CN110237037B - Rhynchophylline solid lipid nanoparticle, preparation method thereof and freeze-dried powder preparation - Google Patents
Rhynchophylline solid lipid nanoparticle, preparation method thereof and freeze-dried powder preparation Download PDFInfo
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Abstract
The invention belongs to the technical field of nano-drugs, and particularly relates to rhynchophylline solid lipid nanoparticles, a preparation method thereof and a freeze-dried powder preparation, wherein the rhynchophylline solid lipid nanoparticles are prepared by adopting a nano-emulsification method: dissolving rhynchophylline in a molten oil phase, adding a water phase, stirring to form a nano-emulsion, and placing the nano-emulsion in an ice-water bath to obtain the nano-emulsion; wherein: the oil phase is a mixture of glyceryl monostearate, tween 80 and polyethylene glycol-15 hydroxystearate; the aqueous phase is purified water. The rhynchophylline solid lipid nanoparticles prepared by the method are spherical and quasi-spherical, are not adhered to each other, are uniformly distributed, have good stability and high encapsulation efficiency, and have high drug loading rate; the dissolution rate of the rhynchophylline can be improved, and the percentage of 6h in-vitro accumulated release of the rhynchophylline solid lipid nanoparticles by the dialysis method is 50.45%; the rhynchophylline solid lipid nanoparticle freeze-dried powder prepared by the invention has smaller particle size after redissolution and better appearance, color and redispersibility.
Description
Technical Field
The invention belongs to the technical field of nano-drugs, and particularly relates to rhynchophylline solid lipid nanoparticles, a preparation method thereof and a freeze-dried powder preparation.
Background
The ramulus Uncariae cum uncis is dry stem branch with hook of Rubiaceae plant ramulus Uncariae cum uncis, and ramulus Uncariae cum uncis or ramulus Uncariae cum uncis. Modern pharmacological research shows that the uncaria rhynchophylla mainly acts on a cardiovascular system and a central nervous system and has the effects of reducing blood pressure, calming, resisting convulsion, epilepsy, resisting inflammation, easing pain, resisting oxidation, resisting mutation, resisting tumor, immunizing, protecting brain, relieving Alzheimer disease and the like. The uncaria rhynchophylla total alkaloids are main drug effect substances of uncaria rhynchophylla playing a clinical treatment role. The rhynchophylline has a chemical structural formula as follows:
the uncaria rhynchophylla total alkaloids mainly comprise oxindole and indole alkaloids, and the content of isocoubine and uncaria rhynchophylla total alkaloids is the highest, and the content of isocoubine and uncaria rhynchophylla total alkaloids is more than 40%. The rhynchophylline has the chemical structural formula as above and the molecular formula is C22H28N2O4Molecular weight 384.46, melting point 216 ℃. It is soluble in methanol and ethanol, but insoluble in water. The rhynchophylline has the characteristic of poor water solubility, so that the bioavailability of rhynchophylline is low, and the clinical efficacy of rhynchophylline is seriously influenced. In addition, the marketed rhynchophylline-containing preparation has a single dosage form, and the dosage forms also have some disadvantages. Therefore, a new rhynchophylline preparation with excellent performance needs to be prepared to better meet the clinical application of the rhynchophylline.
Solid Lipid Nanoparticles (SLNs) are a new type of nano drug delivery system developed in the nineties of the last century. The SLN is a solid colloidal particle delivery system which takes solid natural or synthetic lipoid as a carrier and enables drugs to be wrapped in lipoid cores, and the particle size of the prepared nanoparticles is 10-1000 nm. The SLN has the advantages of small particle size, low toxicity, wide drug applicability, good physiological compatibility, improvement on the stability of sensitive drugs, less drug leakage, good slow release property, realization of targeted drug delivery after surface modification, large-scale production and the like.
Disclosure of Invention
The invention aims to provide an rhynchophylline solid lipid nanoparticle and a preparation method thereof, the prepared rhynchophylline solid lipid nanoparticle can overcome the defect of poor solubility of rhynchophylline, and improve the bioavailability of rhynchophylline, and meanwhile, the invention also provides a freeze-dried powder preparation of the rhynchophylline solid lipid nanoparticle.
