CN102552156A - Nimodipine freeze-dried solid lipid nanoparticle and preparation method thereof - Google Patents
Nimodipine freeze-dried solid lipid nanoparticle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses nimodipine freeze-dried solid lipid nanoparticles, which are prepared by mixing a solid lipid nanoparticle solution with a freeze-drying protective agent and freeze-drying, wherein 20g to 40g of the freeze-drying protective agent is added into every 100mL of the solid lipid nanoparticle solution; the 100mL solid lipid nanoparticle solution is prepared from the following raw materials: 2-20 mg of nimodipine, 0.5-4 g of phospholipid, 0-0.2 g of cholesterol sodium sulfate, 0.02-0.4 g of propylene glycol block polyether and the balance of phosphate buffer solution; the freeze-drying protective agent is one or more of sucrose, glucose, trehalose, maltose and mannitol. The nimodipine freeze-dried solid lipid nanoparticle provided by the invention has the drug loading capacity of 0.2mg/mL, is good in state after re-dissolution, has the characteristics of high efficiency, low toxicity, stability and the like, can improve the compliance of patients, and is suitable for clinical application, and the physicochemical property of the nimodipine freeze-dried solid lipid nanoparticle meets the requirements of intravenous injection.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of Nimodipine freeze-drying solid lipid nanoparticle and preparation method thereof.
Background technology
Nimodipine (Nimodipine NMD) is second filial generation dihydropyridine calcium ion antagonist, and the 1980s is synthetic by Bayer A.G, and its structural formula is following:
Nimodipine can selectively acting in calcium channel, specifically with the reversible combination of relevant receptor, regulate calcium ion concentration in the vascular smooth muscle, cause smooth muscle loosening, reverse vasospasm, improve blood supply.Because nimodipine is a fat-soluble medicine, can pass through blood brain barrier, therefore can protect brain cell, improve it to anoxybiotic toleration.The clinical ischemic cerebrovascular that is usually used in, diseases such as the cerebral vasospasm that subarachnoid hemorrhage causes, apoplexy and migraine also can be improved memory etc.
The nimodipine better tolerance, side effect is little, but has serious liver first-pass effect, and oral administration biaavailability is low, and therefore widely used clinically is its injection.The nimodipine poorly water-soluble contains the ethanol of high concentration in the injection, during use with glucose or normal saline dilution; Separate out deposition sometimes; Therefore and ethanol has zest to blood vessel, and efficient, low toxicity of exploitation and stable nimodipine novel form have great importance.
Solid lipid nanoparticle is structurally similar with liposome, and liposome means drug encapsulation in the lipoids bilayer and the micro-bubbles utricule that forms.It structurally says, have intermediary in water, can water soluble medicament-entrapping, belong to hollow-core construction.And solid lipid nanoparticle is to be carrier with solid natural or synthetic lipoid, with the medicine parcel or clamp the solid micelle drug-supplying system of in lipoid nuclear, processing, says that structurally it belongs to solid construction, more is prone to a bag year fat-soluble medicine.
The prepared liposome of the disclosed Nimodipime nanometer liposome preparation technology of CN1418626A, although safety preferably and biocompatibility are arranged and stride film property, its stability is not fine, the particle diameter of the liposome of this method preparation of usefulness is also bigger than normal.CN1554340A provides a kind of Nimodipime nanometer liposome and precursor freeze-dried composition thereof with good brain targeting, and its mean diameter is below 100nm, but the change of size situation after not providing freeze-dried composition and redissolving and the data of stability.And the quality evaluation after the lyophilizing is the important measurement index of lyophilized formulations.CN1903173A discloses a kind of its preparation method of Nimodipine nanometer granule, its drug loading and stability still can, but particle diameter is bigger, the mean diameter after the redissolution is below 0.3 μ m, bigger particle diameter will be unfavorable for that the brain targeting also is unfavorable for intravenously administrable.
Summary of the invention
Technical problem to be solved by this invention is the deficiency to above-mentioned prior art, and a kind of Nimodipine freeze-drying solid lipid nanoparticle of stable supplied clinical practice is provided.This lyophilized solid lipid nanoparticle is in good condition after redissolving, and its physicochemical property meets the used for intravenous injection requirement, has improved patient's compliance simultaneously, is suitable for clinical practice.
