous filter membrane, get subsequent filtrate and measure release medium Chinese medicine content by " 2.3.1 " lower chromatographic condition, calculate cumulative release rate (Q%).
2.5NMD/TMP-PLGA-NPs pharmacokinetic studies in the rat body
2.5.1 plasma sample processing precision pipettes plasma sample 200 μ L and puts in 2mL tool plug centrifuge tube, adds acetonitrile 800 μ L, vortex mixed 3min, in 10000rmin
-1centrifugal 10min, get supernatant and dry up by nitrogen current in 40 ℃, 200 μ L dissolve with methanol for residue, fully after the vortex vibration in 10000rmin
-1centrifugal 10min, get supernatant 20 μ L sample introduction analyses.
2.5.2 the foundation of NMD assay method in blood plasma
Chromatographic condition chromatographic column: Thermo Hypersil Gold C
18post (250mm * 4.6mm, 5 μ m); Mobile phase: methanol-water (70:30); Flow velocity: 1.0mLmin
-1; Column temperature: 30 ℃; Detect wavelength 238nm.Sampling volume: 20 μ L.
The method specificity is investigated and to be taken 1mg NMD, 10mg TMP in the 10mL volumetric flask, with dissolve with methanol and be diluted to scale, obtains the NMD/TMP reference substance solution.Get respectively rat blank plasma, rat blank plasma and add rat plasma sample after NMD/TMP reference substance solution and rat tail vein injection NMD/TMP-PLGA-NPs, after processing by " 2.5.1 " lower method, sample introduction is measured.
It is appropriate to the NMD reference substance of constant weight that the preparation precision of standard curve takes drying under reduced pressure, is placed in the 25mL measuring bottle, adds dissolve with methanol and be diluted to scale, and being made into mass concentration is 0.040 μ gL
-1reference substance solution, be diluted to before use series concentration.
Precision is drawn blank plasma 1mL7 part, adds respectively the reference substance solution 20 μ L of series concentration, and vortex mixed, obtain mass concentration and be respectively 6.25,12.50,25.00,50.00,100.00,200.00,400.00 μ gL
-1nMD series blood plasma standard solution, after processing by " 2.5.1 " lower method, sample introduction is measured, and with peak area (A), the concentration (C) of NMD in blood plasma is carried out to linear regression, the Criterion curvilinear equation.
It is appropriate that the method response rate and precision mensuration precision measure the NMD reference substance solution, is mixed with 50.00,100.00,200.00 μ gL
-1the plasma sample of basic, normal, high 3 mass concentrations, after processing by " 2.5.1 " lower method, sample introduction is measured, each concentration parallel assay 3 times, calculate recovery rate.In a few days measuring 5 times respectively METHOD FOR CONTINUOUS DETERMINATION 5d(every day 1 time), calculate in a few days and day to day precision.2.5.3 dosage regimen and blood specimen collection
Take 1mg NMD and NMD/TMP(NMD1mg, TMP10mg) former medicated powder end in the 10mL volumetric flask, with appropriate ethanol ultrasonic dissolution, with 0.9% normal saline dilution, to scale, obtain NMD suspension and NMD/TMP suspension.Take 3.6g NMD-PLGA-NPs and NMD/TMP-PLGA-NPs lyophilized powder in the 10mL volumetric flask, with appropriate 0.9% normal saline ultrasonic dissolution and be diluted to scale, obtain NMD-PLGA-NPs and NMD/TMP-PLGA-NPs suspension.
Get 32 of healthy SD rats, fasting 12h, freely drink water, and is divided at random 4 groups, 8 every group.Press NMD2mgkg
-1the single dose tail vein injection gives respectively NMD suspension, NMD/TMP suspension, NMD-PLGA-NPs suspension and NMD/TMP-PLGA-NPs suspension, after administration respectively at 2,5,15,30,60,90,120,180,300,420min gets blood 0.5mL through femoral artery, put in the pretreated 2mL tool of heparin sodium plug centrifuge tube 3000rmin
-1centrifugal 10min, after separated plasma, put-80 ℃ of cryogenic refrigerators and preserve to be measured.Give immediately 0.9% normal saline of equivalent with microsyringe after getting blood at every turn.
3 results
3.1NMD/TMP-PLGA-NPs character
Observe NMD/TMP-PLGA-NPs under transmission electron microscope and be similar round, size and distribution uniform, have no adhesion and gathering (Fig. 1) between particle.The particle size distribution result shows, mean diameter is (631.6 ± 3.2) nm, polydispersity coefficient be (0.097 ± 0.007) (Fig. 2); Zeta potential is (19.25 ± 1.87) mV(Fig. 3).Recording NMD envelop rate in NMD/TMP-PLGA-NPs is (76.25 ± 1.18) %, and drug loading is (1.24 ± 0.01) %; The TMP envelop rate is (39.30 ± 1.00) %, and drug loading is (6.34 ± 0.11) %.