The rhynchophylline solid lipid nanoparticles are prepared by adopting a nano-emulsification method: firstly, dissolving rhynchophylline in a molten oil phase, then adding a water phase and stirring to form a nano-emulsion, and then placing the nano-emulsion in an ice-water bath for cooling;
wherein: the oil phase is a mixture of glyceryl monostearate, tween 80 and polyethylene glycol-15 hydroxystearate;
the aqueous phase is purified water.
The preparation method of the rhynchophylline solid lipid nanoparticle specifically comprises the following steps:
(1) weighing glyceryl monostearate, tween 80 and polyethylene glycol-15 hydroxystearate, mixing to obtain a mixture, and heating the mixture to melt to form an oil phase;
(2) dissolving uncaria rhynchophylla alkali in the oil phase in the step (1) to form an oil phase mixture;
(3) heating with purified water as water phase, quickly adding the water phase after the oil phase mixture in the step (2) is completely melted, and stirring to form nano-emulsion;
(4) and (3) cooling the nanoemulsion in an ice-water bath to obtain the rhynchophylline solid lipid nanoparticle suspension.
The mass ratio of the glyceryl monostearate, the Tween 80 and the polyethylene glycol-15 hydroxystearate is 1: 0.1-20: 0.1 to 40.
The temperature of the oil phase for heating and melting is 65-90 ℃.
The mass ratio of the oil phase to the rhynchophylline to the oil phase is 0.01-0.2: 1.
the heating temperature of the purified water is 65-90 ℃, and the ratio of the volume of the purified water to the volume of the oil phase is 5-100: 1.
the rotating speed of the stirrer during stirring is 50-2000 r/min, and the stirring time is 3-15 min.
The rhynchophylline solid lipid nanoparticle freeze-dried powder preparation is prepared by adding a freeze-drying protective agent into rhynchophylline solid lipid nanoparticle suspension and performing freeze-drying; the freeze-drying protective agent is a compound of mannitol and trehalose.
The dosage of the mannitol and trehalose compound is 2-15% w/v of the volume of the rhynchophylline solid lipid nanoparticle suspension, wherein the mass ratio of mannitol to trehalose in the compound is 0.2-5: 1.
the preparation method of the rhynchophylline solid lipid nanoparticle freeze-dried powder preparation comprises the following steps: adding a freeze-drying protective agent into a penicillin bottle, sucking the suspension of the rhynchophylline solid lipid nanoparticles into the penicillin bottle by using a liquid transfer gun, uniformly swirling the liquid in the penicillin bottle by using a vortex mixer, pre-freezing the liquid in a refrigerator at the temperature of-80 ℃ for 12 hours, and finally freeze-drying the liquid in a freeze-dryer for 12 hours to obtain the rhynchophylline solid lipid nanoparticle freeze-dried powder preparation.
The preferable technical scheme of the preparation method of the rhynchophylline solid lipid nanoparticle is as follows:
weighing 50mg of glyceryl monostearate, 50mg of tween 80 and 100mg of Solutol HS 15 (polyethylene glycol-15 hydroxystearate), heating and melting at 80 ℃ to form an oil phase, and precisely weighing 2.00mg of rhynchophylline to be dissolved in the oil phase; another 10ml of purified water is taken and heated to 80 ℃ to be used as a water phase; after the oil phase is completely melted, quickly adding the water phase into the oil phase, stirring at 2000r/min for 5min to form nanoemulsion, and cooling in ice water bath to obtain the rhynchophylline lipid nanoparticle suspension.
The preparation mechanism of the invention is as follows: the solid lipid material glyceryl monostearate is melted into a liquid oil phase under the condition that the melting point of the glyceryl monostearate is higher than the melting point of the glyceryl monostearate, the liquid oil phase is dissolved together with a fat-soluble medicament uncaria rhynchophylla, a surfactant Tween 80 and Solutol HS 15 to form an oil phase mixture, the oil phase mixture is added into a water phase, the O/W type emulsion droplets are formed by stirring under the action of the surfactant, and the solid lipid nanoparticles carrying uncaria rhynchophylla are formed by cooling and solidifying.
Compared with the prior art, the invention has the following beneficial effects.
