CN102526745B - Slow-release method for controlling medicine-carrying molecules of lyotopic liquid crystal by using micro electric field - Google Patents

Abstract

The invention relates to a slow-release method for controlling medicine-carrying molecules of lyotopic liquid crystal by using a micro electric field. The slow-release method comprises the following steps of: adopting a pulse electric field to carry out controlled release on the carried medicines of the lyotopic liquid crystal; and utilizing the sensitivity of a unique ordered structure consisting of biparental molecules of the lyotopic liquid crystal to the stimulation of external physical factors and the advantage of GMO/F127 lyotopic liquid crystal for carrying the medicines with different polarities and different types, and calculating threshold current density jc equal to sigmaE according to the electric field intensity threshold which is deducted according to the theory and causes the elastic deformation of the liquid crystal, thus designing and finishing pulse controlled release experiment in a mice body and verifying the validity of the slow-release method for controlling the packaged medicines of lyotopic liquid crystal by using the electric field. The method can adopt a quantitative condition to control the release of the medicines and obviously improves the medicine effect and the utilization ratio of the medicines.

Description

A kind of release method that supports drug molecule with electric microfield control lysotropic liquid crystal

Technical field

The present invention relates to the control release technic field of lysotropic liquid crystal packaging medicine, particularly a kind of release method that supports drug molecule with electric microfield control lysotropic liquid crystal, the method can effectively be controlled the release of medicine and improve utilization ratio of drug.

Background technology

In recent years, discharging by particle drug-loaded realization medicine control is an important research field of release technology.At present, the many speed that realize controlled release drug by the architectural characteristic that changes carrier of the sustained-release and controlled release preparation of medicine, however medicine carrying microgranule exists preparation process complicated, the preparation batch between poor repeatability, poor stability, organic solvent residual is serious, cost is higher, the problems such as suitability for industrialized production difficulty.The preparation method of lysotropic liquid crystal is simple, has the method for multiple convenient operation to select.Lysotropic liquid crystal has unique Emission in Cubic co-continuous channel structure, make its have good be transferred to the property of medicine can and good medicine intermiscibility, can support the opposed polarity medicine, improve bioavailability, increase medicine body internal absorption factor, become the pharmaceutical carrier of new generation that contains great potential, cause the broad interest of Chinese scholars.

The lysotropic liquid crystal packaging medicine realizes that control discharges, and the achievement of research is very abundant both at home and abroad, but has attracted to be engaged in drug release studies scholar sight abroad for lysotropic liquid crystal medicine carrying original position controllable release, domesticly but also is in the starting stage.The ordered structure of lysotropic liquid crystal uniqueness and peculiar dynamic performance make it have the to external world high susceptibility of stimulating factor, can stimulate rapidly to external world to respond.Such as light, sound, electricity, temperature, ray and chemical change etc.The people such as Fong of Australia utilize the thermal sensitivity characteristics of parents' molecule, have developed the GMO/ phytantriol lysotropic liquid crystal temperature-sensitive controlled-release medicine with temperature detect switch (TDS) function.When temperature is higher than critical temperature, the interaction of the lipophilic molecule of carrier will cause that carrier shrinks, and drug molecule is discharged in a large number, and when temperature was lower than critical temperature, carrier returned to original state again, and this recovery has reversibility.But too high temperature may exert an influence to the drug effect of medicine, in using in vivo certain limitation is arranged.The high-sequential molecular structure of lysotropic liquid crystal Emission in Cubic is under the effect of electric field, elastic deformation will occur in liquid crystal molecule, pharmaceutical pack is rolled in the middle of the lysotropic liquid crystal system, drug diffusion speed changes with the change of liquid crystal structure, thereby realizes the release of the medicine of impulse electric field control lysotropic liquid crystal parcel.Slow release with impulse electric field control lysotropic liquid crystal medicine carrying is good trial.

Summary of the invention

In order to overcome the defective of above-mentioned prior art, the object of the present invention is to provide a kind of release method that supports drug molecule with electric microfield control lysotropic liquid crystal, adopt heat treating process and emulsion process to prepare GMO/F127 lysotropic liquid crystal microgranule, and support medicine, then utilize lysotropic liquid crystal because of the molecular ordered structure of the parents of uniqueness to external world physical factor stimulate the high susceptibility have, make lysotropic liquid crystal molecule generation elastic deformation realize that the control of medicine discharges by quantitatively regulating and controlling impulse electric field signal, the method has effect and the characteristic of control medicament slow release, provide the technical method support for improving utilization ratio of drug and reducing drug side effect, so that the clinical practice of medicine and disease treatment become possibility.