For solving the problems of the technologies described above; The technical scheme that the present invention adopts is: a kind of Nimodipine freeze-drying solid lipid nanoparticle; It is characterized in that; Mix the back lyophilizing with freeze drying protectant by solid lipid nanoparticle solution and process, add 20g～40g freeze drying protectant in every 100mL solid lipid nanoparticle solution; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 2mg～20mg, and phosphatidase 10 .5g～4g, cholesterol sodium sulfate salt 0g～0.2g, propylene glycol block polyether 0.02g～0.4g, surplus is a PBS; Said freeze drying protectant is one or more in sucrose, glucose, trehalose, maltose and the mannitol.
Above-mentioned a kind of Nimodipine freeze-drying solid lipid nanoparticle; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 20mg, phosphatidase 12 g, cholesterol sodium sulfate salt 0.1g; Propylene glycol block polyether 0.2g, surplus is a PBS.
Above-mentioned a kind of Nimodipine freeze-drying solid lipid nanoparticle, said phospholipid are injection stage Ovum Gallus domesticus Flavus lecithin PL-100M; Said propylene glycol block polyether is propylene glycol block polyether F-68.
Above-mentioned a kind of Nimodipine freeze-drying solid lipid nanoparticle, said freeze drying protectant is mannitol and trehalose, the mass ratio of mannitol and trehalose is 1: 2.
Above-mentioned a kind of Nimodipine freeze-drying solid lipid nanoparticle, mannitol and the trehalose of adding 30g in every 100mL solid lipid nanoparticle solution.
In addition, the present invention also provides the method for preparing of above-mentioned Nimodipine freeze-drying solid lipid nanoparticle, it is characterized in that, this method may further comprise the steps:
Step 1, take by weighing nimodipine, phospholipid and cholesterol sodium sulfate salt respectively, the nimodipine that takes by weighing, phospholipid and cholesterol sodium sulfate salt are mixed back heating for dissolving under magnetic agitation, obtain the homogeneous oil phase;
Step 4, colostrum described in the step 3 is used pH value is 6.5～7.5 PBS standardize solution, ultra-sonic dispersion then, and the ultrafiltration sterilization of cooling back obtains solid lipid nanoparticle solution;
Above-mentioned method, the temperature that heats described in the step 1 are 60 ℃.
Above-mentioned method, stir speed (S.S.) described in the step 3 are 500rpm.
Above-mentioned method, ultransonic power described in the step 4 is 750W, ultrasonic time is 10min.
Above-mentioned method, said ultrasonic employing is ultrasonic power at interval, is specially: the every processing of ultrasound wave 3s, intermittently 1s.
The present invention is model drug with the nimodipine, and utilization emulsifying-ultrasonic method has successfully prepared the Nimodipine solid lipid nanoparticle.Through to the optimization of freeze drying process with to the screening of freeze drying protectant prescription, developing of success is efficient, low toxicity and stable Nimodipine freeze-drying solid lipid nanoparticle.
The present invention compared with prior art has the following advantages:
1, Nimodipine freeze-drying solid lipid nanoparticle of the present invention, its drug loading can reach 0.2mg/mL, and is in good condition after redissolving; Its physicochemical property meets the used for intravenous injection requirement; Have efficient, low toxicity, characteristics such as stable, can improve patient's compliance, be suitable for clinical practice.
2, the present invention is through deep research; Select for use cholesterol sodium sulfate salt (SCS) as stabilizing agent; SCS is derived behind Sulfation by cholesterol; It has emulsification as a kind of composition of new membrane stability material participation solid lipid nanoparticle again when playing adjusting membrane fluidity function.Along with the increase of SCS ratio, the clarity of solid lipid nanoparticle increases, and particle diameter reduces and distributes wide, and the absolute value of zeta current potential becomes greatly simultaneously; Compare with cholesterol; The adding of SCS can be so that the solid lipid nanoparticle particle diameter reduces; Under the identical situation of addition; The solid lipid nanoparticle particle diameter that makes with SCS is than little many of the lipid nanoparticle particle diameter that makes with cholesterol, and the absolute value of zeta current potential wants big, and the size of zeta current potential affects stability of formulation in a way.
