CN115414493A - Nano emulsion and preparation method thereof - Google Patents

Nano emulsion and preparation method thereof Download PDF

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CN115414493A
CN115414493A CN202210973671.0A CN202210973671A CN115414493A CN 115414493 A CN115414493 A CN 115414493A CN 202210973671 A CN202210973671 A CN 202210973671A CN 115414493 A CN115414493 A CN 115414493A
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octanol
alpha
water
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phase
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肖超妮
郑晓辉
梁丽虹
白亚军
张亚军
廖莎
贾璞
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Northwest University
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Abstract

The invention discloses a nano-emulsion and a preparation method thereof, under the condition of ice-water bath, injecting an ethanol solution of alpha-fine octanol into a dichloromethane solution of polyethylene glycol-polylactic acid as an oil phase; dissolving poloxamer 188 in ultrapure water to completely dissolve to obtain a water phase; dropwise adding the oil phase into the water phase in a magnetic stirring state, and continuing magnetic stirring and ultrasonic oscillation to obtain an oil-water mixture; removing the organic solvent in the oil-water mixture by reduced pressure rotary evaporation, and performing suction filtration on the residue through a microporous filter membrane to keep filtrate; and mixing the filtrate with chitosan glacial acetic acid solution in equal volume, and stirring to obtain nanoemulsion suspension. The nano emulsion prepared by the preparation method has small particle size, uniform dispersion, high stability and short in-vitro slow release time, is more suitable for nasal administration of alpha-fine octanol, increases the concentration of the drug reaching the brain, and has no toxicity.

