CN117771212A - Resina Draconis perchlorate solid lipid nanoparticle, and preparation method and application thereof - Google Patents
Resina Draconis perchlorate solid lipid nanoparticle, and preparation method and application thereof Download PDFInfo
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- CN117771212A CN117771212A CN202311820492.4A CN202311820492A CN117771212A CN 117771212 A CN117771212 A CN 117771212A CN 202311820492 A CN202311820492 A CN 202311820492A CN 117771212 A CN117771212 A CN 117771212A
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- perchlorate
- resina draconis
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- solid lipid
- poloxamer
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Abstract
The invention provides a preparation method of solid lipid nanoparticles of resina Draconis perchlorate, which comprises the following steps: a) Mixing glyceryl monostearate, soybean phospholipid and resina Draconis perchlorate, and dissolving with solvent to obtain organic phase; b) An aqueous solution of poloxamer as the aqueous phase; c) The organic phase is added into the water phase and cooled to obtain the product. According to the invention, the glyceryl monostearate, the soybean lecithin and the poloxamer are used as coating materials to coat the resina Draconis perchlorate, so that the finally prepared resina Draconis perchlorate solid lipid nanoparticle has high stability, high encapsulation efficiency and high drug loading.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a resina Draconis perchlorate solid lipid nanoparticle, and a preparation method and application thereof.
Background
Resina Draconis extract as main bioactive component of resina Draconis belongs to flavonoid compound, and is an index compound for quality control of resina Draconis, but its chemical property is unstable, and is easily decomposed by external factors such as illumination, temperature and pH value. The synthetic analogue of the dragon's blood perchlorate is a standard substance for measuring the content of the dragon's blood, which is specified in the pharmacopoeia of the people's republic of China (2020 edition), and the study reports that the dragon's blood perchlorate has various effects of resisting tumor, promoting wound healing, preventing and treating diabetes, resisting leukemia, resisting ulcer, resisting inflammation and the like.
Therefore, it is very necessary to develop a solid lipid nanoparticle of resina Draconis perchlorate with high stability, encapsulation efficiency and drug loading.
Disclosure of Invention
In view of the above, the technical problem to be solved by the invention is to provide a resina Draconis perchlorate solid lipid nanoparticle, which has high stability, high encapsulation efficiency and high drug loading.
The invention provides a preparation method of solid lipid nanoparticles of resina Draconis perchlorate, which comprises the following steps:
a) Mixing glyceryl monostearate, soybean phospholipid and resina Draconis perchlorate, and dissolving with solvent to obtain organic phase;
b) An aqueous solution of poloxamer as the aqueous phase;
c) The organic phase is added into the water phase and cooled to obtain the product.
Preferably, the mass ratio of the glyceryl monostearate to the soybean phospholipid is 1: (1-3);
the mass ratio of the glyceryl monostearate to the soybean phospholipid to the resina Draconis perchlorate is (8-12): (18-22): (1-3).
Preferably, the concentration of the poloxamer aqueous solution is 10-40 mg/mL.
Preferably, the mass ratio of the glyceryl monostearate to the soybean phospholipid to the poloxamer is (8-12): (18-22): (10-14).
Preferably, the solvent of step a) is ethanol; the dissolution is ultrasonic dissolution, and the power of the ultrasonic is 200-300 Hz; the dissolution temperature is 70-80 ℃;
the poloxamer water solution in the step B) is specifically obtained by dissolving poloxamer in water; the dissolution temperature is 70-80 ℃.
Preferably, the addition of the organic phase in step C) into the aqueous phase is specifically: slowly dripping the organic phase into water under the condition of stirring at 70-80 ℃, and stirring for 20-30 min at 80 ℃; the stirring speed is 1000-1400 r/min;
the cooling specifically comprises the following steps: cooling in ice water at 0-2 deg.c, stirring for 50-70 min and cooling at 25-30 deg.c.
The invention provides a resina Draconis perchlorate solid lipid nanoparticle, which is prepared by the preparation method according to any one of the technical schemes.
