CN108144064B

CN108144064B - Dihydromyricetin medicament taking aggregate of Tween80 and chitosan as carrier and preparation method thereof

Info

Publication number: CN108144064B
Application number: CN201810123231.XA
Authority: CN
Inventors: 王仲妮; 董爽爽
Original assignee: Shandong Normal University
Current assignee: Wuxi Xiangyuan Information Technology Co ltd
Priority date: 2018-02-07
Filing date: 2018-02-07
Publication date: 2021-01-08
Anticipated expiration: 2038-02-07
Also published as: CN108144064A

Abstract

The invention relates to a dihydromyricetin medicament based on an aggregate of polyoxyethylene sorbitan monooleate and chitosan as a carrier and a preparation method thereof, the medicament prepared by the application consists of dihydromyricetin, polyoxyethylene sorbitan monooleate, chitosan, isopropyl myristate and water, the sample type characterization is carried out by a phase diagram method and small-angle X-ray diffraction, the content of chitosan, the influence of oil content and water content, the pH value of a system influencing the release of dihydromyricetin are obtained, the chitosan is dissolved in the system and forms a stable aggregate, the coordination and the coordination of all components of the prepared medicament can achieve the effect of controlling the release rate of the dihydromyricetin medicament, and fitting a release curve by using different release kinetics models, and finding that the release process is relatively consistent with first-order kinetics, which indicates that the release of the dihydromyricetin in the sample is caused by concentration diffusion.

Description

Dihydromyricetin medicament taking aggregate of Tween80 and chitosan as carrier and preparation method thereof

Technical Field

The invention belongs to the technical field of medicament preparation, and particularly relates to a dihydromyricetin medicament taking aggregates of Tween80 and chitosan as carriers and a preparation method thereof.

Background

Dihydromyricetin (DMY) is a compound of natural flavone extracted from plants, and has been widely noticed due to numerous physiological activities, such as protecting liver, regulating blood lipid, resisting bacteria, resisting oxidation, etc. However, its solubility in water is poor (0.2mg/mL,25 ℃), resulting in low bioavailability, which greatly limits practical use. In recent years, in order to improve the above problems of DMY, it has been studied to increase the solubility of DMY by solubilizing a drug by entrapping DMY with a drug carrier such as microemulsion, liposome, micelle, or the like.

The surfactant is an amphiphilic organic compound with a hydrophilic head group and a hydrophobic tail, the hydrophobic tails of molecules are mutually associated to form micelles, and when the concentration of the surfactant exceeds the value, the micelle aggregates can be spontaneously formed in aqueous solution. When the inner micelles aggregate to a certain critical level, a lyotropic liquid crystalline phase will exist. Structurally, the structure is a short-range disordered and long-range ordered aggregate. The liquid crystal material is mainly divided into a hexagonal phase, a lamellar phase and a cubic phase liquid crystal, wherein the hexagonal phase is formed by orderly arranging rod-shaped micelles in two dimensions, oil-soluble substances can be solubilized in a hydrophobic core of the liquid crystal material, and water-soluble compounds can be solubilized in a hydrophilic area of the liquid crystal material.

However, the lyotropic liquid crystal is generally selected from a biocompatible carrier system which is green and low in toxicity and harmless to organisms, so that amphiphilic molecules which are non-toxic, biodegradable and biocompatible are selected for constructing the target lyotropic liquid crystal. Among them, polyoxyethylene sorbitan fatty acid derivative (Tween80), which is a non-ionic surfactant with mild properties and slightly bitter taste, is frequently used as an emulsifier and solubilizer and is widely used in drug delivery systems. Research shows that the Tween80 as surfactant can constitute lyotropic liquid crystal as medicine carrier, can solubilize curcumin as insoluble medicine, raise the solubility of medicine and protect unstable curcumin in light and heat condition, so that Tween80 may be used as ideal surfactant for constituting ordered aggregate of lyotropic liquid crystal, etc.