To achieve these goals, the technical solution taked of the present invention is as follows:

A kind of release method that supports drug molecule with electric microfield control lysotropic liquid crystal comprises the following steps:

Step 1, adopt heat treating process and emulsion process to prepare GMO/F227 lysotropic liquid crystal microgranule, mass ratio by F127 and GMO is 10: 80-120 takes by weighing raw material, with 5-10 minute mixing of oscillator physics concussion, oscillator power is 2000-2500W, the concussion frequency is 80-100Hz, put into steady temperature and be 50 ℃-60 ℃ water-bath, the employing magnetic stir bar obtained the loose homogenizing of rough segmentation in 8-12 hour with 40-60 rev/min speed stirring, leave standstill hatching 7-10 days, with biomixer ultrasonic 3-5 time of ultrasonic probe intermittently, each 15-20 minute, intermittently 5-10 minute, ultrasonic power was 800-1000W, supersonic frequency is 20-25KHz, then in centrifuge with per minute 10,000 rotary speeds centrifugal 5-8 minute, leave standstill and can make the nanometer liquid crystal particle in 20-30 hour, keep in Dark Place under the 20-30 ℃ of condition;

Step 2, preparation GMO/F127 lysotropic liquid crystal medicine-carried system, under 20 ℃-30 ℃ of steady temperatures, with the nanometer liquid crystal particle for preparing in the step 1 with rotating speed 20-50rmp low speed rotation, and with 5-12 drip/minute speed, ratio in 1.5-2.0mg/ml dropwise adds the medicine that will support, evenly mixed 3-5 hour, make GMO/F127 lysotropic liquid crystal medicine-carried system, be statically placed in 20-30 ℃ and keep in Dark Place;

Step 3, draw the standard solution working curve of medicine to be supported, detect the encapsulation ratio that the GMO/F127 lysotropic liquid crystal supports medicine, configure at first as required the pharmaceutical standards solution of variable concentrations gradient, utilize characteristic absorption peak and the absorbance of the medicine of measurement of ultraviolet-visible spectrophotometer variable concentrations, thereby draw out the standard curve of medicine to be supported, with the absorbance of medicine free in the solution behind the measurement of ultraviolet-visible spectrophotometer GMO/F127 lysotropic liquid crystal packaging medicine, reflect the concentration of medicine with the variation of absorbance.

By the encapsulation ratio computing formula:

In the formula

W is total---total content of carrier Chinese medicine

W trip---the content of the outer free drug of carrier

Calculate the encapsulation ratio of GMO/F127 lysotropic liquid crystal supported carrier medicine;

Step 4, make up the counting system that elastically-deformable threshold value occurs under field effect lysotropic liquid crystal: the thickness of supposition lysotropic liquid crystal is d, zero is taken at the central authorities of film, get simultaneously the z axle and vow that with sensing n is parallel, be the upper of film, lower interface is in Z=± d/2 position, applying electric field E perpendicular to pointing to the direction X-direction of vowing n, then electric field will make the arrangement of pointing to arrow n change, from large regional integration, not parallel to each other between the molecule, so, the Emission in Cubic structural equivalents of liquid crystal is in a lot of crooked liquid crystal cells arranged vertically, liquid crystal is subjected under the external electrical field effect deformation to occur, and causing the required energy of deformation is the curvature elastic energy, when the sensing of GMO/F127 lysotropic liquid crystal vows that deformation has occured n, according to liquid crystal continuous elastomeric theory and law of conservation of energy, the Gibbs free energy of liquid crystal system under electric field action:

G＝G _el-G _e (1-2)

Then have:

δG＝δG _el-δG _e (1-3)

In the formula:

G _El---the elastic energy of deformation of GMO/F127 lysotropic liquid crystal;

G _e---the electric field free energy of GMO/F127 lysotropic liquid crystal.

$G_{\mathrm{el}}=\∫g_{\mathrm{el}}\mathrm{d\τ}=\frac{1}{2}\∫[k_{11}{(\▿\·n)}^2+k_{22}{(n\·\▿\×n)}^2+k_{33}{(n\×\▿\×n)}^2]\mathrm{d\τ}---(1-4)$

In the formula:

k ₁₁---open up bent elastic constant;

k ₂₂---the distortion elastic constant;

k ₃₃---bend elastic constant.