(1) The rhynchophylline solid lipid nanoparticles prepared by the method are spherical and quasi-spherical, are not adhered to each other, are uniformly distributed, and have good stability;
(2) the encapsulation efficiency measured by the rhynchophylline solid lipid nanoparticle prepared by the method is (82.6 +/-1.8)%, and the drug-loading rate is (3.52 +/-0.20)%, which shows that the rhynchophylline solid lipid nanoparticle prepared by the nanoemulsion method has higher encapsulation efficiency and higher drug-loading rate;
(3) the rhynchophylline solid lipid nanoparticle prepared by the method can improve the dissolution rate of rhynchophylline, and the in-vitro cumulative release percentage of the rhynchophylline solid lipid nanoparticle prepared by a dialysis method for 6 hours is 50.45%;
(4) the rhynchophylline solid lipid nanoparticle freeze-dried powder prepared by the invention has smaller particle size after redissolution and better appearance, color and redispersibility.
Drawings
FIG. 1: scanning photos of the rhynchophylline solid lipid nanoparticles prepared in the embodiment 1 of the invention by a transmission electron microscope;
FIG. 2: the appearance photograph of the rhynchophylline solid lipid nanoparticle prepared in the embodiment 1 of the invention;
FIG. 3: the particle size distribution diagram of the rhynchophylline solid lipid nanoparticles prepared in the embodiment 1 of the invention;
FIG. 4: the Zeta potential distribution diagram of the rhynchophylline solid lipid nanoparticle prepared in the embodiment 1 of the invention;
FIG. 5: an in-vitro release curve of the rhynchophylline solid lipid nanoparticle prepared in the embodiment 1 of the invention and an rhynchophylline solution is provided;
FIG. 6: a is an appearance photograph of rhynchophylline SLN freeze-dried powder without a freeze-drying protective agent in embodiment 2 of the invention; b is the picture of the appearance of rhynchophylline SLN freeze-dried powder which is combined by mannitol and trehalose and serves as a freeze-drying protective agent in the embodiment 2 of the invention.
Detailed Description
The invention is further illustrated by the following examples and figures of the specification.
Example 1
Weighing 50mg of glyceryl monostearate, 50mg of tween 80 and 100mg of Solutol HS 15 (polyethylene glycol-15 hydroxystearate), heating and melting at 80 ℃ to form an oil phase, and precisely weighing 2.00mg of rhynchophylline to be dissolved in the oil phase; another 10ml of purified water is taken and heated to 80 ℃ to be used as a water phase; after the oil phase is completely melted, quickly adding the water phase into the oil phase, stirring at the rotating speed of 2000r/min for 5min to form a nano-emulsion, and then placing in an ice-water bath for cooling to obtain the rhynchophylline solid lipid nanoparticle suspension.
The encapsulation rate and the drug-loading rate of the rhynchophylline solid lipid nanoparticles are determined by an ultrafiltration method: diluting 0.5ml of the prepared rhynchophylline solid lipid nanoparticle suspension with ultrapure water to 3ml, mixing uniformly, placing in an ultrafiltration tube, centrifuging for 5min at 3000r/min, taking supernatant, injecting sample under chromatographic conditions (octadecylsilane chemically bonded silica is used as filler for chromatographic column, methanol-0.02% triethylamine solution (70:30) is used as mobile phase, detecting wavelength is 244nm, flow rate is 1ml/min, column temperature is 30 ℃, sample injection amount is 20 mul), and determining mass concentration W of free drugfree(ii) a Diluting 0.5ml of the preparation with anhydrous ethanol to 3ml, performing ultrasonic demulsification for 5min, performing centrifugation for 5min at 3000r/min, collecting supernatant, introducing sample under chromatographic conditions (octadecylsilane chemically bonded silica as filler, methanol-0.02% triethylamine solution (70:30) as mobile phase, detection wavelength of 244nm, flow rate of 1ml/min, column temperature of 30 deg.C, and sample amount of 20 μ l), and determining the mass concentration W of the total drugtotal. The Encapsulation Efficiency (EE) and Drug Loading (DL) of the rhynchophylline solid lipid nanoparticle are calculated according to the following formulas (1) and (2).
In the formula WfreeIn terms of free drug concentration, WtotalIs the total concentration of the medicine in the suspension; wdrugAmount of drug encapsulated in rhynchophylline SLN, WlipidThe mass of the mixed lipid in the prescription.
The encapsulation efficiency of the rhynchophylline solid lipid nano-encapsulation prepared by the embodiment is (82.6 +/-1.8)%, and the drug-loading rate is (3.52 +/-0.20)%.