Chitosan is a naturally occurring high-molecular saccharide, is the only alkaline mucopolysaccharide in nature, widely exists in bodies of marine organisms such as shrimps and crabs, and also exists in cell walls of some fungi. Chitosan has the characteristics of no toxicity, easy degradation and the like, and has physiological activities of antibiosis, antioxidation and the like, so the chitosan is widely applied to food, medicine and cosmetics. However, the structure of chitosan itself results in poor water solubility, which seriously hinders its practical application. In recent years, chitosan is modified into a chitosan derivative by an organic reaction or the like, so that the solubility of chitosan is improved and the application range thereof is expanded. The chitosan structure has hydrophilic and hydrophobic groups and has certain self-aggregation capability, and the practical application of the chitosan is limited due to poor solubility.

Isopropyl myristate (IPM) is a food grade additive, frequently used as a penetrant and solubilizer in topical and transdermal drug delivery systems in drug delivery systems, and is widely used in the cosmetic industry and in drug delivery systems. In previous reports, isopropyl myristate has been shown not only to solubilize drugs in large quantities, but also not to damage skin during use, when used as a penetrant for transdermal administration.

Disclosure of Invention

In view of the problems in the prior art, it is an object of the present invention to provide a dihydromyricetin preparation based on aggregates of Tween80 and chitosan as carriers. The viscosity of lyotropic liquid crystal constructed based on Tween80 is higher, the solubility of dihydromyricetin is improved by the lyotropic liquid crystal arranged in a microstructure, non-toxic chitosan with various physiological functions is introduced to participate in the construction of the aggregate, the viscosity and the stability of the aggregate are increased by the introduction of the chitosan, and the influence of the introduction of the chitosan on the behaviors such as lyotropic liquid crystal phase behavior and release is further researched.

In order to solve the technical problems, the technical scheme of the invention is as follows:

a dihydromyricetin preparation based on polyoxyethylene sorbitan monooleate (Tween80) and chitosan (WCS) aggregate as carrier comprises dihydromyricetin, Tween80, chitosan (WCS), isopropyl myristate (IPM) and water. The concentration of the dihydromyricetin is 1.5mg/g, a carrier system is composed of Tween80, WCS, IPM and water, and the carrier system comprises 34-44 parts of Tween80, 0-8 parts of WCS, 2-11 parts of IPM and 45-53 parts of water by mass; where the mass of the WCS is not 0.

Tween80 and WCS are surfactants; isopropyl myristate is used as oil phase.

The ratio of surfactant to oil phase was 4: 1.

The pH of the agent was 7.4.

The solubility of the chitosan is 0.04 g/g.

A method for preparing dihydromyricetin medicament based on Tween80 and chitosan aggregate as carrier comprises: the method comprises the following specific steps:

1) stirring and uniformly mixing Tween80 and IPM in a water bath according to a certain mass ratio;

2) adding dihydromyricetin into the mixture obtained in the step 1), and stirring and uniformly mixing in a water bath;

3) adding WCS into the mixture obtained in the step 2), mixing and placing the mixture into a colorimetric tube, and uniformly dispersing the WCS in Tween 80;

4) dropwise adding secondary distilled water into the colorimetric tube obtained in the step 3), uniformly stirring by using a magnetic stirrer, and then placing in a water bath for balancing to obtain the medicament.

Preferably, the mass ratio of the Tween80 to the chitosan in the step 1) is 9: 2-10: 1.

preferably, the temperature of step 1) is 60-70 ℃.

Preferably, the water is added in multiple times in the step 4);

further preferably, the mass of the water in the step 4) is divided into a plurality of parts on average, and the mass part of the water added in each time is two parts (for example, the mass part of the water in the carrier is 45 parts, and the mass part of the water in the carrier is 2 parts in each time).

Preferably, the temperature of the water bath in the step 3) is 25 ℃.