$G_e=\∫g_e\mathrm{d\τ}=\frac{1}{8\mathrm{\π}}\∫E\·\mathrm{Dd\τ},---(1-5)$

Wherein electric field strength E is constant, so

When lysotropic liquid crystal reaches poised state, be a kind of steady statue, according to minimum energy principle in the classical physics, G=G _El-G _eHave minima, to the G minimizing:

$G=\frac{1}{2}\∫[k_{11}{(\▿\·n)}^2+k_{22}{(n\·\▿\×n)}^2+k_{33}{(n\×\▿\×n)}^2-\frac{1}{4\mathrm{\π}}{\mathrm{\ϵ}}_a{(n\·E)}^2]\mathrm{d\τ}---(1-6)$

In the formula:

k ₁₁---the Splay elastic constant of liquid crystal;

k ₂₂---the distortion coefficient of elasticity of liquid crystal;

k ₃₃---the elasticity of flexure coefficient of liquid crystal,

Under electric field action, be that the sensing at z place vows will be into θ angle with Z axis apart from initial point, and θ be the function of z is θ=θ (z), n then ₁=sin θ (z), n ₂=0, n ₃=cos θ (z), therefore, the free energy density of GMO/F127 lysotropic liquid crystal is:

$g=\frac{1}{2}\underset{\frac{d}{2}}{\overset{\frac{d}{2}}{\text{\&Integral;}}}[(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\sin }^2\mathrm{\&theta;}]\mathrm{dz}---(1-7)$

(1-7) in the formula, only there is k ₁₁And k ₃₃, do not have k ₂₂, show that the GMO/F127 lysotropic liquid crystal is merely able to produce exhibition song and Bending Deformation under electric field action, can not produce twist distortion.Free energy density should have minima under the equilibrium state, then can derive following formula:

$\frac{d[(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\sin }^2\mathrm{\&theta;}]}{\mathrm{dz}}=0---(1-8)$

In (1-8), because integrand is and x ₃, θ, Relevant function, therefore the Euler-Lagrange equation of free energy density g is:

$\frac{(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\mathrm{<figure-callout\; id="2"\; label="d"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">d</figure-callout>}}^2\mathrm{\&theta;}}{{\mathrm{<figure-callout\; id="2"\; label="dz"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">dz</figure-callout>}}^2}+(k_{11}-k_{33})\sin \mathrm{\&theta;}\cos \mathrm{\&theta;}{\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2\sin \mathrm{\&theta;}\cos \mathrm{\&theta;}}{4\mathrm{\&pi;}}=0---(1-9)$

(1-9) formula both sides are multiplied by respectively

Then have:

$\frac{d(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;})}{\mathrm{dz}}{\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{{\mathrm{\&epsiv;}}_a{E}^{2}d\left({\sin }^2\mathrm{\&theta;}\right)}{4\mathrm{\&pi;dz}}=0---(1-10)$

(1-10) formula both sides z is carried out integration from 0 to d/2, notice that there is θ=0 in the z=d/2 place, at the largest deformation angle of z=0 place lysotropic liquid crystal θ _MHave

Can get:

$(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\sin }^2\mathrm{\&theta;}=\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\sin }^2{\mathrm{\&theta;}}_M---(1-11)$

When z＞0, θ increases progressively θ with z and reduces gradually, can get:

$-\frac{\mathrm{d\&theta;}}{\mathrm{dz}}={\left[\frac{\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2({\sin }^2{\mathrm{\&theta;}}_M-{\sin }^2\mathrm{\&theta;})}{k_{33}+(k_{11}-k_{33}){\sin }^2\mathrm{\&theta;}}\right]}^{\frac{1}{2}},---(1-12)$

If k=sin is θ _M, $\mathrm{\&eta;}=\frac{k_{11}-k_{33}}{k_{33}},$ $\mathrm{\&xi;}={\left(\frac{{4\mathrm{\&pi;k}}_{33}}{{\mathrm{\&epsiv;}}_a{E}^2}\right)}^{\frac{1}{2}},$ Sin θ=ksin λ can get:

$[\frac{1+\frac{\mathrm{\&eta;}}{2}}{\sqrt{1-{\mathrm{<figure-callout\; id="2"\; label="k"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">k</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&lambda;}}}-\frac{\mathrm{\&eta;}}{2}\sqrt{1-{\mathrm{<figure-callout\; id="2"\; label="k"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">k</figure-callout>}}^2{\sin }^2\mathrm{\&lambda;}}]\mathrm{d\&lambda;}=-\frac{\mathrm{dz}}{\mathrm{\&xi;}},---(1-13)$

Note boundary condition z=0 place, θ=θ _M, λ=pi/2; At the z=d/2 place, θ=0, λ=0.With (1-13) formula both sides x ₃Be integrated to d/2 from 0 respectively, can get:

$(1+\frac{\mathrm{\&eta;}}{2})F\left(k\right)-\frac{\mathrm{\&eta;}}{2}E\left(k\right)=\frac{\mathrm{<figure-callout\; id="2"\; label="d"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">d</figure-callout>}}{2\mathrm{\&xi;}}---(1-14)$

In the formula:

F (k)---complete elliptic integral of the first kind;

E (k)---complete elliptic integral of the second kind.