Description

Nano emulsion and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical pharmacy, in particular to a nano-emulsion and a preparation method thereof.
Background
alpha-Fine octanol (trans-3- (2, 4, 5-trimethoxyphenyl) prop-2-en-1-ol, C 12 H 17 O 4 MW = 225.1) is an active ingredient in a compound of anti-epilepsy traditional Chinese medicine rhizoma acori graminei and rhizoma arisaematis cum bile-rhizoma acori graminei, and is also a core effector of in vivo metabolism of a polygala tenuifolia-rhizoma acori graminei and a clinical medicine alpha-asarone capsule. According to the development program of antiepileptic drugs implemented by national institutes of health, in the research of three different epilepsy models, the antiepileptic activity of alpha-fine octanol is found to be superior to that of alpha-asarone capsule, stiripentol and carbamazepine, but the neurotoxicity is lower. Alpha-octanol regulates the GABAA receptor primarily through the benzodiazepine binding site, controls epileptogenesis from an energy metabolism perspective by inhibiting LDH activity in neuronal and glial cells, and exerts its activity by promoting the peroxisome proliferator-activated receptor PPAR-gamma.
The alpha-fine octanol is light yellow powder, has good solubility in organic solvents such as methanol, ethanol, acetone, dichloromethane and the like, is slightly soluble in water, and belongs to drug molecules with medium polarity. The alpha-fine octanol is dissolved in water, and the bioavailability in a rat body is low after the intragastric administration, so that the concentration reaching the brain is lower; after intravenous injection, the drug is distributed in brain, heart, spleen and kidney tissues of rats, but the brain targeting property is poor. After nasal administration, the medicine can directly enter the brain through olfactory bulb on olfactory epithelium and is rapidly distributed in each brain area, but the medicine is metabolized too fast in the brain, the detention time is only 2min, and the medicine is not beneficial to the treatment of epileptic diseases. At present, no dosage form of alpha-fine octanol is reported. Therefore, the development of a novel alpha-fine octanol nasal delivery preparation is an effective way for increasing the brain-entering concentration of the alpha-fine octanol to achieve targeted therapy of epilepsy.
Disclosure of Invention
Aiming at the existing problems, the invention aims to provide the chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion and the preparation method thereof, which can greatly improve the affinity of the alpha-octanol and mucosal cells, enhance the absorption of nasal and cerebral passages, increase the concentration of the drug reaching the brain and have no toxicity.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for preparing nano-emulsion is characterized by comprising the following steps,
s1: injecting an ethanol solution of alpha-fine octanol into a dichloromethane solution of polyethylene glycol-polylactic acid under the condition of ice water bath to serve as an oil phase;
s2: dissolving poloxamer 188 in ultrapure water to be completely dissolved to be used as a water phase;
s3: dropwise adding all the oil phase into the water phase in a magnetic stirring state, and continuously stirring to obtain an oil-water mixture;
s4: removing the organic solvent in the oil-water mixture, performing suction filtration on the residue through a microporous filter membrane, and retaining the filtrate;
s5: and (5) mixing the filtrate obtained in the step (S4) and the chitosan glacial acetic acid solution in equal volume, and stirring to obtain the nano-emulsion suspension.
Further, in the step S1, the mass ratio of α -fine octanol to polyethylene glycol-polylactic acid is 1.
Further, in the step S1, the mass ratio of the alpha-fine octanol to the polyethylene glycol-polylactic acid is 1.
Further, the concentration of poloxamer 188 in the aqueous phase of step S2 was 0.62g/ml.
Further, in the step S3, the volume ratio of the oil phase to the water phase is 1 to 5, and after the oil phase is completely dripped into the water phase under the magnetic stirring state, ultrasonic oscillation is performed for 4 to 6min at a power of 250W, and then stirring is performed for 20 to 40min at normal temperature.
Further, in step S3, the volume ratio of the oil phase to the water phase is 1, after all the oil phase is added dropwise to the water phase under the magnetic stirring state, ultrasonic oscillation is performed for 5min at a power of 250W, and then stirring is performed at normal temperature for 30min.
Further, in step S4, the organic solvent in the oil-water mixture was removed by a reduced pressure rotary evaporation method, and the degree of vacuum was 0.1MP.
Further, the concentration of the chitosan glacial acetic acid solution in the step S5 is 0.1g/ml, the molecular weight of the chitosan is 50-90KD, and the deacetylation degree is 60%.
A nanoemulsion characterized by being prepared by the preparation method.
Further, the nano-emulsion comprises 1.0g of alpha-fine octanol, 12.34g of polyethylene glycol-polylactic acid, 0.2232g of poloxamer, 0.036g of chitosan, 36ml of water and 36ml of glacial acetic acid.
The beneficial effects of the invention are:
1. the preparation method of the chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion disclosed by the invention adopts a natural easily-degradable polyethylene glycol-polylactic acid (PEG-PLA) copolymer as a carrier, and the alpha-octanol molecules are encapsulated in the core-shell structure compact nanocapsules formed by the copolymer, and uses chitosan with extremely strong cell adhesion to modify the outer surface of the nanocapsules based on the ionic static self-assembly interaction, so that a novel method for loading the nanoemulsion is developed, wherein the method is based on the condition of low-temperature reaction, the alpha-octanol is firstly dissolved in ethanol and then slowly injected into a dichloromethane solution of the polyethylene glycol-polylactic acid, the stability of the drug can be kept and is not easily decomposed, and the alpha-octanol is not directly dissolved in the dichloromethane, so that more drug is encapsulated in the microcapsules formed by the polyethylene glycol-polylactic acid, and the drug loading capacity is increased; when the oil phase and the water phase are mixed, only magnetic stirring and ultrasonic oscillation are needed, and then the organic solvent is removed by rotary evaporation, so that the operation is simple, high-end instruments are not needed, and the method is simple and feasible.
2. The chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion prepared by the preparation method can reach 172.97 +/-4.42 nm in particle size, the polydispersity coefficient reaches 0.244 +/-0.094, the zeta potential is 36.00 +/-2.28 mV, the encapsulation rate and the drug loading rate can reach 66% and 5%, and the cumulative drug release rate in vitro can reach 50% in 6 hours.
Drawings
FIG. 1 shows the effect of single factor level on the preparation of nano-emulsion in the second embodiment of the present invention.
FIG. 2 is the response surface results of the encapsulation efficiency and particle size for single factor examination in example two of the present invention.
Fig. 3 is a morphological characterization diagram of a chitosan-modified polyethylene glycol-polylactic acid-loaded alpha-octanol nanoemulsion prepared by using the optimal formula conditions in example two of the present invention.
FIG. 4 is a graph showing the in vitro cumulative release of alpha-octanol as a function of time in example three of the present invention.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following further describes the technical solution of the present invention with reference to the drawings and the embodiments.
The first embodiment is as follows:
a method for preparing nano-emulsion comprises the following steps,
s1: under the condition of ice-water bath, injecting an ethanol solution of alpha-fine octanol into a dichloromethane solution of polyethylene glycol-polylactic acid to serve as an oil phase;