The invention provides a dragons perchlorate medicine, which comprises dragons perchlorate solid lipid nano particles in the technical proposal.
Preferably, the dosage form of the medicine is one or more of powder, suspension, tablet, capsule, granule or powder.
The invention provides application of the resina Draconis perchlorate solid lipid nanoparticle in preparing a medicament for treating injury neuralgia.
Preferably, the treatment comprises decreasing expression of NMDAR1 and/or increasing pain threshold.
Compared with the prior art, the invention provides a preparation method of solid lipid nanoparticles of resina Draconis perchlorate, which comprises the following steps: a) Mixing glyceryl monostearate, soybean phospholipid and resina Draconis perchlorate, and dissolving with solvent to obtain organic phase; b) An aqueous solution of poloxamer as the aqueous phase; c) The organic phase is added into the water phase and cooled to obtain the product. According to the invention, the glyceryl monostearate, the soybean lecithin and the poloxamer are used as coating materials to coat the resina Draconis perchlorate, so that the finally prepared resina Draconis perchlorate solid lipid nanoparticle has high stability, high encapsulation efficiency and high drug loading.
Drawings
FIG. 1 is a drawing of a standard of resina Draconis perchlorate;
FIG. 2 is a standard curve of resina Draconis perchlorate;
FIG. 3 is a star point effect and contour plot;
FIG. 4SLN particle size plot;
FIG. 5 effect of tincture on rat sciatic nerve pathology (HE staining, 200X);
FIG. 6 is an in vitro release profile of resina Draconis drug substance and resina Draconis emulsion.
Detailed Description
The invention provides a resina Draconis perchlorate solid lipid nanoparticle, a preparation method and application thereof, and a person skilled in the art can properly improve process parameters by referring to the content of the resina Draconis perchlorate solid lipid nanoparticle. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and they are intended to be within the scope of the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the invention can be practiced and practiced with modification and alteration and combination of the methods and applications herein without departing from the spirit and scope of the invention.
The invention provides a preparation method of solid lipid nanoparticles of resina Draconis perchlorate, which comprises the following steps:
a) Mixing glyceryl monostearate, soybean phospholipid and resina Draconis perchlorate, and dissolving with solvent to obtain organic phase;
b) An aqueous solution of poloxamer as the aqueous phase;
c) The organic phase is added into the water phase and cooled to obtain the product.
The preparation method of the resina Draconis perchlorate solid lipid nanoparticle comprises the steps of firstly mixing glyceryl monostearate, soybean lecithin and resina Draconis perchlorate;
in a part of the preferred embodiment of the present invention, the mass ratio of the glyceryl monostearate to the soybean lecithin is 1: (1-3);
specifically, the mass ratio of the glyceryl monostearate to the soybean phospholipid is 1:1, 1:2 or 1:3; or a point value between any two of the above.
In a preferred embodiment of the present invention, the mass ratio of the glyceryl monostearate to the soybean phospholipid to the resina Draconis perchlorate is preferably (8 to 12): (18-22): (1-3);
in a preferred embodiment of the present invention, the mass ratio of the glyceryl monostearate to the soybean phospholipid to the resina Draconis perchlorate is preferably (9 to 11): (19-21): (1.1-2.8);
in one preferred embodiment of the present invention, the mass ratio of the glyceryl monostearate to the soybean phospholipid to the resina Draconis perchlorate is preferably 10:20:2.
the invention adopts solvent to dissolve after mixing to obtain organic phase; the solvent includes, but is not limited to, ethanol; the dissolution is ultrasonic dissolution, and the power of the ultrasonic is 200-300 Hz; the dissolution temperature is 70-80 ℃; more preferably, the temperature of dissolution is 80 ℃.
An aqueous solution of poloxamer was used as the aqueous phase. The poloxamer water solution is specifically obtained by dissolving poloxamer in water; the dissolution temperature is 70-80 ℃; more preferably, the temperature of dissolution is 80 ℃.
In certain embodiments, the concentration of the aqueous solution of poloxamer is between 10 and 40mg/mL;
in certain embodiments, the concentration of the aqueous poloxamer solution is between 15 and 35mg/mL.