Surfactant (b): tween80 as surfactant in the form of intermediate phase of lyotropic liquid crystal in water solution with hexagonal phase structure, chitosan as surfactant, and Tween80

The oil phase has the following functions: the increase of the IPM content of the oil phase causes the swelling of the hydrophobic core, the loose structure of the aggregate and the reduction of viscoelasticity, so that the DMY is released quickly.

Function of chitosan: the introduction of chitosan, especially at high chitosan content, has higher elasticity and more stable structure, thus resulting in slower release rate of DMY.

The function of water: the increase of the water content is beneficial to the formation of hydrogen bonds and the extension of chitosan, and the release rate of DMY is promoted to be slow.

Effect of pH: under the acidic condition, the protonation of amino groups in the chitosan is promoted, the repulsion between molecules is increased, the aggregate structure is loosened, and the release of DMY is promoted.

From the analysis, the viscoelasticity of the system influences the release of DMY, IPM can reduce the viscoelasticity of the solution, the structure is loose, the release of DMY is promoted, the viscoelasticity of the aggregate can be increased by chitosan, a better slow release effect is achieved, and the chitosan and water have the effect of promoting the formation of hydrogen bonds.

Under acidic conditions, the amino group of the chitosan is protonated, and further, the aggregate structure is influenced to a certain extent. The aggregate structure is loosened.

The invention has the beneficial effects that:

1) tween 80/WCS/IPM/H of the application₂The coordination of all the components in the O system has solubilization effect on the dihydromyricetin and has slow release and controlled release effects on the release of the dihydromyricetin;

2) tween 80/WCS/IPM/H of the application₂O improves the solubility of chitosan;

3) the result shows that the introduction of the chitosan increases the stability of the drug-loaded sample, prolongs the release time of the DMY in the sample and has good slow release effect on the DMY.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application.

FIG. 1 shows Tween 80/chitosan (10:1, wt: wt)/IPM/H₂O system is similar to a ternary phase diagram (25 ℃); wherein the mass ratio of the Tween80 to the chitosan is 1:0(a),10:1(b),9:2(c)

FIG. 2 shows a sample (S) at 25 ℃₀And S₁) Spectrum of SAXS

FIG. 3 shows the construction of Tween 80/chitosan/IPM/H with different chitosan contents (0%, 4%, 8%) of dihydromyricetin₂Release Profile in O System (25 ℃ C.)

FIG. 4(a) Dihydromyricetin samples (S) were constructed at different surfactant (Tween 80/chitosan) and IPM contents (8:2,9:1,9.5:0.5)₁O₁,S₁O₂,S₁O₃) Release profile (25 ℃); (b) samples (S) constructed with dihydromyricetin at different water contents (45%, 49%, 53%)₁W₁,S₁W₂,S₁W₃) Release Curve (25 ℃ C.)

FIG. 5 shows the concentration of dihydromyricetin in samples (S) at different pH₂) Release Curve (25 ℃ C.)

FIG. 6 (a) Dihydromyricetin/liquid Crystal (S)₁) White liquid crystal (BS)₁) DMY infrared spectrum (DMY), and (b) dihydromyricetin/liquid crystal samples with different chitosan contents (S)₁,S₂,S₃) Infrared spectrogram

FIG. 7 (a) Dihydromyricetin/liquid Crystal samples (S) constructed with different Tween80: Chitosan/IPM content₁O₁,S₁O₂,S₁O₃) Infrared spectrum, (b) dihydromyricetin/liquid crystal sample (S) under different water content₁W₁,S₁W₂,S₁W₃) Infrared spectrogram

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

Polyoxyethylene sorbitan monooleate (Tween80, national drug group chemical reagent Co., Ltd.), isopropyl myristate (IPM, national drug group chemical reagent Co., Ltd.), chitosan (WCS, degree of deacetylation > 85%, Cinan Haidebei ocean bioengineering Co., Ltd.), dihydromyricetin (Nanjing Zeron medicine science and technology Co., Ltd.), and water as redistilled water.