3, the deep research of process among the present invention selects for use the nonionic emulsifier propylene glycol block polyether as emulsifying agent, in the dissolubility that increases liposoluble constituent, can improve the stability of the envelop rate and the solid lipid nanoparticle of medicine; Simultaneously, select for use existing lipophilic group that the injection stage Ovum Gallus domesticus Flavus lecithin PL-100M of hydrophilic group is arranged again, in the preparation process, be prone to form vesicle.
4, adopt the Nimodipine solid lipid nanoparticle of method preparation of the present invention in freeze-drying process, to have good mouldability; Can be by intact protection; Before the lyophilizing with rehydration after the form and the particle diameter of solid lipid nanoparticle have only minor variations; Mean diameter is about 100nm, and it is stable that each item physicochemical property keeps before and after lyophilizing, meets the intravenous administration requirement.
5, the result that investigates of Nimodipine freeze-drying solid lipid nanoparticle long-time stability of the present invention showed: 25 ± 2 ℃ condition held 3 months; Its outward appearance, residual moisture, pH value, particle diameter and envelop rate all do not have significant change, still meet the requirement of intravenous administration.
Below in conjunction with accompanying drawing and embodiment, technical scheme of the present invention is done further to describe in detail.
Description of drawings
Fig. 1 is the preceding transmission electron microscope photo of Nimodipine freeze-drying solid lipid nanoparticle lyophilizing of the embodiment of the invention 1 preparation.
Fig. 2 is the transmission electron microscope photo after the Nimodipine freeze-drying solid lipid nanoparticle of the embodiment of the invention 1 preparation redissolves.
Fig. 3 is the drug release curve in containing 30% alcoholic acid pH 7.4 phosphate buffers before and after the Nimodipine freeze-drying solid lipid nanoparticle lyophilizing of the embodiment of the invention 1 preparation.
Fig. 4 is single dose vena femoralis injection Nimodipine freeze-drying solid lipid nanoparticle of the present invention and the average blood drug level of solution-type nimotop vial and the curve of time.
The specific embodiment
Embodiment 1
The Nimodipine freeze-drying solid lipid nanoparticle of present embodiment mixes the back lyophilizing by solid lipid nanoparticle solution and processes with freeze drying protectant; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 20mg, and phosphatidase 12 g, cholesterol sodium sulfate salt 0.1g, propylene glycol block polyether 0.2g, surplus is a PBS; Said freeze drying protectant is mannitol and trehalose, and wherein the consumption of mannitol is that every 100mL solid lipid nanoparticle solution is used 10g mannitol, and the consumption of trehalose is that every 100mL solid lipid nanoparticle solution is used the 20g trehalose; Said phospholipid is injection stage Ovum Gallus domesticus Flavus lecithin PL-100M; Said propylene glycol block polyether is propylene glycol block polyether F-68.
The method for preparing of the Nimodipine freeze-drying solid lipid nanoparticle of present embodiment may further comprise the steps:
Step 1, take by weighing 20mg nimodipine, 2g injection stage Ovum Gallus domesticus Flavus lecithin PL-100M and 0.1g cholesterol sodium sulfate salt respectively; The nimodipine that takes by weighing, injection stage Ovum Gallus domesticus Flavus lecithin PL-100M and cholesterol sodium sulfate salt are mixed the back under stirring condition, be heated to 60 ℃ of dissolvings, obtain the homogeneous oil phase;
Step 4, colostrum described in the step 3 is used pH value is that 6.5 PBS is settled to 100mL; Be ultrasonic (the every processing of ultrasound wave 3s at interval under the condition of 750W at power then; 1s intermittently) disperses 10min; The sterilization of 0.22 μ m ultrafilter membrane is crossed in the cooling back, obtains solid lipid nanoparticle solution;
Present embodiment is identical with embodiment 1; Wherein difference is: said freeze drying protectant is a kind of in sucrose, glucose, trehalose, maltose and the mannitol or more than three kinds; Perhaps being two kinds in sucrose, glucose, maltose and the mannitol, perhaps is the mixture of a kind of and trehalose in sucrose, glucose and the maltose.