In a specific embodiment, the concentration of the aqueous solution of poloxamer is 20-30 mg/mL.
In certain embodiments of the present invention, the mass ratio of glyceryl monostearate, soybean phospholipid and poloxamer is (8-12): (18-22): (10-14).
In certain embodiments of the present invention, the mass ratio of glyceryl monostearate, soybean phospholipid and poloxamer is (9-11): (19-21): (11-13).
In certain embodiments of the present invention, the mass ratio of glyceryl monostearate, soybean phospholipid and poloxamer is 10:20:12.
after the organic phase and the aqueous phase were obtained separately, the organic phase was added to the aqueous phase. The steps are preferably specifically as follows: slowly dripping the organic phase into water under the condition of stirring at 70-80 ℃, and stirring for 20-30 min at 80 ℃; the stirring speed is 1000-1400 r/min; more preferably 1000 to 1300r/min; most preferably 1000 to 1200r/min.
In certain embodiments, the above steps are preferably specific to: under the condition of 75-80 ℃ and stirring, the organic phase is slowly instilled into water and stirred for 25-30 min at 80 ℃;
in certain embodiments, the above steps are preferably specific to: the organic phase was slowly instilled into water with stirring at 80℃and stirred for 30min at 80 ℃.
The above-mentioned slow drop is specifically, the dropping speed is controlled to 60-80 drops/min.
Adding the organic phase into the water phase, and cooling to obtain the organic phase; the cooling specifically comprises the following steps: cooling in ice water at 0-2 deg.c, stirring for 50-70 min and cooling at 25-30 deg.c. More preferably specifically: cooling in ice water at 0-2 deg.c, stirring for 60min and cooling at 25-30 deg.c.
The invention provides a resina Draconis perchlorate solid lipid nanoparticle, which is prepared by the preparation method according to any one of the technical schemes.
The present invention has been clearly described with respect to the above preparation method, and will not be described in detail herein.
The invention provides a dragons perchlorate medicine, which comprises dragons perchlorate solid lipid nano particles in the technical proposal.
The medicament comprises the resina Draconis perchlorate solid lipid nanoparticle according to the technical scheme, and further comprises conventional auxiliary materials in the field of medicaments, which are well known to those skilled in the art, and the inventor does not limit the method.
Wherein, the dosage form of the medicine comprises one or more of powder, suspension, tablet, capsule, granule or powder.
The invention preferably prepares the medicaments into freeze-dried powder.
The invention also provides a preparation method of the resina Draconis perchlorate freeze-dried powder, which comprises the following steps: mixing the solid lipid nanoparticles of the resina Draconis perchlorate with glucose solution, pre-freezing, and freeze-drying.
Wherein the parameters of the pre-freezing are pre-freezing for 12 hours at the temperature of-80 ℃; the parameters of freeze drying are specifically as follows: freeze drying at-80 deg.c for 10-12 hr.
The concentration of the glucose solution is preferably a 9% glucose solution.
The invention provides application of the resina Draconis perchlorate solid lipid nanoparticle in preparing a medicament for treating injury neuralgia.
Wherein the treatment comprises decreasing expression of NMDAR1 and/or increasing pain threshold.
The invention also provides a method for treating the injury neuralgia, which comprises the step of administering the resina Draconis perchlorate medicament. Preferably, the method of administering the drug is oral.
The invention provides a preparation method of solid lipid nanoparticles of resina Draconis perchlorate, which comprises the following steps: a) Mixing glyceryl monostearate, soybean phospholipid and resina Draconis perchlorate, and dissolving with solvent to obtain organic phase; b) An aqueous solution of poloxamer as the aqueous phase; c) The organic phase is added into the water phase and cooled to obtain the product. According to the invention, the glyceryl monostearate, the soybean lecithin and the poloxamer are used as coating materials to coat the resina Draconis perchlorate, so that the finally prepared resina Draconis perchlorate solid lipid nanoparticle has high stability, high encapsulation efficiency and high drug loading.
In order to further illustrate the invention, the following describes in detail the solid lipid nanoparticle of resina Draconis perchlorate and its preparation method and application in combination with examples.