Electronic balance (AL104, mettler-toledo instruments ltd), thermal-arrest thermostatically-heated stirrer (model DF-101S, engyu instrument factory, tou city), centrifuge (TDL-4, shanghai ann pavilion scientific instrument factory), UV-spectrophotometer (UV-5500PC, shanghai metaanalysis instruments ltd), small-angle X-ray scatterometer (SAXSess, austria, antopapa), fourier transform infrared spectrometer (AlphaT, Bruker Optik GmbH, Germany), gold leaf brand automatic double-pure water distiller (SZ-93A, shanghai asian honor biochemical instrument factory).

The invention will be further illustrated by the following examples

For the preparation of the support

Example 1

The surfactant/oil/water ratio was 44/11/45, the chitosan mass fraction was 4%, Tween80 and WCS (as surfactant) were weighed and placed in a colorimetric cylinder, and chitosan was uniformly dispersed in Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, the water content is increased at intervals of 2%, stirring uniformly by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the polyChanges in the phase and appearance of the aggregates require extended equilibration times when the phase boundaries are approached. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₁

Example 2

The surfactant/oil/water ratio is 44/11/45, the chitosan mass fraction is 8%, Tween80 and WCS (as surfactant) are weighed and placed in a colorimetric cylinder, and the mixture is uniformly mixed to uniformly disperse the chitosan in the Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, wherein the water content is increased at intervals of 2%, uniformly stirring by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the changes of the phase state and appearance of the aggregate, and prolonging the balancing time of the aggregate when the colorimetric tube is close to a phase boundary. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₂。

Comparative example 1

The surfactant/oil/water ratio is 44/11/45, the chitosan mass fraction is 0%, Tween80 and WCS (as surfactant) are weighed and placed in a colorimetric cylinder, and the mixture is uniformly mixed to uniformly disperse the chitosan in the Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, wherein the water content is increased at intervals of 2%, uniformly stirring by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the changes of the phase state and appearance of the aggregate, and prolonging the balancing time of the aggregate when the colorimetric tube is close to a phase boundary. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₀。

Example 3

The ratio of the surfactant to the oil is 9:1, the mass fraction of the chitosan is 4.5%, the water content is 45%, Tween80 and WCS (serving as the surfactant) are weighed and placed in a colorimetric tube, and the mixture is uniformly mixed to uniformly disperse the chitosan in the Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube to obtain the water contentThe aggregates were homogenized at 2% intervals using a magnetic stirrer and then equilibrated in a water bath at 25 c, and changes in phase and appearance of the aggregates were observed and recorded, requiring extended equilibration times as phase boundaries were approached. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₁O₂.

Example 4

The ratio of the surfactant to the oil is 9.5:0.5, the mass fraction of the chitosan is 4.75%, the water content is 45%, Tween80 and WCS (as the surfactant) are weighed and placed in a colorimetric cylinder, and the mixture is uniformly mixed to uniformly disperse the chitosan in the Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, wherein the water content is increased at intervals of 2%, uniformly stirring by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the changes of the phase state and appearance of the aggregate, and prolonging the balancing time of the aggregate when the colorimetric tube is close to a phase boundary. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₁O₃。

Example 5

The ratio of the surfactant to the oil was 8:2, the chitosan mass fraction was 3.71%, the water content was 49%, Tween80 and WCS (as surfactants) were weighed and placed in a colorimetric cylinder, and the mixture was uniformly mixed to disperse the chitosan uniformly in Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, wherein the water content is increased at intervals of 2%, uniformly stirring by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the changes of the phase state and appearance of the aggregate, and prolonging the balancing time of the aggregate when the colorimetric tube is close to a phase boundary. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₁W₂。

Example 6

The surfactant to oil ratio was 8:2, the chitosan mass fraction was 3.42%, the water content was 53%, Tween80 and WCS (as surface) were weighedActive agent) and placed in a colorimetric tube, and uniformly mixed to uniformly disperse the chitosan in the Tween 80. IPM was added and mixed well under stirring in a water bath at 65 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, wherein the water content is increased at intervals of 2%, uniformly stirring by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the changes of the phase state and appearance of the aggregate, and prolonging the balancing time of the aggregate when the colorimetric tube is close to a phase boundary. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. Is marked as S₁W₃。