Work as θ _M=0, k=0 then, and F (0)=E (0)=pi/2 can get π=d/ ξ by (1-14) formula, substitution

Can obtain intensity threshold:

$E_c=\frac{2\mathrm{\&pi;}}{d}\sqrt{\frac{{\mathrm{\&pi;k}}_{33}}{{\mathrm{\&epsiv;}}_a}}---(1-15)$

Can try to achieve threshold current density by threshold field strength is:

jc＝σE (1-16)

In the formula:

σ---liquid crystal molecule electrical conductivity;

Step 5, GMO/F127 lysotropic liquid crystal medicine-carried system realize that under impulse electric field control control discharges,

The GMO/F127 lysotropic liquid crystal system that supports medicine is placed impulse electric field, and the intensity of regulating impulse electric field is when electric field strength surpasses threshold value E _cOr the electric current density that flows through liquid crystal molecule is greater than threshold value jc, to cause GMO/F127 lysotropic liquid crystal Emission in Cubic membrane structure generation deformation, cause structure and the character of pharmaceutical carrier to change, with drug release out, will cause that like this concentration difference and the driving force of medicine in carrier changes; When electric field strength is lower than threshold value E _cOr the electric current density that flows through liquid crystal molecule is less than threshold value jc, and the GMO/F127 lysotropic liquid crystal system that supports medicine will stop to discharge medicine, thereby realizes pulse control drug release.Simultaneously, the control electric field strength can not be higher than the elastic deformation ability of GMO/F127 lysotropic liquid crystal, otherwise excessive electric field intensity has surpassed the elastic deformation ability of GMO/F127 lysotropic liquid crystal, can destroy its structure, the effect of impact control drug release.

Under Electro-pulsing Field, elastic deformation will occur in the parents' molecule in the lysotropic liquid crystal Emission in Cubic structure.The film formed long-chain of liquid crystal parents molecule has high-sequential, and when film was a flat bed structure, its parents' molecular film normal direction was consistent with the director orientation of liquid crystal parents molecule.Cubic Lyotropic Liquid Crystals forms the cubic structure that has symmetrically, causes the bending of normal direction line owing to the bending on film surface, and molecule points to arrow and also will change thereupon.Because in electric field, the lysotropic liquid crystal of GMO/F127 is subjected to the response of impulse electric field, and shearing deformation does not occur, only there are stretching, extension, Bending Deformation.By the electric field intensity threshold expression, can find, the deformation of lysotropic liquid crystal parents molecule has only produced Bending Deformation.The bending of molecule will change the swelling ratio of carrier, and the structure of liquid crystal will change, and the pressure combined effect that osmotic pressure and structural change form is in drug molecule, and this driving force will make drug molecule discharge from carrier rapidly.

Method of the present invention comes quantitative regulating impulse electric field signal to realize that the slow release of lysotropic liquid crystal packaging medicine has positive effect because the lysotropic liquid crystal of GMO/F127 has the advantage that supports opposed polarity, variety classes medicine so that the encapsulation ratio of lysotropic liquid crystal packaging medicine significantly improves according to the index that theoretical derivation calculates.

Description of drawings

Fig. 1 is GMO/F127 lysotropic liquid crystal parents molecule field effect equivalent model.

Fig. 2 is electric field pulse controllable drug release systems schematic diagram.

Fig. 3 is the variation of mouse blood sugar concentration after the various Comparative formulation of injection.

The specific embodiment

Below in conjunction with the drawings and specific embodiments, the present invention is described in further detail.

Embodiment one:

Step 1, adopt heat treating process and emulsion process to prepare GMO/F127 lysotropic liquid crystal microgranule, be to take by weighing raw material at 10: 100 by the mass ratio of F127 and GMO, with 5 minutes mixings of oscillator physics concussion, oscillator power is 2300W, the concussion frequency is 90Hz, put into steady temperature and be 55 ℃ water-bath, the employing magnetic stir bar obtained the loose homogenizing of rough segmentation in 10 hours with 50 rev/mins speed stirring, leave standstill hatching 8 days, with biomixer ultrasonic 3 times of ultrasonic probe intermittently, each 20 minutes, intermittently 10 minutes, ultrasonic power was 900W, supersonic frequency is 22KHz, then in centrifuge with per minute 10,000 rotary speeds centrifugal 5 minutes, leave standstill and can make nanometer GMO/F127 lysotropic liquid crystal microgranule in 24 hours, keep in Dark Place under 20 ℃ of conditions;

Step 2, preparation GMO/F127 lysotropic liquid crystal medicine-carried system, under 25 ℃ of steady temperatures, with the nanometer GMO/F127 lysotropic liquid crystal microgranule for preparing in the step 1 with rotating speed 30rmp low speed rotation, and dropwise add the medicine that will support with 10 droplets/minute speed in the ratio of 1.5mg/ml, evenly mixed 4 hours, make GMO/F127 lysotropic liquid crystal medicine-carried system, be statically placed in 20 ℃ and keep in Dark Place;