EXAMPLE 1 establishment of method for measuring content of Dragon's blood perchlorate
1.1 chromatographic conditions
Chromatographic conditions: chromatographic column: agilent ZORBAX SB-C18 (5 μm, 4.6X1250 mm); mobile phase: acetonitrile-pure water aqueous solution;
isocratic elution: 0-10min,80% acetonitrile; 20% pure water;
flow rate: 1mL min-1; sample injection amount: 10. Mu.L; sample cell temperature: 4 ℃; column temperature: 40 ℃;
detection wavelength: the dragon's blood perchlorate is 440nm.
1.2 preparation of solutions
9.06mg of the resina Draconis high phosphate reference substance is respectively weighed precisely and dissolved in a 10ml volumetric flask to prepare a methanol reference substance stock solution with the concentration of 0.906 mg/ml.
Preparation of test solution: precisely sucking 0.1mL of the sample solution, adding 1mL of methanol, performing ultrasonic treatment, and filtering with a microporous filter membrane of 0.22 μm to obtain the final product.
1.3 specificity investigation
As can be seen from FIG. 1, the resina Draconis perchlorate is detected under the chromatographic condition of item 1.1, and the specificity is good. FIG. 1 shows a drawing of a standard of resina Draconis perchlorate.
1.4 drawing of Standard Curve
Precisely transferring a certain amount of resina Draconis perchlorate reference stock solution, precisely preparing into resina Draconis perchlorate samples with concentration of 0.00906 mg/mL-1, 0.01812 mg/mL-1, 0.03624 mg/mL-1, 0.07248 mg/mL-1 and 0.14496 g/mL-1 by methanol, and detecting according to chromatographic conditions. Carrying out curve fitting regression on the sample concentration (X) by using the peak area (Y) of the component to be detected to obtain a standard curve of the resina Draconis perchlorate as Y=2E+07X-33740 R2= 0.9988, wherein the linear range is as follows: 0.00906-0.14496 mg/ml. FIG. 2 shows a standard curve of resina Draconis perchlorate.
1.5 precision investigation
The results of the precision experiments of the medicinal components are shown in Table 1. The RSD values of the peak areas of the medicines are 1.94% and less than 2.0%, which shows that the method has good precision.
TABLE 1 results of precision experiments
Example 2
And preparing the solid lipid nanoparticle by adopting a high-temperature emulsification-low-temperature solidification method. Weighing 100mg of glyceryl monostearate, 200mg of soybean phospholipid and 20mg of resina Draconis perchlorate in 2ml of ethanol, dissolving by ultrasonic, and preserving the temperature at 80 ℃ for later use. Poloxamer 407 (F127) 120mg was dissolved in 4ml deionized water and heated in a 80℃water bath to dissolve as the aqueous phase. Slowly instilling the organic phase into the aqueous phase under the condition of stirring at 80 ℃ and 1000r/min, continuously stirring at 80 ℃ for 30min to form colostrum, pouring into 20mL (0-2 ℃) ice water, continuously stirring for 1h, and cooling at room temperature to obtain the SLN suspension. (50 mg of sodium dodecyl sulfate was added to the aqueous phase to prepare negatively charged solid lipid nanoparticles).
Preparing freeze-dried powder of solid lipid nanoparticles of the dragon's blood perchlorate: adding 9% glucose solution with the same volume as the solid lipid nanoparticle into a penicillin bottle, slightly shaking, pre-freezing at-80 ℃ for 12 hours, and freeze-drying at-80 ℃ for 12 hours to obtain SLN freeze-dried powder, sealing, drying and preserving.
EXAMPLE 3 investigation of poloxamer usage
The influence of the addition amount of F127 on SLN stability and moldability was examined, and other components were kept unchanged, and 30mg, 60mg, 120mg, 180mg and 240mg of F127 were weighed, and blank SLN was prepared by the method of example 2, and its stability and particle size were measured, and the results are shown in Table 4.