The Nimodipine freeze-drying solid lipid nanoparticle of present embodiment mixes the back lyophilizing by solid lipid nanoparticle solution and processes with freeze drying protectant; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 10mg, and phosphatidase 11 g, cholesterol sodium sulfate salt 0.05g, propylene glycol block polyether 0.1g, surplus is a PBS; Said freeze drying protectant is mannitol and trehalose, and wherein the consumption of mannitol is that every 100mL solid lipid nanoparticle solution is used 10g mannitol, and the consumption of trehalose is that every 100mL solid lipid nanoparticle solution is used the 20g trehalose; Said phospholipid is injection stage Ovum Gallus domesticus Flavus lecithin PL-100M; Said propylene glycol block polyether is propylene glycol block polyether F-68.
The method for preparing of the Nimodipine freeze-drying solid lipid nanoparticle of present embodiment may further comprise the steps:
Step 1, take by weighing 10mg nimodipine, 1g injection stage Ovum Gallus domesticus Flavus lecithin PL-100M and 0.05g cholesterol sodium sulfate salt respectively; The nimodipine that takes by weighing, injection stage Ovum Gallus domesticus Flavus lecithin PL-100M and cholesterol sodium sulfate salt are mixed the back under stirring condition, be heated to 60 ℃ of dissolvings, obtain the homogeneous oil phase;
Step 4, colostrum described in the step 3 is used pH value is that 7.5 PBS is settled to 100mL; Be ultrasonic (the every processing of ultrasound wave 3s at interval under the condition of 750W at power then; 1s intermittently) disperses 10min; The sterilization of 0.22 μ m ultrafilter membrane is crossed in the cooling back, obtains solid lipid nanoparticle solution;
Embodiment 4
Present embodiment is identical with embodiment 3; Wherein difference is: said freeze drying protectant is a kind of in sucrose, glucose, trehalose, maltose and the mannitol or more than three kinds; Perhaps being two kinds in sucrose, glucose, maltose and the mannitol, perhaps is the mixture of a kind of and trehalose in sucrose, glucose and the maltose.
The Nimodipine freeze-drying solid lipid nanoparticle of present embodiment mixes the back lyophilizing by solid lipid nanoparticle solution and processes with freeze drying protectant; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 2mg, and phosphatidase 10 .5g, propylene glycol block polyether 0.02g, surplus is a PBS; Said freeze drying protectant is a sucrose, and the consumption of sucrose is that every 100mL solid lipid nanoparticle solution is used 20g sucrose; Said phospholipid is injection stage Ovum Gallus domesticus Flavus lecithin PL-100M; Said propylene glycol block polyether is propylene glycol block polyether F-68.
The method for preparing of the Nimodipine freeze-drying solid lipid nanoparticle of present embodiment may further comprise the steps:
Step 1, take by weighing 2mg nimodipine and 0.5g injection stage Ovum Gallus domesticus Flavus lecithin PL-100M respectively, the nimodipine that takes by weighing and injection stage Ovum Gallus domesticus Flavus lecithin PL-100M are mixed the back under stirring condition, be heated to 60 ℃ of dissolvings, obtain the homogeneous oil phase;
Step 4, colostrum described in the step 3 is used pH value is that 7.0 PBS is settled to 100mL; Be ultrasonic (the every processing of ultrasound wave 3s at interval under the condition of 750W at power then; 1s intermittently) disperses 10min; The sterilization of 0.22 μ m ultrafilter membrane is crossed in the cooling back, obtains solid lipid nanoparticle solution;
Present embodiment is identical with embodiment 5, and wherein difference is: said freeze drying protectant is glucose, trehalose, maltose or mannitol, perhaps is at least two kinds in sucrose, glucose, trehalose, maltose and the mannitol.
Embodiment 7
The Nimodipine freeze-drying solid lipid nanoparticle of present embodiment mixes the back lyophilizing by solid lipid nanoparticle solution and processes with freeze drying protectant; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 20mg, and phosphatidase 14 g, cholesterol sodium sulfate salt 0.2g, propylene glycol block polyether 0.4g, surplus is a PBS; Said freeze drying protectant be sucrose, glucose, trehalose, maltose and mannitol by etc. mass ratio mix, the freeze drying protectant total amount is every 100mL solid lipid nanoparticle solution 40g freeze drying protectant; Said phospholipid is injection stage Ovum Gallus domesticus Flavus lecithin PL-100M; Said propylene glycol block polyether is propylene glycol block polyether F-68.