The standard solution working curve of step 3, drafting insulin, detect the encapsulation ratio that the GMO/F127 lysotropic liquid crystal supports medicine, configure at first as required the pharmaceutical standards solution of variable concentrations gradient, utilize characteristic absorption peak and the absorbance of the insulin of measurement of ultraviolet-visible spectrophotometer variable concentrations, thereby draw out the standard curve of insulin, with the absorbance of insulin free in the solution behind the measurement of ultraviolet-visible spectrophotometer GMO/F127 lysotropic liquid crystal Islets element, reflect the concentration of insulin with the variation of absorbance.

By the encapsulation ratio computing formula:

In the formula

W is total---total content of carrier Chinese medicine

W trip---the content of the outer free drug of carrier

Calculate according to experimental data, the GMO/F127 lysotropic liquid crystal protein matter medicine insulin of experiment preparation has higher encapsulation ratio, and it is 72.2% that experiment detects encapsulation ratio;

The counting system of elastically-deformable threshold value occurs in step 4, structure lysotropic liquid crystal under field effect:

As shown in Figure 1, the thickness of supposing lysotropic liquid crystal is d, zero O is taken at the central authorities of film, get simultaneously the z axle and vow that with sensing n is parallel, the upper and lower interface that is film is in Z=± d/2 position, applying electric field E perpendicular to pointing to the direction X-direction of vowing n, then electric field will make the arrangement of pointing to arrow change, from large regional integration, not parallel to each other between the molecule, so, the Emission in Cubic structural equivalents of liquid crystal is in a lot of crooked liquid crystal cells arranged vertically, liquid crystal is subjected under the external electrical field effect deformation to occur, and causing the required energy of deformation is the curvature elastic energy

When the sensing of GMO/F127 lysotropic liquid crystal vows that deformation has occured n, according to liquid crystal continuous elastomeric theory and law of conservation of energy, the Gibbs free energy of liquid crystal system under electric field action:

G＝G _el-G _e (1-2)

Then have:

δG＝δG _el-δG _e (1-3)

In the formula:

G _El---the elastic energy of deformation of GMO/F127 lysotropic liquid crystal;

G _e---the electric field free energy of GMO/F127 lysotropic liquid crystal.

$G_{\mathrm{el}}=\&Integral;g_{\mathrm{el}}\mathrm{d\&tau;}=\frac{1}{2}\&Integral;[k_{11}{(\&dtri;\&CenterDot;n)}^2+k_{22}{(n\&CenterDot;\&dtri;\&times;n)}^2+k_{33}{(n\&times;\&dtri;\&times;n)}^2]\mathrm{d\&tau;}---(1-4)$

In the formula:

k ₁₁---open up bent elastic constant;

k ₂₂---the distortion elastic constant;

k ₃₃---bend elastic constant.

$G_e=\&Integral;g_e\mathrm{d\&tau;}=\frac{1}{8\mathrm{\&pi;}}\&Integral;E\&CenterDot;\mathrm{Dd\&tau;},---(1-5)$

Wherein electric field strength E is constant, so

When lysotropic liquid crystal reaches poised state, be a kind of steady statue, according to minimum energy principle in the classical physics, G=G _El-G _eHave minima, to the G minimizing:

$G=\frac{1}{2}\&Integral;[k_{11}{(\&dtri;\&CenterDot;n)}^2+k_{22}{(n\&CenterDot;\&dtri;\&times;n)}^2+k_{33}{(n\&times;\&dtri;\&times;n)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{(n\&CenterDot;E)}^2]\mathrm{d\&tau;}---(1-6)$

In the formula:

k ₁₁---the Splay elastic constant of liquid crystal;

k ₂₂---the distortion coefficient of elasticity of liquid crystal;

k ₃₃---the elasticity of flexure coefficient of liquid crystal.

Under electric field action, be that the sensing at z place vows will be into θ angle with Z axis apart from initial point, and θ be the function of z is θ=θ (z).N then ₁=sin θ (z), n ₂=0, n ₃=cos θ (z).Therefore, the free energy density of GMO/F127 lysotropic liquid crystal is:

$g=\frac{1}{2}\underset{\frac{d}{2}}{\overset{\frac{d}{2}}{\text{\&Integral;}}}[(k_{11}{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}]\mathrm{dz}---(1-7)$

(1-7) in the formula, only there is k ₁₁And k ₃₃, do not have k ₂₂, show that the GMO/F127 lysotropic liquid crystal is merely able to produce exhibition song and Bending Deformation under electric field action, can not produce twist distortion.Free energy density should have minima under the equilibrium state, then can derive following formula:

$\frac{d[(k_{11}{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}]}{\mathrm{dz}}=0---(1-8)$

In (1-8), because integrand is and x ₃, θ,

Relevant function, therefore the Euler-Lagrange equation of free energy density g is:

$\frac{(k_{11}{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\mathrm{<figure-callout\; id="2"\; label="d"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">d</figure-callout>}}^2\mathrm{\&theta;}}{{\mathrm{<figure-callout\; id="2"\; label="dz"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">dz</figure-callout>}}^2}+(k_{11}-k_{33})\sin \mathrm{\&theta;}\cos \mathrm{\&theta;}{\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2\sin \mathrm{\&theta;}\cos \mathrm{\&theta;}}{4\mathrm{\&pi;}}=0---(1-9)$

(1-9) formula both sides are multiplied by respectively

Then have:

$\frac{d(k_{11}{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;})}{\mathrm{dz}}{\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{{\mathrm{\&epsiv;}}_a{E}^{2}d\left({\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}\right)}{4\mathrm{\&pi;dz}}=0---(1-10)$

(1-10) formula both sides z is carried out integration from 0 to d/2, notice that there is θ=0 in the z=d/2 place, at the largest deformation angle of z=0 place lysotropic liquid crystal θ _MHave

Can get:

$(k_{11}{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}+k_{33}{\mathrm{<figure-callout\; id="2"\; label="cos"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">cos</figure-callout>}}^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}=\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{\mathrm{<figure-callout\; id="2"\; label="E"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">E</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2{\mathrm{\&theta;}}_M---(1-11)$

When z＞0, θ increases progressively θ with z and reduces gradually, can get:

$-\frac{\mathrm{d\&theta;}}{\mathrm{dz}}={\left[\frac{\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2({\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2{\mathrm{\&theta;}}_M-{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;})}{k_{33}+(k_{11}-k_{33}){\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&theta;}}\right]}^{\frac{1}{2}},---(1-12)$

If k=sin is θ _M, $\mathrm{\&eta;}=\frac{k_{11}-k_{33}}{k_{33}},$ $\mathrm{\&xi;}={\left(\frac{{4\mathrm{\&pi;k}}_{33}}{{\mathrm{\&epsiv;}}_a{E}^2}\right)}^{\frac{1}{2}},$ Sin θ=ksin λ can get:

$[\frac{1+\frac{\mathrm{\&eta;}}{2}}{\sqrt{1-{\mathrm{<figure-callout\; id="2"\; label="k"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">k</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&lambda;}}}-\frac{\mathrm{\&eta;}}{2}\sqrt{1-{\mathrm{<figure-callout\; id="2"\; label="k"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">k</figure-callout>}}^2{\mathrm{<figure-callout\; id="2"\; label="sin"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">sin</figure-callout>}}^2\mathrm{\&lambda;}}]\mathrm{d\&lambda;}=-\frac{\mathrm{dz}}{\mathrm{\&xi;}},---(1-13)$

Note boundary condition z=0 place, θ=θ _M, λ=pi/2; At the z=d/2 place, θ=0, λ=0.With (1-13) formula both sides x ₃Be integrated to d/2 from 0 respectively, can get:

$(1+\frac{\mathrm{\&eta;}}{2})F\left(k\right)-\frac{\mathrm{\&eta;}}{2}E\left(k\right)=\frac{\mathrm{<figure-callout\; id="2"\; label="d"\; filenames="HDA0000133677160000011.png,HDA0000133677160000021.png"\; state="\{\{state\}\}">d</figure-callout>}}{2\mathrm{\&xi;}}---(1-14)$

In the formula:

F (k)---complete elliptic integral of the first kind;

E (k)---complete elliptic integral of the second kind.

Work as θ _M=0, k=0 then, and F (0)=E (0)=pi/2 can get π=d/ ξ by (1-14) formula, substitution

Can obtain intensity threshold:

$E_c=\frac{2\mathrm{\&pi;}}{d}\sqrt{\frac{{\mathrm{\&pi;k}}_{33}}{{\mathrm{\&epsiv;}}_a}}---(1-15)$

Can try to achieve threshold current density by threshold field strength is:

jc＝σE (1-16)

In the formula:

σ---liquid crystal molecule electrical conductivity.