TABLE 4 Effect of different poloxamer amounts on formulations
EXAMPLE 4 investigation of the feed ratio of Glycerol monostearate to soybean Phospholipids
The effect of the feed ratio of glyceryl monostearate to soybean phospholipid on SLN preparation was examined, the other components were kept unchanged, and the feed ratios of glyceryl monostearate to soybean phospholipid were respectively 2:1, 1:1, 1:2, 1:3 and 1:4, and the stability and particle size were measured according to the preparation blank SLN of example 2. The results are shown in Table 5.
TABLE 5 Effect of glycerol monostearate and soybean phospholipid feed ratios on formulations
Example 5 Water phase volume investigation
The effect of aqueous phase volume on SLN production and its stability was examined, F127 was dissolved in 2ml, 4ml, 6ml, 8ml, 10ml deionized water, respectively, and the other components were kept unchanged, and SLN was produced according to example 2, and its stability and particle size were measured, and the results are shown in Table 6.
TABLE 6 influence of aqueous phase volume on formulation
EXAMPLE 6 investigation of stirring Rate
SLN was prepared as in example 2 and examined for its effect on the stability of the formulation at different stirring speeds of 500r/min, 1000r/min, 1500 r/min. The preparation stabilizing time is longer than 500r/min at 1000r/min and 1500r/min, but the rotating speed is too high at 1500r/min, liquid splashing is easy to occur, a sample is lost, and the energy consumption is high, so the rotating speed of 1000r/min is selected.
TABLE 7 influence of stirring Rate on preparation Process
EXAMPLE 7 Star Point Effect design optimization SLN
6.1, determining the investigation level of each factor according to a single factor result by taking the feeding ratio (A) of glyceryl monostearate and soybean phospholipid, the using amount (B) of poloxamer 408 and the water phase volume (C) as factors, and taking the particle size as an index. The factor level design is shown in Table 2, and the experimental design and results are shown in Table 3.
Table 2 design experiment factors and levels
Table 3BBD Experimental design and results
6.2 best Process validation experiment
3 parts of the optimal formulation (100 mg of glyceryl monostearate, 200mg of soybean phospholipid and 408 mg of poloxamer 120mg contained in 4ml of water) obtained by BBD optimization were prepared in parallel, and the particle size and the dispersity thereof were measured.
6.3 determination of drug loading
Respectively weighing 10mg, 15mg, 20mg and 25mg of resina Draconis perchlorate standard substances, dissolving in an oil phase, preparing perchlorate-SLN, and measuring the encapsulation efficiency and the drug loading rate.
6.4BBD design optimization SLN
As is clear from Table 3, the factors affecting SLN particle size are A>C>B. The results of equation fitting the data in Table 3 using Design-expert.V8.0.6 software are shown in Table 8. The equation is Y= +7029.9588-6016.59835A-34.88524B-880.88321C+1.95274AB+303.35821AC+1.32292BC+3325.23947A 2 +00.10602B 2 +48.41875C 2 R 2 = 0.9244, fig. 3 star effect and contour plot.
TABLE 8 analysis of variance of quadratic polynomial regression model
6.5 Low speed centrifugation method for determining encapsulation efficiency
Precisely weighing 2ml of SLN, centrifuging at 4000r/min for 10min, precisely removing supernatant, demulsifying and diluting with methanol for 10 times, filtering with 0.22 μm filter membrane, and detecting with liquid phase to obtain the content of resina Draconis, denoted as W1, which is the content of the drug encapsulated in lipid nanoparticle; in addition, the equivalent SLN is precisely removed, ultrasonic demulsification is carried out after methanol volume fixation, the content of the medicine is measured and is respectively recorded as W2, and the sum of the encapsulated medicine and the non-encapsulated medicine in the lipid nano suspension is obtained. The specific encapsulation efficiency calculation formula comprises: encapsulation efficiency = W1/W2 x 100%
The drug loading calculation formula is as follows: drug loading = W1/W Total (S) ×100％ W Total (S) : SLN Total Mass
The results are shown in Table 9, and when 25mg of the resina Draconis perchlorate standard substance was added, the encapsulation efficiency was 81.97%, so that the addition of 20mg of the drug was finally confirmed, and the drug loading was 0.072%.