Drawing of phase diagrams

Tween80 and WCS (as surfactant) are weighed according to a certain mass ratio (10:1 or 9:2) and placed in a colorimetric tube, and chitosan is uniformly dispersed in the Tween80 after uniform mixing. Secondly, sequentially adding IPM into the surfactant according to the change of the oil phase ratio of the surfactant from 10:0 to 0:10, and stirring and uniformly mixing in a water bath at 60-70 ℃. Finally, adding redistilled water dropwise into the colorimetric tube, wherein the water content is increased at intervals of 2%, uniformly stirring by using a magnetic stirrer, then placing the colorimetric tube in a water bath at 25 ℃ for balancing, observing and recording the changes of the phase state and appearance of the aggregate, and prolonging the balancing time of the aggregate when the colorimetric tube is close to a phase boundary. The phase boundaries are initially judged by visual inspection of the color, clarity, hardness, viscosity, etc. exhibited by the aggregate. As shown in fig. 1.

Small angle X-ray scattering test

The small-angle X-ray scatterometer selects a copper target as a light source, the wavelength of an excited X-ray is 0.1542nm, the working voltage and the current are 40kV and 50mA respectively, the distance between a sample and a detector is 264.5nm, and the test needs to be carried out under the vacuum condition to prevent air scattering. The measurements were carried out on the liquid crystal samples studied at 25 ℃. The SAXS spectrogram obtained by measurement can be used for determining the structure type of the lyotropic liquid crystal and analyzing the microstructure and corresponding structural parameters of the liquid crystal sample.

In vitro Release test of Dihydromyricetin

The in vitro release behavior of dihydromyricetin was studied by means of in vitro dialysis, first, approximately 0.5g of liquid crystal loaded with drug was weighed out and placed in a treated dialysis bag (small intestine casing). Next, it was placed in a beaker containing 60ml of LPBS buffer medium (containing 20 wt% ethanol), and then, magnetons were put into the beaker and stirred in a water bath of a magnetic heating stirrer at a constant temperature. Finally, 5mL of release medium was removed at regular intervals while 5mL of release medium was replenished to maintain a constant volume until drug release reached equilibrium. And measuring the absorbance of the DMY at the position of 289nm of the maximum absorption wavelength of the DMY by using an ultraviolet spectrophotometer, obtaining the concentration of the DMY according to the standard absorption curve of the DMY, and calculating the cumulative release rate of the DMY according to the following formula.

TABLE 1 nomenclature and composition of the samples

TABLE 2 in vitro Release kinetics parameters of Dihydromyricetin in samples

TABLE 3 Primary Release kinetics parameters of Dihydromyricetin in samples

The experimental results are as follows:

as shown in FIG. 1a, clear, transparent, no-flow and relatively viscous liquid crystal phase regions are found in the phase diagram, and the liquid crystal phase regions are preliminarily judged to be hexagonal liquid crystal. And the water content in this phase region varied from 20 to 60 wt%, with a maximum solubilized oil content of 32 wt%.

As shown in fig. 1b and 1c, a region with high viscosity and no flow when inverted appears in each phase diagram, and the transparency of the aggregates gradually decreases and the color gradually deepens as the content of chitosan increases. As the chitosan content increases, the phase region gradually moves to the high water content region, because under the conditions of high surfactant content and low water content, the water-soluble chitosan is not completely dissolved, so that the system does not form transparent ordered aggregates, and the phase region of the system becomes smaller and moves to the high water content region.

As shown in FIG. 2, sample S₀Shows 3 Bragg peaks whose ratio of relative peak positions corresponds to

This indicates the relation of sample S₀Belonging to a hexagonal liquid crystal structure. Sample S₀After chitosan is introduced into a hexagonal liquid crystal structure, the liquid crystal formed by the system is not complete.