3.2NMD/TMP-PLGA-NPs tablets in vitro
In pH7.4PBS medium (containing volume fraction 30% ethanol), NMD and TMP tablets in vitro curve are shown in Fig. 4.The former medicine mixed-powder of NMD/TMP-Sol() in, the release in release medium of two medicines is all very fast, 0.75h NMD and TMP cumulative release percentage rate are respectively 57.28% and 56.67%, during 3h, two medicines all discharge fully substantially, and the cumulative release percentage rate is respectively 95.5% and 95.39%.NMD/TMP-PLGA-NPs is respectively 27.10% and 23.61% at 0.75h NMD and TMP cumulative release percentage rate, with NMD/TMP-Sol, compares, and has obvious sustained releasing character; 24hNMD and TMP cumulative release percentage rate are respectively 75.6% and 55.3%.
3.4 pharmacokinetic studies
3.4.1 after the blank rat plasma of method specificity, blank rat plasma add NMD reference substance and rat tail vein drug administration by injection NMD/TMP-PLGA-NPs, plasma sample HPLC chromatogram is shown in Fig. 5.As shown in Figure 5, the method good separating effect of setting up, specificity is strong, the equal interference measurement not of impurity or endogenous material in blood plasma.
3.4.2 standard curve and methodological study as a result in blood plasma the standard curve equation of NMD be A=0.251C-0.046(r=0.9995), show that NMD blood plasma mass concentration is at 6.25～400.00 μ gL
-1the internal linear relation is good.
3.4.3 precision, the method response rate are investigated the method response rate of basic, normal, high 3 kinds of plasma concentration NMD and are respectively (90.08 ± 5.09) %, (93.96 ± 2.93) %, (90.55 ± 2.49); In a few days RSD is respectively 5.66%, 3.12%, 2.75%; In the daytime RSD is respectively 7.55%, 3.74%, 3.04%, meets the methodology requirement.
3.4.4, after blood drug level-time graph and pharmacokinetic parameters rat tail vein injection NMD suspension, NMD/TMP suspension, NMD-PLGA-NPs suspension and NMD/TMP-PLGA-NPs suspension, average blood drug level-time graph is shown in Fig. 6.Data meet open two-compartment model after matching, and the main pharmacokinetic parameters of gained is in Table 1, and it is carried out to statistical analysis.As shown in Table 1, NPs group (NMD-PLGA-NPs suspension and NMD/TMP-PLGA-NPs suspension) is compared t with suspension group (NMD suspension and NMD/TMP suspension)
1/2significant prolongation (p<0.01), AUC significantly improves (p<0.01), illustrates that NPs has delayed the elimination of medicine; Two medicine coupling groups (NMD/TMP-Sol and NMD/TMP-PLGA-NPs) are compared with alone NMD group (NMD-Sol and NMD-PLGA-NPs), and the CL value obviously improves (p<0.05), V
βvalue enlarges markedly (p<0.01), illustrates that TMP has affected pharmacokinetics behavior in the NMD body to a certain extent.
Table 1: pharmacokinetic parameters after the rat tail vein administration
*p<0.05,
**p<0.01,NMD-Sol?vs?NMD/TMP-Sol
△p<0.05,
△△p<0.01,NMD-PLGA-NPs?vs?NMD/TMP-PLGA-NPs
▲p<0.05,
▲▲p<0.01,NMD-Sol?vs?NMD-PLGA-NPs?or?NMD/TMP-PLGA-NPs
4 discuss
Two drug-carrying nanometer particles, as the new method of a kind of compatibility administration, efficacy enhancing and toxicity reducing, obtain and pay close attention to gradually in recent years.The present invention be take PLGA as carrier material, P-gp inhibitor TMP and NMD use in conjunction have been prepared to NMD/TMP-PLGA-NPs, short at the drug half-life of avoiding simply share existence, easily suppressed P-gp when producing the deficiencies such as cytotoxicity and effluxed effect, promoted the distribution of NMD to tissue, with single drug-carrying nanometer particle, compared and there is some superiority.
The present invention adopts the emulsified solvent sedimentation method to prepare NMD/TMP-PLGA-NPs.Because TMP is soluble in water, easily from oil phase, break away from emulsion process and constantly diffuse in water, envelop rate is reduced, and can stay duct on the NPs surface, make its rate of release in elementary drug release process very fast.Therefore, be to improve TMP envelop rate in NPs, this effects the impact of each factor on envelop rate.Result shows, the TMP envelop rate mainly is subject to PLGA molecular weight and concentration, outer water PVA concentration affects: with PLGA molecular weight and concentration, increase, the organic facies viscosity increases, and TMP slows down to the water diffusion rate, with PLGA interaction of molecules time lengthening, envelop rate improves; With water PVA concentration, increase, organic facies and aqueous phase interface surface tension reduce, more easily form less emulsion droplet, the NPs particle diameter is reduced, the water viscosity increases simultaneously, therefore be unfavorable for the diffusion of medicine to water, envelop rate improves, but too high PLGA molecular weight and concentration, PVA concentration can cause its particle diameter larger.Through investigating, it is carrier material (consumption is 50mg) that this experiment adopts the PLGA that molecular weight is 20000Da, and 0.75%PVA is that water is to obtain better particle diameter and higher TMP envelop rate.