Table 9 determination of encapsulation efficiency and drug loading
6.6 verification test
3 parts were prepared in parallel according to the BBD optimized optimum recipe and the particle size was determined to be 599 on average and rsd=8.72 particle size chart is shown in fig. 4. FIG. 4SLN particle size plot.
Verification example of pharmacodynamics evaluation of resina Draconis perchlorate solid lipid nano preparation
The resina Draconis perchlorate solid lipid nanoparticle preparation prepared in the embodiment 2 of the invention can improve the pain threshold of neuropathic rats by reducing the expression of NMDAR1, and has a therapeutic effect on injured neuralgia.
1 Experimental materials
1.1 animals
SD rats, males, body weight range 200-220g. The certificate number SCXK 2016-0002 was purchased from Beijing Bei Fu laboratory animal science and technology, and was fed to Beijing university animal houses.
1.2 reagents and pharmaceutical products
Dragon's blood perchlorate; resina Draconis perchlorate solid lipid nanoparticle; absolute ethyl alcohol; physiological saline; hydrating chloral; 10% neutral formalin fixation; 4% paraformaldehyde; penicillin; NMDAR1 antibody; fenbifen-kapian.
1.3 instruments
OLYMPUSBX51 microscope (beijing, mildy instruments science limited); FA1204B analytical balance (Shanghai precision instruments, inc.); an electric heating thermostatic water bath (Teste instruments Co., ltd.) and the like.
2 Experimental methods
2.1 construction of CCI animal models
CCI model according to Bennett et al [5-6] The method of (1) is as follows: anesthesia was performed with 10% chloral hydrate (0.3 ml/100 g) administered intraperitoneally. The rat is fixed on a rat plate in a prone position, dehairing and disinfection are carried out, the skin is cut parallel to the femur at the position about 1cm below the femur of the right hind limb, subcutaneous tissue and muscle are separated in a blunt manner, sciatic nerve is exposed, about 7mm is released, 4 loose ligatures are carried out on the skin by using 4.0 chromium enteric threads, the ligature interval is about 1mm, the tightness during ligature is noted, the slight twitching of the muscle is seen when the rat is knotted, the incision is washed by using 0.9% sodium chloride injection, suturing is carried out layer by layer after ligature, 40 ten thousand U penicillin is injected intramuscularly to prevent infection, and after the rat wakes up, the rat is fed in a separate cage. Sham animals only exposed sciatic nerve but not ligatured, and the rest of the procedure was the same as described above.
2.2 grouping and administration of animals
SD rats were randomly divided into Model group (Model group), sham group (Sham group), resina Draconis perchlorate group (1.2 mg/200g, DP group), resina Draconis perchlorate solid lipid nanoparticle group (1.2 mg/200g, DP-NM group) and Positive drug (Positive group), each group was 12. The sham operation group and the model group were given physiological saline to irrigate the stomach. Dosing was started the next day after modeling was completed, once a day, until the end of the experiment.
2.3 evaluation of drug efficacy
2.3.1PWMT assay
The mechanical stimulation foot retraction reflecting threshold value (paw withdrawal mechanical threshold, PWMT) of the rat is measured before the operation 1d, after the operation 7d, 14d and 21d, after the rat is adapted to the environment, the Von Frey probe is used for vertically stimulating the skin in the midfoot of the rat to the hind limb of the rat to pump or lift the foot to evade according to the ascending quality sequence, and the value (in g) at the moment is recorded [7] . At intervals of 10min, 5 determinations were performed consecutively.
2.3.2PWTL assay
Measurement of thermal stimulation foot-shrinking reflex latency (paw withdrawal thermal latency, PWTL) in rats at preoperative 1d, postoperative 7d, 14d, 21d, measurement of thermal stimulation response of the rat left hind limb plantar middle skin after stabilization of the rats using a thermal pain meter, PWTL threshold time from irradiation to foot-shrinking response to foot lifting, avoidance or foot licking actions [8] . At intervals of 10min, 5 determinations were performed consecutively.