From fig. 1, it can be seen that chitosan has a tendency to gradually dissolve in the system. From FIG. 2, it can be seen that chitosan affects the content of each component in the system. While affecting the structure formed by the system. The structure of the system after the chitosan is added is not a hexagonal phase structure, but the formed new system is still a stable aggregate structure, and only moves towards the direction of the water phase, so that the gel-like state with the same appearance as that of the lyotropic liquid crystal, and the gel-like state is shiny, does not flow and has increased viscoelasticity.

FIG. 3 is a graph of DMY release profiles for samples constructed at different chitosan concentrations, as seen in the early release phase (<1000min), DMY in sample S₀,S₁And S₂The release rate in (1) is faster, mainly due to the release of DMY located in the interface layer. As the release proceeds, the release rate gradually slows, eventually reaching equilibrium and the cumulative release rate reaches a maximum. It was found that the release rate of DMY in the hexagonal phase liquid crystal was significantly decreased as the concentration of chitosan was increased during the entire release period, and DMY was in sample S₂The medium release rate was the slowest, probably due to the high chitosan content, with the sample havingHigher elasticity and more stable structure, resulting in slower release rate of DMY. The result shows that the introduction of chitosan increases the stability of the drug-loaded sample, prolongs the release time of DMY in the sample, and has good slow release effect on DMY, so that the release behavior can be regulated and controlled through the introduction of chitosan.

FIG. 4a is a graph showing the release profile of DMY in samples of different surfactants/oils, as seen from the graph, in comparison with sample S₁O₂And S₁O₃In contrast, DMY was in sample S₁O₁The faster release rate is probably due to the swelling of the hydrophobic core, the loose structure of the aggregates and the decrease of the elasticity with increasing oil content.

As shown in fig. 4b, it can be seen that the release rate of DMY is slowed down with the increase of water content, and the chitosan is fully stretched in the aggregate, so that the release of DMY can be prevented to slow down the release rate and the cumulative release rate, and the aggregate can have better slow-release effect by increasing the water content.

From fig. 3 and 4, it can be seen that the oil content, chitosan content and water content affect the release behavior of DMY.

As shown in fig. 5. It can be seen that the release rates of DMY in the samples were significantly different at different pH values, with cumulative release rates of 90% (pH 7.4) and 99% (pH 5.6), respectively. Release media of different pH were formulated by controlling the amount of added sodium dihydrogen phosphate and disodium hydrogen phosphate. From FIG. 5, it can be seen that pH affects the DMY release behavior.

To investigate the DMY release behavior in aggregates, we used sample S₀-S₂For example, different kinetic models were fitted, mainly including a Zero-order kinetic model (Zero-order), a First-order kinetic model (First-order), a Higuchi model, a Hixson-Crowell model and a Korsmeyer-Peppas model, with the kinetic parameters obtained as shown in table 2. The maximum correlation (R) obtained using first order kinetic fitting was found²>0.9935) indicating that the release of DMY in the sample is a concentration-diffusion dependent process. Correlation (R) obtained by Korsmeyer-Peppas model²>0.9316) was only after the first order kinetics, indicating that the release of DMY from the liquid crystal sample most closely followed the first order kinetics.

The first order kinetic equation is as follows:

wherein K is a kinetic constant; n is a release index for characterizing the release mechanism of the drug; m₀/M_tIs the percent of drug released at time t.

And further selecting a first-order kinetic equation to fit all samples, wherein the obtained fitting equation and related parameters are shown in a table 3. Comparing the obtained correlation coefficients (R)²) The correlation R obtained by the first-order dynamic model fitting is found²Both are greater than 0.9920, indicating that the in vitro release behavior of DMY is more consistent with the first order kinetic model, indicating that the in vitro release process is controlled by concentration diffusion.