The GMO/F127 lysotropic liquid crystal of experiment preparation satisfies following condition: k ₃₃=5.75 (10 ^-12N), ε a=1.643, d=200nm, σ=3.93mS/cm then can be calculated E by (1-15) _CBe 10.41V/m, can be calculated threshold current density jc by (1-16) is 3.93mA/cm ²

Step 5, GMO/F127 lysotropic liquid crystal medicine-carried system are realized controllable release under impulse electric field control:

As shown in Figure 2, the GMO/F127 lysotropic liquid crystal system that supports medicine is placed impulse electric field, the intensity of regulating impulse electric field, the electric current density that surpasses threshold value 10.41V/m or flow through liquid crystal molecule when electric field strength is greater than threshold value 3.93mA/cm ², will cause GMO/F127 lysotropic liquid crystal Emission in Cubic membrane structure generation deformation, cause the structure of pharmaceutical carrier and character to change, with drug release out, will cause that like this concentration difference and the driving force of medicine in carrier changes; The electric current density that is lower than threshold value 10.41V/m or flows through liquid crystal molecule when electric field strength is less than threshold value 3.93mA/cm ²The GMO/F127 lysotropic liquid crystal system that supports medicine will stop to discharge medicine, thereby the pulse control that realizes medicine discharges, but the time, should note controlling electric field strength can not be too high, otherwise excessive electric field intensity has surpassed the elastic deformation ability of GMO/F127 lysotropic liquid crystal, can destroy its structure, the effect of impact control drug release.

Carry out in the Mice Body GMO/F127 lysotropic liquid crystal according to the method for above-mentioned experimental procedure and support insulin in impulse electric field control control release experiment, concrete operations and experimental result are as follows:

Selecting body weight is that the Healthy female mice of 30g is got 25, is divided at random 5 groups, the hungry processing for 1 night.The 1st group is the blank group of normal saline, and the 2nd group is blank GMO/F127 vehicle group, and the concentration of carrier is 1.5mg/mL, the 3rd group is the insulin solution group, insulin concentration is 1.5mg/mL, and the 4th group for supporting insulin carrier slow release group, and the amount of insulin is 1.5mg/mL in carrier.The 5th group for supporting insulin carrier pulse controlled release group.The 5th group pulse electric field signal adopts electrophresis apparatus power supply current stabilization mode, with mouse web portion and back cropping, sticks electrode slice, and electrode slice connects regulated power supply, 1.5 hours and added electric field pulse in 3.5 hours behind the injection medicament, and applying electric current density is 4mA/cm ², the burst length is 5 minutes, measures the blood sugar concentration of mice the 2nd hour and the 4th hour, every group of mouse web portion subcutaneous injection medicament 0.4ml.Injection medicament 1, after 2,4,6,8,10,12 hours, measure the blood sugar concentration of afterbody peripheral blood with blood glucose meter.

Give respectively 1～5 group of mouse subcutaneous injection normal saline, blank GMO/F127 vehicle group, insulin solution group, support the insulin carrier.Measure the variation of 5 groups of mouse blood sugars, each Measuring Time point blood glucose value of mice and blood glucose initial value are compared, calculate every group in average and the standard variance mapping of each time point, as shown in Figure 3.Vertical coordinate is the percentage ratio of each time point blood glucose value and initial blood glucose value, and abscissa is time point.

The content of insulin is associated in mouse blood sugar concentration and the body, by can qualitative detection to the variation of mouse blood sugar concentration going out the changes of contents of insulin in the body.The blank GMO/F127 vehicle group of the normal saline of the 1st group of injected in mice and the 2nd group of injected in mice, the blood sugar concentration of mice changes little, with these two groups as the blank group.The insulin solution of the 3rd group of injected in mice, the blood glucose of mice reduces rapidly, and after 8 hours, the blood glucose of mice tends towards stability.The 4th group of injected in mice be the lysotropic liquid crystal that supports insulin GMO/F127, mouse blood sugar concentration underspeeds not as the 3rd group, reaches stable in the blood sugar concentration of the 4th group of small mouse at the 4th hour, the blood sugar concentration of mice increases gradually after the 4th hour.After the 5th group of injected in mice supports the lysotropic liquid crystal of insulin GMO/F127, applied electric field at the 2nd hour and the 4th hour, the blood sugar concentration of mice between the 3rd group and the 4th group, is 54% of initial blood glucose value than the 4th group of reduce fast; At the 4th hour, blood sugar concentration was 34% of initial value near the 3rd group of blood glucose value.