The dissolubility of NMD in water is minimum, while selecting common release medium, only has the trace medicine in dissolution fluid.The equilbrium solubility of NMD in pH7.4PBS buffer solution (containing volume fraction 30% ethanol) is about 82.98 μ gmL
-1, the drug level after NPs discharges fully is 1.32 μ gmL
-1, meet sink conditions, so this experimental selection pH7.4PBS buffer solution (containing volume fraction 30% ethanol) is as vitro Release Medium.The result demonstration, the NPs of this experiment preparation has certain slow release characteristic.
The pharmacokinetic studies result shows: with the suspension group, compare, NPs organizes t
1/2 βsignificant prolongation (p<0.01), CL significantly reduces (p<0.01), and AUC approximately improves 4 times, and prompting NPs has certain slow releasing function, and has reduced the elimination speed of NMD; Compare two medicine coupling group t with alone NMD group
1/2 αsignificantly reduce (p<0.01), V
βobviously improve (p<0.05) with CL, AUC obviously reduces (p<0.05), and this conforms to P-gp inhibitor coupling result of study with other drug.T
1/2 αreduce prompting TMP and may promote to a certain extent the distribution of NMD to tissue, reduced medicine holdup time in blood plasma, effectively brought into play the effect of P-gp inhibitor.
Claims (5)
1. two medicine carrying PLGA nanoparticles of a nimodipine/ligustrazine, make by the following method: precision takes nimodipine, ligustrazine phosphate and the Poly(D,L-lactide-co-glycolide that mass ratio is 1:5～20:40～60, is dissolved in acetone, as organic facies; The PVA aqueous solution of mass concentration 0.5～1.0% is as water; Under agitation organic facies is slowly splashed in water, drip to finish, 40～50 ℃ of constant temperature continue to stir 2～4h, fling to organic solvent, centrifugal, and lyophilizing after distilled water wash 2～3 times for precipitation, obtain the two medicine carrying PLGA nanoparticles of described nimodipine/ligustrazine.
2. as claimed in claim 1 pair of medicine carrying PLGA nanoparticle, is characterized in that described nimodipine, ligustrazine phosphate and poly lactic-co-glycolic acid mass ratio are 1:10:50.
3. the method for preparing the two medicine carrying PLGA nanoparticles of nimodipine/ligustrazine claimed in claim 1, described method comprises: precision takes nimodipine, ligustrazine phosphate and the Poly(D,L-lactide-co-glycolide that mass ratio is 1:5～20:40～60, be dissolved in acetone, as organic facies; The PVA aqueous solution of mass concentration 0.5～1.0% is as water; Under agitation organic facies is slowly splashed in water, drip and finish, 40～50 ℃ of constant temperature continue to stir 2～4h, fling to organic solvent, 10000～15000rmin
-1centrifugal 20～30min, get lyophilizing after distilled water wash 2～3 times for precipitation, obtains the two medicine carrying PLGA nanoparticles of described nimodipine/ligustrazine.
4. method as claimed in claim 2, the ratio that it is characterized in that described nimodipine, ligustrazine phosphate and poly lactic-co-glycolic acid consumption is 1:10:50.
5. method as claimed in claim 2, is characterized in that described acetone consumption is 2～10mL/mg nimodipine, and the water volume is 5～20 times of organic facies volume.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758261A (en) * | 2015-04-30 | 2015-07-08 | 中国医学科学院生物医学工程研究所 | Icariin PLGA nano particles and preparing method and application thereof |
| CN107158070A (en) * | 2017-06-09 | 2017-09-15 | 南方医科大学 | A kind of pharmaceutical composition and its production and use |
| CN108309943A (en) * | 2018-04-02 | 2018-07-24 | 中国药科大学 | A kind of compound preparation based on drug granule |
| CN117288793A (en) * | 2023-09-06 | 2023-12-26 | 青岛大学附属医院 | Titanium-containing test piece of cross-linked PLGA drug-loaded coating, and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758261A (en) * | 2015-04-30 | 2015-07-08 | 中国医学科学院生物医学工程研究所 | Icariin PLGA nano particles and preparing method and application thereof |
| CN107158070A (en) * | 2017-06-09 | 2017-09-15 | 南方医科大学 | A kind of pharmaceutical composition and its production and use |
| CN107158070B (en) * | 2017-06-09 | 2020-09-04 | 南方医科大学 | Pharmaceutical composition and preparation method and application thereof |
| CN108309943A (en) * | 2018-04-02 | 2018-07-24 | 中国药科大学 | A kind of compound preparation based on drug granule |
| CN108309943B (en) * | 2018-04-02 | 2021-05-04 | 中国药科大学 | Compound preparation based on medicine particles |
| CN117288793A (en) * | 2023-09-06 | 2023-12-26 | 青岛大学附属医院 | Titanium-containing test piece of cross-linked PLGA drug-loaded coating, and preparation method and application thereof |
| CN117288793B (en) * | 2023-09-06 | 2024-04-02 | 青岛大学附属医院 | Titanium-containing test piece of cross-linked PLGA drug-loaded coating, and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN103494820B (en) | 2015-07-29 |
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