specifically, 1.0g of alpha-fine octanol is dissolved in 3ml of ethanol to form an ethanol solution of the alpha-fine octanol; 12.34g of polyethylene glycol-polylactic acid was dissolved in 3ml of methylene chloride to form a methylene chloride solution of polyethylene glycol-polylactic acid.
S2: dissolving poloxamer 188 in ultrapure water to completely dissolve to obtain an aqueous phase, wherein the concentration of poloxamer 188 in the aqueous phase is 0.62g/ml, and the volume is 36ml;
s3: dropwise adding the oil phase into the water phase under the magnetic stirring state, and continuously stirring to obtain an oil-water mixture; the volume ratio of the oil phase to the water phase is 1;
s4: removing 6ml of organic solvent in the oil-water mixture by using a reduced pressure rotary evaporation method, wherein the vacuum degree is 0.1MP; filtering the residue with microporous membrane, and retaining 30ml of filtrate;
s5: uniformly mixing and stirring 30ml of filtrate obtained in the step S4 and 30ml of chitosan glacial acetic acid solution to obtain a nano-emulsion suspension; the nanoemulsion suspension is specifically a chitosan-modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion; wherein the concentration of the chitosan glacial acetic acid solution is 0.1g/ml, the molecular weight of the chitosan is 50-90KD, and the deacetylation degree is 60%.
The second embodiment:
the second embodiment is the chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion prepared by the preparation method in the first embodiment.
The nano-emulsion comprises 1.0g of alpha-octanol, 12.34g of polyethylene glycol-polylactic acid, 0.2232g of poloxamer, 0.036g of chitosan, 36ml of water and 36ml of glacial acetic acid.
The encapsulation efficiency of the nano-emulsion is determined by adopting an ultrafiltration centrifugation method, 450 mu L of chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nano-emulsion is taken to be arranged in an inner tube of an ultrafiltration centrifugal tube, the centrifugation is carried out for 10min at 4000r/min, the solution in the outer tube is taken to be diluted by a certain multiple and then passes through a 0.45 mu m filter membrane, 20 mu L of chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nano-emulsion is taken to be analyzed by HPLC, the concentration of free alpha-octanol in the nano-preparation is determined, the solution is taken to be diluted by a certain multiple and then passes through 0.45 mu m, 20 mu L of chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nano-emulsion is taken to be analyzed by HPLC, and the total concentration of alpha-octanol in the nano-preparation is determined.
Chromatographic conditions for HPLC analysis were: a chromatographic column: agilent C18 (5 μm, 4.6X 250 mm), mobile phase: methanol (a) and 2 formic acid (B), gradient elution: 0-15min,40% -70%, 1-5min-25min, 70% -90% by weight B,25min-40min,90% -40% by weight B, column temperature: 30 ℃, flow rate: 0.7mL/min, detection wavelength: 314nm, injection volume: 10 μ L.
The formula for calculating the entrapment efficiency (EE%) of the chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion is as follows: EE% = (total dose-free dose)/total dose × 100%.
The particle size and the encapsulation efficiency are taken as indexes, the influence of the volume ratio of dichloromethane to ethanol and the single-factor level of chitosan content on the preparation of the nanoparticles is examined, and the result is shown in figure 1.
(1) The volume ratio of the fixed oil phase to the water phase is 1:5, poloxamer 188 concentration of 0.5g/ml, alpha-octanol and polyethylene glycol-polylactic acid (drug loading ratio) of 1:10, controlling other factors and conditions to be unchanged, and changing the volume ratio of the dichloromethane to the ethanol to be 3: 1. 3: 2. 3: 3. 3: 4. 3:5, as shown in A in the attached figure 1, when the volume ratio of the dichloromethane to the ethanol is 3: the encapsulation efficiency is maximum at 3.
(2) The volume ratio of the fixed oil phase to the water phase is 1:5, the concentration of poloxamer 188 is 0.5g/ml, and the drug-loading ratio is 1:10, the volume ratio of dichloromethane to ethanol is 3: and 3, controlling other factors to be unchanged, and changing the concentrations of the chitosan glacial acetic acid solution to be 0.1g/ml, 0.2g/ml, 0.3g/ml and 0.4g/ml. As a result, as shown in B of FIG. 1, the encapsulation efficiency was maximized when the concentration of the chitosan glacial acetic acid solution was 0.1 g/ml.
The response surface of the encapsulation efficiency and the particle size for single-factor investigation is drawn according to design expert8.0.6 software, and the result is shown in figure 2, wherein the concentration of poloxamer 188 is 0.62%, and the volume ratio of the oil phase to the water phase is 1:5.98, the proportion of the medicine to the carrier is 1:12.34, the predicted value of the encapsulation efficiency is 67.9899%, and the particle size is 182.253nm.
According to the predicted value of the response surface, three batches of samples are prepared under the optimal prescription conditions (the drug loading ratio is 1, the concentration of poloxamer 188 is 0.62%, the volume ratio of oil phase to water phase is 1.
Table 1 verification of optimum process conditions
Figure BDA0003797858470000061
The physical form characterization of the nanoemulsion prepared by using the optimal prescription conditions is shown in figure 3, and it can be seen from figure 3 that the nanoemulsion has a particle size distribution coefficient less than 0.3, which indicates that the particle size distribution is uniform. The Zeta potential value is more than 30mV, which shows that the nano-emulsion system is more stable, the grain diameter is less than 200nm, and the nano-emulsion meets the nano-level. The transmission electron microscope shows that the nano preparation has the appearance of quasi-sphere, smooth surface, no adhesion among nano particles, good dispersibility and uniform distribution.
Example three:
example three, the drug release performance of the chitosan modified polyethylene glycol-polylactic acid loaded alpha-octanol nanoemulsion prepared by the preparation method in example one is measured.
Taking 5mL of the alpha-octanol-loaded chitosan-modified polyethylene glycol polylactic acid nanoemulsion in a dialysis bag, fastening two ends of the alpha-octanol-loaded chitosan-modified polyethylene glycol polylactic acid nanoemulsion, placing the alpha-octanol-loaded chitosan-modified polyethylene glycol polylactic acid nanoemulsion in a conical flask containing phosphate buffer solution (PBS, pH 7.4), placing the conical flask in a constant-temperature shaking instrument, keeping the temperature at 37 ℃ and the rotating speed at 100r/min, taking 2mL of samples from a release medium in 0, 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours respectively, and supplementing the same amount of PBS buffer solution after each sampling. Filtering with 0.45 μm filter membrane, detecting alpha-fine octanol concentration with High Performance Liquid Chromatography (HPLC), plotting with time as abscissa and cumulative release percentage as ordinate, and plotting in vitro release curve of the alpha-fine octanol nanoparticles, with the result shown in figure 4.
As can be seen from the attached figure 4, the in vitro release rate of the alpha-fine octanol ethanol aqueous solution in 2 hours reaches 90%, and the in vitro release rate of the alpha-fine octanol nano emulsion in 6 hours is 50%, compared with the alpha-fine octanol aqueous solution, the nano emulsion can obviously delay the in vitro release time of the alpha-fine octanol, and has a certain slow release effect.
The foregoing has shown and described the fundamental principles of the invention, its essential features and advantages. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, and such changes and modifications are within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (10)