2.3.3 sample collection
And taking a section of sciatic nerve in the ligature area at the injury part of the rat molding side, and performing conventional paraffin embedding slice and HE staining slice sealing and optical examination.
2.3.4 immunohistochemical determination of spinal dorsal root ganglion NMDAR1
After measuring pain threshold at 21d, the rat was deeply anesthetized, its four limbs were fixed, the abdominal cavity was opened under the xiphoid process, the heart was exposed through the diaphragm, a perfusion needle was inserted into the left ventricle and fixed, and the right auricle was cut off to perform heart perfusion. The liquid is poured quickly with sterile normal saline at 4 ℃ until the liquid is clarified, and then 4% paraformaldehyde is poured quickly and slowly to fix for about 30min. Then find the sciatic nerve at the center of the femur of the right hind limb, find the L4-6 spinal ganglion connected with the sciatic nerve along the ascending direction of the sciatic nerve, separate and take out the sciatic nerve, fix the sciatic nerve in 10% neutral formaldehyde for 48 hours, embed the sciatic nerve in paraffin, and cut 4mm continuously [7] . Staining was performed according to the immunohistochemical kit instructions and the analysis results were observed using an image-pro plus 6.0 image analysis system, the results being expressed as average optical density.
3 results of experiments
3.1PWMT assay results
CCI model group rats showed significant mechanical pain from day 1 to day 21 compared to sham operated groups; compared with the model group, PWMT of the Positive group, the DP group and the DP-NM group is obviously increased (p is less than 0.01), and the DP-NM group is also increased (p is less than 0.05), which proves that the mechanical pain in the CCI model can be effectively inhibited by a certain dose of the resina Draconis perchlorate; the DP-NM group and the DP-L group have the same dosage, but have analgesic effect on mechanical pain, and the DP-NM group is superior to the DP group (p is less than 0.05 at 14 d), which shows that the solid lipid nanoparticle drug delivery system is helpful for improving the anti-mechanical pain effect of the resina Draconis perchlorate, and the specific results are shown in Table 1.
Table 1 rats of each group were compared for different time periods PWMT (g,' x±s, n=6)
Table 1Comparison of PWMT in different time periods of rats in each group
Note that: in contrast to the set of models, * p＜0.05， ** p is less than 0.01; in contrast to the DP group, # p＜0.05
3.2 measurement of thermal stimulation foot-retraction reflex latency
CCI model group rats showed significant thermal pain from day 1 to day 21 compared to sham operated groups. Compared with the model group, PWTL of the Positive group and the DP-NM group is obviously increased (p is less than 0.01), and the DP-M group is also increased (p is less than 0.05), which proves that the mechanical pain in the CCI model can be effectively inhibited by a certain dose of resina Draconis perchlorate.
Table 2 rats of each group were compared for different periods of time PWTL (s,' x±s, n=6)
Table 2Comparison of PWTL in different time periods of rats in each group
Note that: in contrast to the set of models, * p＜0.05， ** p＜0.01。
3.3 rat sciatic nerve tissue pathological section
The periplasm and the nerve fiber of the sciatic nerve of the Sham group animals have complete structure and orderly arrangement, and no abnormal change is seen; in contrast to the Sham group, the Model group animals all seen vacuoles in the cytoplasm, irregular cell nuclei arrangement, and many mast cells. The sciatic nerve edema and vacuolation degeneration degree were reduced in the administration group compared with the Sham group, and the specific results are shown in fig. 5. FIG. 5 effect of tincture on rat sciatic nerve pathology (HE staining, 200X).
3.4 immunohistochemical results
The DP-H and DP-M groups were significantly different from the Model group (p < 0.05). It is explained that proper amount of resina Draconis perchlorate can relieve pain sensitivity of ischialgia rats and inhibit expression of spinal cord NMDAR 1.