The method for preparing of the Nimodipine freeze-drying solid lipid nanoparticle of present embodiment may further comprise the steps:
Step 1, take by weighing 20mg nimodipine, 4g injection stage Ovum Gallus domesticus Flavus lecithin PL-100M and 0.2g cholesterol sodium sulfate salt respectively; The nimodipine that takes by weighing, injection stage Ovum Gallus domesticus Flavus lecithin PL-100M and cholesterol sodium sulfate salt are mixed the back under stirring condition, be heated to 60 ℃ of dissolvings, obtain the homogeneous oil phase;
Step 4, colostrum described in the step 3 is used pH value is that 6.5 PBS is settled to 100mL; Be ultrasonic (the every processing of ultrasound wave 3s at interval under the condition of 750W at power then; 1s intermittently) disperses 10min; The sterilization of 0.22 μ m ultrafilter membrane is crossed in the cooling back, obtains solid lipid nanoparticle solution;
Embodiment 8
Present embodiment is identical with embodiment 7, and wherein difference is: said freeze drying protectant is four kinds at the most in sucrose, glucose, trehalose, maltose and the mannitol.
Nimodipine freeze-drying solid lipid nanoparticle of the present invention is carried out following detection test:
One, the outward appearance of Nimodipine freeze-drying solid lipid nanoparticle detects
Nimodipine freeze-drying solid lipid nanoparticle of the present invention is carried out perusal, be spongy agglomerate, visible obvious blue opalescence, naked eyes and microscopically are observed does not all have insoluble composition or block aggregate.Nimodipine freeze-drying solid lipid nanoparticle outward appearance is not subsided, not shrinkage, color even, hole fine and close, any surface finish, and volume keeps the volume before the lyophilizing.Outward appearance was translucent milky after the Nimodipine freeze-drying solid lipid nanoparticle redissolved.
Fig. 1 is the preceding transmission electron microscope photo of Nimodipine freeze-drying solid lipid nanoparticle lyophilizing of the embodiment of the invention 1 preparation, and Fig. 2 is the transmission electron microscope photo after the Nimodipine freeze-drying solid lipid nanoparticle of the embodiment of the invention 1 preparation redissolves.Can know the preceding and equal rounding of redissolution back profile of Nimodipine freeze-drying solid lipid nanoparticle lyophilizing, structure homogeneous by Fig. 1 and Fig. 2.
Two, the particle size distribution of Nimodipine freeze-drying solid lipid nanoparticle is investigated
Be diluted to suitable concentration respectively with sample after sample and the redissolution of Nimodipine freeze-drying solid lipid nanoparticle before the water for injection of 0.22 μ m microporous filter membrane ultrafiltration is with the Nimodipine solid lipid nanoparticle lyophilizing of the embodiment of the invention 1 and embodiment 7 preparations, put into Nicomp immediately after then
TMIn 380 particle size analyzers, measure particle size distribution, compare with the particle size distribution of solid lipid nanoparticle solution before the lyophilizing, the result sees table 1.
Table 1 particle size distribution measuring result
| Embodiment | PSD (nm) before the lyophilizing | PSD after the redissolution (nm) |
| 1 | 106±45 | 153±47 |
| 7 | 110±39 | 150±54 |
Can find out that from table 1 particle size distribution of Nimodipine freeze-drying solid lipid nanoparticle before and after lyophilizing of embodiment 1 and embodiment 7 preparations changes very little, all below 200nm, satisfies the used for intravenous injection requirement.
Three, the zeta potential measurement of Nimodipine freeze-drying solid lipid nanoparticle
Adopt Nicomp
TM380 carry out the mensuration of zeta current potential.After sample is diluted to suitable concentration respectively before the Nimodipine solid lipid nanoparticle lyophilizing that the embodiment of the invention 1 and embodiment 7 is prepared through the water for injection of 0.22 μ m microporous filter membrane ultrafiltration, put into Nicomp immediately
TMIn 380 sample cells, measure the zeta current potential, the result sees table 2.