1. A method for preparing nano-emulsion is characterized by comprising the following steps,
s1: injecting an ethanol solution of alpha-fine octanol into a dichloromethane solution of polyethylene glycol-polylactic acid under the condition of ice water bath to serve as an oil phase;
s2: dissolving poloxamer 188 in ultrapure water to be completely dissolved to be used as a water phase;
s3: dropwise adding the oil phase into the water phase under the magnetic stirring state, and continuously stirring to obtain an oil-water mixture;
s4: removing the organic solvent in the oil-water mixture, performing suction filtration on the residue through a microporous filter membrane, and retaining the filtrate;
s5: and (5) mixing the filtrate obtained in the step (S4) and the chitosan glacial acetic acid solution in equal volume, and stirring to obtain the nano-emulsion suspension.
2. The method of claim 1, wherein the step of preparing the nano-emulsion comprises: in the step S1, the mass ratio of the alpha-octanol to the polyethylene glycol-polylactic acid is 1.
3. The method of claim 2, wherein the nanoemulsion comprises: in the step S1, the mass ratio of the alpha-fine octanol to the polyethylene glycol-polylactic acid is 1.
4. The method of claim 1, wherein the nanoemulsion comprises: the concentration of poloxamer 188 in the aqueous phase of step S2 was 0.62g/ml.
5. The method of claim 1, wherein the nanoemulsion comprises: and in the step S3, the volume ratio of the oil phase to the water phase is 1-8, after the oil phase is completely dripped into the water phase in the magnetic stirring state, ultrasonic oscillation is carried out for 4-6 min at the power of 250W, and then stirring is carried out for 20-40 min at normal temperature.
6. The method of claim 5, wherein the step of preparing the nano-emulsion comprises: and in the step S3, the volume ratio of the oil phase to the water phase is 1.
7. The method of claim 1, wherein the step of preparing the nano-emulsion comprises: in step S4, the organic solvent in the oil-water mixture is removed by a reduced pressure rotary evaporation method, and the vacuum degree is 0.1MP.
8. The method of claim 1, wherein the nanoemulsion comprises: in the step S5, the concentration of the chitosan glacial acetic acid solution is 0.1g/ml, the molecular weight of the chitosan is 50-90KD, and the deacetylation degree is 60%.
9. A nanoemulsion obtained by the preparation method according to any one of claims 1 to 8.
10. A nanoemulsion as claimed in claim 9, characterised in that: the nano-emulsion comprises 1.0g of alpha-octanol, 12.34g of polyethylene glycol-polylactic acid, 0.2232g of poloxamer, 0.036g of chitosan, 36ml of water and 36ml of glacial acetic acid.
CN202210973671.0A 2022-08-15 2022-08-15 Nano emulsion and preparation method thereof Pending CN115414493A (en)

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