As can be seen from FIG. 6a, the-OH peak position was from 3384cm after introduction of chitosan into the system^-1(S₀) Down peak 3374cm^-1(S₁) The migration indicates that more hydrogen bonds are formed in the system, i.e. the introduction of chitosan is beneficial to the formation of hydrogen bonds and the stabilization of aggregates, which is consistent with the slow release rate and cumulative release rate caused by high content of chitosan in the in vitro release behavior. Wherein the thickness is 2851cm^-1At a position of 2923cm^-1The absorption peak is-CH on the alkyl chain of each component₂Symmetric stretching vibration and antisymmetric stretching symmetric peak. 1461cm^-1The position is a bending vibration absorption peak of C-H on an alkyl chain. At 1739cm^-1Has an absorption peak, which is mainly generated by a stretching vibration peak of-C ═ O in a DMY molecule. 1643cm^-1is-NH in chitosan₂1437cm from the peak of absorption of stretching vibration^-1Is the stretching vibration peak of-N-H in chitosan, and is 1091cm^-1The absorption peak at (A) is the stretching vibration peak of Tween80 and-C-O in DMY molecules.

From FIG. 7 can be seenIt is seen that the stretching vibration peak position of-OH is from 3376cm^-1Variation 3374cm^-1Indicating that more hydrogen bonds are formed in the system. Increasing the water content, it was found that the-OH peak was broadened, indicating that the increase in water content favors the formation of hydrogen bonds and the sample structure is more stable, consistent with the result that increasing the water content results in slower release rates.

To summarize:

the medicament prepared by the application has a good slow release effect on DMY. The in vitro release behavior of DMY is in accordance with the first order kinetic model, which indicates that the in vitro release process is controlled by concentration diffusion. Chitosan in the medicament influences the release behavior of DMY, oil content influences the release of DMY, water content influences the release of DMY, and the pH value of the system also influences the release of DMY. The coordination and coordination of the components of the medicament prepared herein may achieve the effect of controlling the release rate of the DMY drug.

Firstly, a lyotropic liquid crystal is constructed based on Tween80 to improve the solubility of dihydromyricetin, and the microemulsion solute liquid crystal with a certain microstructure and solubilization capacity has higher viscosity; the introduction of the chitosan which is non-toxic and has various physiological functions participates in the construction of the aggregate, the viscosity and the stability of the aggregate are increased by the introduction of the chitosan, and the influence of the introduction of the chitosan on the behaviors such as lyotropic liquid crystal phase behavior, release and the like is further researched.

The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A dihydromyricetin preparation based on Tween80 and chitosan aggregate as carrier comprises dihydromyricetin, Tween80, chitosan, isopropyl myristate (IPM) and water; the carrier system comprises 34-44 parts of Tween80, 3.42-8 parts of chitosan, 2-11 parts of isopropyl myristate and 45-53 parts of water;

the pH value of the medicament is 7.4;

the concentration of the dihydromyricetin is 1.5 mg/g;

the solubility of the chitosan is 0.04 g/g;

the water is double distilled water.

2. A method for preparing a dihydromyricetin pharmaceutical formulation as claimed in claim 1, wherein: the method comprises the following specific steps:

3) adding chitosan into the mixture obtained in the step 2), mixing and placing the mixture into a colorimetric tube, and uniformly dispersing the chitosan into Tween 80;

3. The method for preparing dihydromyricetin pharmaceutical preparation according to claim 2, wherein: the mass ratio of the Tween80 to the chitosan in the step 3) is 9: 2-10: 1.

4. The method for preparing dihydromyricetin pharmaceutical preparation according to claim 2, wherein: the temperature of the step 1) is 60-70 ℃.

5. The method for preparing dihydromyricetin pharmaceutical preparation according to claim 2, wherein: the temperature of the water bath in the step 2) is 25 ℃.

6. The method for preparing dihydromyricetin pharmaceutical preparation according to claim 2, wherein: and adding water for multiple times in the step 4).

7. The method for preparing dihydromyricetin pharmaceutical preparation according to claim 6, wherein: in the step 4), the mass of the water is averagely divided into a plurality of parts, and the mass part of the water added each time is two parts.