Table 2zeta potential measurement result
| Embodiment | 1 | 7 |
| Zeta potential (mv) | -14.15 | -13.96 |
Can find out that from table 2 the zeta current potential of sample is about-14mv before the Nimodipine solid lipid nanoparticle lyophilizing of the present invention preparation, stability better.
Four, the nimodipine assay of Nimodipine freeze-drying solid lipid nanoparticle and the investigation of envelop rate
Adopt the methanol breakdown of emulsion, with the content of nimodipine in the Nimodipine freeze-drying solid lipid nanoparticle of the HPLC mensuration embodiment of the invention 1 and embodiment 7 preparations, measure envelop rate with the method for external microdialysis, the result is as shown in table 3.
Table 3 Nimodipine solid lipid nanoparticle content and entrapment efficiency determination result
| Embodiment | 1 | 7 |
| Content (%) | 98.45 | 98.32 |
| Envelop rate (%) | 92.56 | 93.14 |
Can find out that from table 3 content of the Nimodipine freeze-drying solid lipid nanoparticle of the present invention preparation is all more than 98%, envelop rate all about 93%, steady quality.
Five, the investigation of the long-time stability of Nimodipine freeze-drying solid lipid nanoparticle
The Nimodipine freeze-drying solid lipid nanoparticle of the embodiment of the invention 1 preparation was positioned over room temperature (25 ℃ ± 2 ℃) drying condition under storage 3 months; Respectively at carrying out the inspection and the mensuration of each item physicochemical property with placement back the 1st, 2, sampling in March before placing, the result sees table 4.
Table 4 Nimodipine freeze-drying solid lipid nanoparticle long-term stable experiment result (25 ℃ ± 2 ℃)
Can find out that from table 4 25 ℃ ± 2 ℃ drying condition held 3 months, the outward appearance of Nimodipine freeze-drying solid lipid nanoparticle, residual moisture, pH value, particle diameter and envelop rate did not all have significant change, still meet the intravenous administration requirement.
Six, the release in vitro before and after the lyophilizing of Nimodipine freeze-drying solid lipid nanoparticle
Accurate respectively measure before the lyophilizing with redissolve after Nimodipine solid lipid nanoparticle 2mL put in the bag filter, tighten at two ends, places the 50mL conical flask, adds 40mL release medium (containing 30% alcoholic acid pH 7.4 PBSs), gets 3 parts in sample with legal system.Conical flask put in 37 ℃ the water bath chader, 100 times/minute vibrations in 0.5,1,2,3,4,6,8,12,24,36, the 48h 100 μ L that take a sample, and replenish the fresh medium with volume, and the medium of taking-up is analyzed with the HPLC method.The result sees table 5.
The release behavior of table 5 Nimodipine freeze-drying solid lipid nanoparticle before and after lyophilizing
Can be known that by table 5 all there is tangible burst effect in two preparations, discharge very fast early stage, and the later stage is tending towards slow.Data curve plotting according to this, the result sees Fig. 3.Two curves are quite similar, show that Nimodipine freeze-drying solid lipid nanoparticle its state before and after lyophilizing does not take place than about-face.
Seven, the zoopery of Nimodipine freeze-drying solid lipid nanoparticle-rat body giving drugs into nose is for dynamics research
The Wister kind male white rat that to select 12 body weight for use be 200 ± 20g; Fasting feedwater before the experiment is divided into two groups at random with rat: matched group and to be checked group, 6 every group; Mode administration with the right back vena femoralis injection of rat; Matched group injection nimotop vial, the to be checked group of Nimodipine freeze-drying solid lipid nanoparticle that injection water for injection redissolves, ID is 0.75mgkg
-1, respectively at 5min after the administration, 10min, 20min, 30min, 45min, 1h, 2h, 4h, the 6h eye socket is got blood 0.5mL, places the 1.5mL conical centrifuge tube of heparinization in advance, the centrifugal 10min of 4000rpm, separated plasma ,-70 ℃ of preservations, to be measured.