As shown in fig. 1, a rhynchophylline SLN suspension prepared by diluting with ultrapure water appropriately is dripped on a copper mesh in an appropriate amount, dyed with 2% phosphotungstic acid, and dried in the air, and then the morphology of the rhynchophylline SLN is observed under a transmission electron microscope, so that the nanoparticles are spherical and spheroidal, are not adhered to each other, are uniformly distributed, and meet the measurement result of a particle sizer;
as in fig. 2, rhynchophylline SLN was prepared clear and translucent with a pale blue milky luster;
as shown in fig. 3, 200 μ l of rhynchophylline SLN suspension is diluted with ultrapure water by 20 times, and the particle size and potential of the suspension are measured by a laser particle sizer, wherein the average particle size of rhynchophylline SLN is 29.09 nm; PDI value of 0.262; the particle size of the rhynchophylline solid lipid nanoparticles is normally distributed, and the distribution range is narrow;
as shown in fig. 4, the potential of the rhynchophylline SLN is (-16.2 ± 0.87) mV, and the result shows that no aggregation phenomenon occurs between particles, and the rhynchophylline solid lipid nanoparticle is preliminarily determined to have good stability;
as shown in FIG. 5, when the in vitro release of rhynchophylline SLN is determined by dialysis, the dissolution medium is phosphate buffer solution (pH7.4) containing 0.2% Tween 80; as can be seen from the figure, the cumulative release percentage of the rhynchophylline SLN is obviously higher than that of the rhynchophylline solution at any time within 6h, which indicates that the rhynchophylline SLN can improve the dissolution rate of the rhynchophylline, the drug release is faster within 2h before the rhynchophylline SLN, probably because the free drug in the rhynchophylline SLN and the drug adsorbed on the surface of the SLN are released firstly, and the cumulative release percentage of the rhynchophylline SLN in 6h in vitro is 50.45%.
Example 2
The freeze-drying protective agent is added before the rhynchophylline SLN is prepared into freeze-dried powder, so that the rhynchophylline SLN is prevented from being damaged in the freeze-drying process, and the freeze-dried powder which is compact and full in appearance, free of color difference, free of layering and small in particle size is obtained.
In this example, the optimal lyoprotectants were selected from mannitol, sucrose, glucose and trehalose, and the amounts and ratios thereof are shown in Table 1.
The experimental operation for preparing rhynchophylline SLN freeze-dried powder in the embodiment is as follows: 15 prescription amounts of lyoprotectants (calculated as the% (w/v) of the rhynchophylline SLN suspension) were weighed according to Table 1 using analytical balance, added to 15 vials in sequence, and 2ml of the prepared rhynchophylline SLN suspension was aspirated by pipette gun and added to the vials in sequence. 2ml of the prepared rhynchophylline SLN suspension is sucked up by a pipette gun and added into a 16 th penicillin bottle without adding a freeze-drying protective agent, and the control group is used. Uniformly swirling the liquid in 16 cillin bottles by using a vortex mixer, pre-freezing the liquid in a refrigerator at minus 80 ℃ for 12h, and finally freeze-drying the liquid in a freeze dryer for 12h to obtain the rhynchophylline SLN freeze-dried powder, wherein the quality grading standard is shown in table 1, the evaluation result is shown in table 2, and the measurement result of the particle size of the freeze-dried powder after redissolution is shown in table 3 (the freeze-dried powder prescriptions 1-16 respectively represent test numbers 1-16 in 2).
TABLE 1 quality evaluation criteria
Table 2 evaluation results of different lyoprotectants added
In the table: "-" represents no addition
TABLE 3 measurement of particle size of each lyophilized powder after reconstitution with different lyoprotectants
The results in tables 1, 2 and 3 were used to evaluate that the combination of 3% mannitol and 1% trehalose was the best cryoprotectant.
As shown in fig. 6, by comparing a and b, the rhynchophylline SLN lyophilized powder using mannitol and trehalose as combined cryoprotectants has better appearance, color and redispersibility than rhynchophylline SLN nanoparticle lyophilized powder without cryoprotectants.