Table 3 expression of rat spinal cord NMDAR1 for each group (n=6,' x±s)
Table 3The expression of NMDAR-1in spinal cord of rats in each group
Note that: in contrast to the set of models, * p＜0.05
4.1 liquid phase Condition of the resina Draconis sample
Chromatographic column: ACQUITY UPLCTM BEH C18 (1.7 μm, 2.1X150 mm); mobile phase: acetonitrile-water; gradient elution: 0min,20% acetonitrile; 6min,35% acetonitrile; 6.1min,20% acetonitrile; column temperature 35 ℃ and sample temperature 4 ℃;
detection wavelength: 440nm.
4.2 method of formulation release
And (3) precisely moving in parallel, wherein 3mL of each part is added into 100mL of 0.5% SDS release external liquid, 10mL of release medium is added into a pretreated dialysis bag, and then the solution is immersed into the release external liquid, and the solution is oscillated in a constant-temperature water bath at 37 ℃. The two groups are respectively 0.167h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 1d, 2d, 3d, 6d, 9d, 12d, 15d, 18d, 21d, 24d, 27d and 30d. 2mL of release medium (simultaneously, equal amount of release medium at the same temperature) was aspirated from the dialysis bag, the content of resina Draconis was determined by HPLC, the cumulative percent release of the drug was calculated and the release kinetics model fitting was performed.
The cumulative release percentage Qn at different time points was calculated according to the following formula.
Qn is the cumulative percent (%) released at the nth point; v is the volume of release medium (mL); cn is the mass concentration of the drug (mg.mL-1) measured at the nth point; 2 is sampling 2mL; w is the total amount (mg) administered.
4.3 experimental results
The in vitro release curves of the resina Draconis raw medicine and the resina Draconis emulsion are drawn by taking the accumulated release percentage of each time point as an ordinate and taking the sampling time as an abscissa, the results are shown in figure 6, and the figure 6 is the in vitro release curve of the resina Draconis raw medicine and the resina Draconis emulsion. As can be seen from FIG. 6, the cumulative release rate of the resina Draconis emulsion is higher than that of the resina Draconis original drug group.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The preparation method of the resina Draconis perchlorate solid lipid nanoparticle is characterized by comprising the following steps of:
a) Mixing glyceryl monostearate, soybean phospholipid and resina Draconis perchlorate, and dissolving with solvent to obtain organic phase;
b) An aqueous solution of poloxamer as the aqueous phase;
c) The organic phase is added into the water phase and cooled to obtain the product.
2. The preparation method according to claim 1, wherein the mass ratio of the glyceryl monostearate to the soybean phospholipid is 1: (1-3);
the mass ratio of the glyceryl monostearate to the soybean phospholipid to the resina Draconis perchlorate is (8-12): (18-22): (1-3).
3. The preparation method according to claim 1, wherein the concentration of the aqueous poloxamer solution is 10-40 mg/mL.
4. The preparation method according to claim 1, wherein the mass ratio of the glyceryl monostearate to the soybean phospholipid to the poloxamer is (8-12): (18-22): (10-14).
5. The method of claim 1, wherein the solvent of step a) is ethanol; the dissolution is ultrasonic dissolution, and the power of the ultrasonic is 200-300 HZ; the dissolution temperature is 70-80 ℃;
the poloxamer water solution in the step B) is specifically obtained by dissolving poloxamer in water; the dissolution temperature is 70-80 ℃.
6. The method of claim 1, wherein step C
The organic phase is specifically: slowly dripping the organic phase into water under the condition of stirring at 70-80 ℃, and stirring for 20-30 min at 80 ℃; the stirring speed is 1000-1400 r/min;
the cooling specifically comprises the following steps: cooling in ice water at 0-2 deg.c, stirring for 50-70 min and cooling at 25-30 deg.c.
7. A solid lipid nanoparticle of resina Draconis perchlorate, characterized in that it is prepared by the preparation method of any one of claims 1-6.
8. A dragons perchlorate drug comprising dragons perchlorate solid lipid nanoparticle according to claim 7.
9. The medicament according to claim 8, wherein the dosage form of the medicament is one or more of powder, suspension, tablet, capsule, granule or powder.
10. Use of the dragons perchlorate solid lipid nanoparticle of claim 7 in the preparation of a medicament for treating injury neuralgia.
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