The plasma sample 100 μ L that preserve are placed the 7mL centrifuge tube, add 20 μ L inner mark solution (4 μ gmL
-1Nitrendipine solution), 20 μ L methanol and 20 μ L NaOH (0.1M), vortex 30 seconds, mixing; Add 3mL ether-normal hexane (volume ratio 1: 1), vortex 10min; Then in the centrifugal 10min of 4000rpm; Get supernatant 2mL and place the 5mL centrifuge tube, remove with the vacuum evaporation under 40 ℃ of conditions of the centrifugal concentrate drying appearance of U.S. LABCONCO company and desolvate, residue adds 1mL methanol and redissolves; Vortex 5min mixes; The centrifugal 10min of refrigerated centrifuger 12000rpm gets supernatant 5 μ L sample introduction UPLC-ESI-MS/MS and analyzes, rat each the time blood drug level result see table 6 and table 7.
The present invention of table 6 single dose vena femoralis injection
Behind the Nimodipine freeze-drying solid lipid nanoparticle rat each the time blood drug level
Behind the table 7 single dose vena femoralis injection nimotop vial rat each the time blood drug level
Draw matched group and to be checked group of average blood drug level of rat and time relation curve, the result sees Fig. 4.As can be seen from the figure; Behind intravenous injection Nimodipime nanometer solid lipid nanoparticle and the nimodipine solution-type injection; Two kinds of preparations are similar basically in the intravital pharmacokinetics behavior of rat; But because the blood drug level of initial stage solid lipid nanoparticle group is higher than the solution group, the blood drug level that causes nanoparticle in the whole observation process is all the time greater than the solution group.This possibly be owing to medicine after the administration of nimodipine solution is distributed to rapidly its initial plasma drug level to be reduced rapidly.And for the nanoparticle group, the nimodipine medicament more than 90% is present in phospholipid bilayer and surface thereof.Therefore after the administration, medicine needs the regular hour, is diffused in the blood plasma, and then is distributed in the tissue, therefore causes the initial blood drug level of Nimodipine nanometer granule group to be higher than its solution.Simultaneously can know that by the compartment model parameter two preparations all meet three compartment models, the pharmacokinetics behavior basically identical of its medicine.Thereby cause in whole metabolic process, the blood drug level of nanoparticle group is higher than the solution group.
Using DAS2.0 statistical computation software (mathematics pharmacology Professional Committee of Chinese Pharmacological Society) pharmacokinetics program handles the blood drug level data of Nimodipine freeze-drying solid lipid nanoparticle and nimotop vial.Judge that according to AIC value and degree of fitting both compartment models belong to, result of calculation shows that the blood drug level data of Nimodipine freeze-drying solid lipid nanoparticle and nimotop vial all meet three compartment models.
The evaluation of non-compartment model pharmacokinetic parameter and bioequivalence: adopt statistical moment that the blood drug level data are calculated; The physiological disposition of analyzing medicine with statistical moment belongs to a kind of analytical method of non-compartment, so it does not need medicine is set special compartment.The pharmacokinetics program of DAS2.0 statistical computation software is used in this experiment; According to blood drug level-described physiological disposition of time measured data; Calculate the statistical moment pharmacokinetic parameter of Nimodipine freeze-drying solid lipid nanoparticle and nimotop vial, the result sees table 8.
The non-compartment model match of table 8 nimodipine of the present invention
Each item pharmacokinetic parameters of lyophilized solid lipid nanoparticle and reference solution agent
| Parameter | Unit | The Nimodipine freeze-drying solid lipid nanoparticle | Nimotop vial |
| AUC(0-t) | ?μg/L*h | 469.953±67.75 | 343.677±82.791 |
| AUC(0-∞) | ?μg/L*h | 484.489±78.058 | 345.956±84.314 |
| Maximum plasma concentration | ?μg/L | 804.433±117.519 | 600.6±133.676 |
| Peak time of drug | ?h | 0.083±0 | 0.083±0 |
| Half-life | ?h | 0.797±0.187 | 0.545±0.108 |
Use the bioequivalence program of DAS2.0 statistical computation software, the pharmacokinetic parameters of his-and-hers watches 8 is estimated.Employing is to number conversion, and to AUC, maximum plasma concentration has carried out two-way one-side t check, and the result shows the equivalence of two preparations.