Example 3
Weighing 500mg of glyceryl monostearate, 50mg of tween 80 and 50mg of Solutol HS 15 (polyethylene glycol-15 hydroxystearate), heating and melting at 65 ℃ to form an oil phase, and precisely weighing 6.0mg of rhynchophylline to be dissolved in the oil phase; another 3.0ml of purified water is taken and heated to 65 ℃ to be used as a water phase; after the oil phase is completely melted, quickly adding the water phase into the oil phase, stirring at the rotating speed of 50r/min for 15min to form a nano-emulsion, and then placing in an ice-water bath for cooling to obtain the rhynchophylline solid lipid nanoparticle suspension.
Example 4
Weighing 500mg of glyceryl monostearate, 5000mg of tween 80 and 10000mg of Solutol HS 15 (polyethylene glycol-15 hydroxystearate), heating and melting at 80 ℃ to form an oil phase, and precisely weighing 1550mg of rhynchophylline to dissolve in the oil phase; heating 775ml purified water to 80 deg.C to obtain water phase; after the oil phase is completely melted, quickly adding the water phase into the oil phase, stirring at the rotating speed of 1000r/min for 5min to form a nano-emulsion, and then placing in an ice-water bath for cooling to obtain the rhynchophylline solid lipid nanoparticle suspension.
Example 5
Weighing 500mg of glyceryl monostearate, 10000mg of tween 80 and 20000mg of Solutol HS 15 (polyethylene glycol-15 hydroxystearate), heating and melting at 90 ℃ to form an oil phase, and precisely weighing 6020mg of rhynchophylline to dissolve in the oil phase; heating 3050ml of purified water to 65 ℃ and 90 ℃ to obtain a water phase; after the oil phase is completely melted, quickly adding the water phase into the oil phase, stirring at the rotating speed of 2000r/min for 3min to form a nano-emulsion, and then placing in an ice-water bath for cooling to obtain the rhynchophylline solid lipid nanoparticle suspension.
Claims (4)
1. A preparation method of rhynchophylline solid lipid nanoparticles is characterized by comprising the following steps: the method specifically comprises the following steps:
(1) weighing glyceryl monostearate, tween 80 and polyethylene glycol-15 hydroxystearate, mixing to obtain a mixture, and heating the mixture to melt to form an oil phase;
(2) dissolving uncaria rhynchophylla alkali in the oil phase in the step (1) to form an oil phase mixture;
(3) heating with purified water as water phase, quickly adding the water phase after the oil phase mixture in the step (2) is completely melted, and stirring to form nano-emulsion;
(4) cooling the nanoemulsion in ice-water bath to obtain rhynchophylline solid lipid nanoparticle suspension;
the mass ratio of the glyceryl monostearate, the Tween 80 and the polyethylene glycol-15 hydroxystearate is 1: 0.1-20: 0.1 to 40;
the temperature for heating and melting the oil phase is 65-90 ℃;
the mass ratio of the rhynchophylline to the oil phase is 0.01-0.2: 1;
the heating temperature of the purified water is 65-90 ℃, and the ratio of the volume of the purified water to the volume of the oil phase is 5-100: 1;
the rotating speed of the stirrer during stirring is 50-2000 r/min, and the stirring time is 3-15 min.
2. A rhynchophylline solid lipid nanoparticle freeze-dried powder preparation is characterized in that: adding the rhynchophylline solid lipid nanoparticle suspension prepared in the method of claim 1 into a freeze-drying protective agent for freeze drying; the freeze-drying protective agent is a compound of mannitol and trehalose.
3. The rhynchophylline solid lipid nanoparticle freeze-dried powder preparation according to claim 2, which is characterized in that: the dosage of the mannitol and trehalose compound is 2-15% w/v of the volume of the rhynchophylline solid lipid nanoparticle suspension, wherein the mass ratio of mannitol to trehalose in the compound is 0.2-5: 1.
4. the lyophilized powder preparation of rhynchophylline solid lipid nanoparticles according to claim 2 or 3, which is characterized in that: the preparation method comprises the following steps: adding a freeze-drying protective agent into a penicillin bottle, sucking the suspension of the rhynchophylline solid lipid nanoparticles into the penicillin bottle by using a liquid transfer gun, uniformly swirling the liquid in the penicillin bottle by using a vortex mixer, pre-freezing the liquid in a refrigerator at the temperature of-80 ℃ for 12 hours, and finally freeze-drying the liquid in a freeze-dryer for 12 hours to obtain the rhynchophylline solid lipid nanoparticle freeze-dried powder preparation.
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