In sum, Nimodipine freeze-drying solid lipid nanoparticle of the present invention, its drug loading can reach 0.2mg/mL; It is in good condition to redissolve the back, and its physicochemical property meets the used for intravenous injection requirement, has efficient, low toxicity, characteristics such as stable; Can improve patient's compliance, be suitable for clinical practice.The equivalence of Nimodipine freeze-drying solid lipid nanoparticle of the present invention and nimotop vial has avoided in the injection ethanol to the zest of blood vessel, is efficient, low toxicity, stable nimodipine novel form.
The above; It only is preferred embodiment of the present invention; Be not that the present invention is done any restriction, every technical spirit changes any simple modification, change and the equivalent structure that above embodiment did according to the present invention, all still belongs in the protection domain of technical scheme of the present invention.
Claims (10)
1. a Nimodipine freeze-drying solid lipid nanoparticle is characterized in that, mixes the back lyophilizing with freeze drying protectant by solid lipid nanoparticle solution and processes, and adds 20g～40g freeze drying protectant in every 100mL solid lipid nanoparticle solution; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 2mg～20mg, and phosphatidase 10 .5g～4g, cholesterol sodium sulfate salt 0g～0.2g, propylene glycol block polyether 0.02g～0.4g, surplus is a PBS; Said freeze drying protectant is one or more in sucrose, glucose, trehalose, maltose and the mannitol.
2. a kind of Nimodipine freeze-drying solid lipid nanoparticle according to claim 1; It is characterized in that; The said solid lipid nanoparticle solution of 100mL is processed by following raw material: nimodipine 20mg, phosphatidase 12 g, cholesterol sodium sulfate salt 0.1g; Propylene glycol block polyether 0.2g, surplus is a PBS.
3. a kind of Nimodipine freeze-drying solid lipid nanoparticle according to claim 1 and 2 is characterized in that, said phospholipid is injection stage Ovum Gallus domesticus Flavus lecithin PL-100M; Said propylene glycol block polyether is propylene glycol block polyether F-68.
4. a kind of Nimodipine freeze-drying solid lipid nanoparticle according to claim 1 and 2 is characterized in that said freeze drying protectant is mannitol and trehalose, and the mass ratio of mannitol and trehalose is 1: 2.
5. a kind of Nimodipine freeze-drying solid lipid nanoparticle according to claim 4 is characterized in that, adds mannitol and the trehalose of 30g in every 100mL solid lipid nanoparticle solution.
6. method for preparing Nimodipine freeze-drying solid lipid nanoparticle according to claim 1 or claim 2 is characterized in that this method may further comprise the steps:
Step 1, take by weighing nimodipine, phospholipid and cholesterol sodium sulfate salt respectively, the nimodipine that takes by weighing, phospholipid and cholesterol sodium sulfate salt are mixed back heating for dissolving under magnetic agitation, obtain the homogeneous oil phase;
Step 2, to take by weighing propylene glycol block polyether and the propylene glycol block polyether that takes by weighing is dissolved in pH value be in 6.5～7.5 the PBS, obtains water;
Step 3, water described in the step 2 is heated to identical with the temperature of oil phase described in the step 1, the water after under stirring condition, will heating then splashes into described in the step 1 in the oil phase, disperses to obtain colostrum;
Step 4, colostrum described in the step 3 is used pH value is 6.5～7.5 PBS standardize solution, ultra-sonic dispersion then, and the ultrafiltration sterilization of cooling back obtains solid lipid nanoparticle solution;
Step 5, take by weighing freeze drying protectant and the freeze drying protectant that takes by weighing is dissolved in the solution of solid lipid nanoparticle described in the step 4, packing, lyophilizing obtains the Nimodipine freeze-drying solid lipid nanoparticle.
7. method according to claim 6 is characterized in that, the temperature that heats described in the step 1 is 60 ℃.
8. method according to claim 6 is characterized in that, stir speed (S.S.) described in the step 3 is 500rpm.
9. method according to claim 6 is characterized in that, ultransonic power described in the step 4 is 750W, and ultrasonic time is 10min.
10. method according to claim 9 is characterized in that, said ultrasonic employing is ultrasonic power at interval, is specially: the every processing of ultrasound wave 3s, intermittently 1s.
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