The 1st group of mouse blood sugar concentration and the 2nd group of mouse blood sugar concentration change are not obvious, show that normal mouse has the function of stronger feedback regulation blood sugar concentration.The 3rd group of mouse blood sugar concentration sharply descends, and shows that the injection of insulin has comparatively significantly blood sugar decreasing effect.After the 4th group of injection supports the lysotropic liquid crystal of insulin GMO/F127, because a part of insulin does not discharge immediately, the blood sugar decreasing effect of mice is not as the 3rd group, the drug effect optimum time point of insulin for reducing blood sugar was at the 2nd hour, the blood sugar concentration of the 2nd hour mice is minimum, and surpasses after the 2nd hour, and the blood sugar concentration of mice has the trend of rising, this drug effect that shows insulin reduces gradually, thereby because the feedback regulation effect of mice so that blood sugar concentration recover gradually.Underspeeding with blood glucose value obviously not as the 3rd group of the 4th group of mouse blood sugar concentration, the release of insulin is a lasting process, compare the 3rd group, insulin drug effect optimum time point is at the 4th hour, the lysotropic liquid crystal of this explanation GMO/F127 to the slow release of insulin so that the drug effect optimum time point postpone.From accompanying drawing 3 as seen, the 4th group of insulin release is more steady, the 3rd group of blood sugar concentration do not occur and is beginning rapid decline phenomenon in 2 hours, and this mild release more is conducive to the curative effect of medicine.Added the electric field pulse effect in the 5th group, located at the 2nd hour, insulin is fierce during not as the 3rd group the 2nd hour on the impact of blood glucose, but than the 4th group of impact greatly, this has illustrated under the effect of electric field, and the part insulin can discharge from the lysotropic liquid crystal of GMO/F127.Located at the 4th hour, insulin is larger than the 4th group of impact on the impact of blood glucose, has illustrated that under the electrical field stimulation, insulin further discharges from LCD vector, and LCD vector is made response to the stimulation of electric field.

By the experiment of impulse electric field controllable release on the mouse blood sugar impact, can find, the lysotropic liquid crystal of GMO/F127 has the effect of control medicament slow release and have the characteristic of accelerated release in vitro medicine under extra electric field stimulates.The high-sequential structure that the lysotropic liquid crystal of this and GMO/F127 has has relation, and liquid crystal molecule produces elastic deformation under the effect of electric field, thereby has affected the rate of release of medicine.By the intensity of regulation and control applying pulse electric field, thus the controllable release of realization medicine.

Comparative Examples one

All the other are all identical for the present embodiment and embodiment 1, and difference is: the impulse electric field signal adopts and applies electric current density is 3mA/cm ², elastically-deformable threshold value occurs less than the GMO/F127 lysotropic liquid crystal that makes that calculates, can not reach the purpose of impulse electric field control drug release.

Comparative Examples two

All the other are all identical with implementing 1 for the present embodiment, and difference is: the impulse electric field signal adopts and applies electric current density is 10mA/cm ², greater than the GMO/F127 lysotropic liquid crystal that makes that calculates elastically-deformable threshold value occurs, simultaneously again in the limit range of the elastic deformation ability that the GMO/F127 lysotropic liquid crystal can bear. and can reach equally the purpose of impulse electric field control drug release.

Prove through many experiments, after the impulse electric field signal reached the threshold value of electric current density of Theoretical Calculation, adopting and applying electric current density was 4mA/cm ²～10mA/cm ², all can reach preferably purpose of the present invention.

Method of the present invention and traditional extracting method result contrast:

The pulse controllable release of utilizing method design of the present invention and finishing in the Mice Body is tested, by the variation of detection mouse blood sugar concentration, thus the dosage of judgement insulin release.Research finds that the GMO/F127 lysotropic liquid crystal that has supported insulin has medicament slow release characteristic equally, compares the matched group of insulin in Mice Body, and mouse blood sugar concentration reduces slowly and steadily.Under impulse electric field, insulin will discharge from the GMO/F127 lysotropic liquid crystal, and the blood sugar concentration of mice reduces rapidly.This release is because the bendability of liquid crystal molecule causes the carrier swelling ratio to change and causes, the variation of swelling ratio will cause the pressure to internal structure, this pressure will with the osmotic pressure combined effect, formed the driving force of drug release.

Experimental result shows that the GMO/F127 lysotropic liquid crystal can be used as a kind of good sustained-release and controlled release pharmaceutical carrier, has preferably response under the effect of electric field.The controlled lysotropic liquid crystal medicine carrying of impulse electric field effect discharges obvious sustained-release and controlled release effect is arranged, and this situation for some subcutaneous certain medicine of urgent need provides a kind of medicine carrying mode.

Claims (1)

1. a release method that supports drug molecule with electric microfield control lysotropic liquid crystal is characterized in that, comprises the following steps:

Step 1, adopt heat treating process and emulsion process to prepare GMO/F127 lysotropic liquid crystal microgranule, mass ratio by F127 and GMO is that 10:80-120 takes by weighing raw material, with 5-10 minute mixing of oscillator physics concussion, oscillator power is 2000-2500W, the concussion frequency is 80-100Hz, put into steady temperature and be 50 ℃-60 ℃ water-bath, the employing magnetic stir bar obtained the loose homogenizing of rough segmentation in 8-12 hour with 40-60 rev/min speed stirring, leave standstill hatching 7-10 days, with biomixer ultrasonic 3-5 time of ultrasonic probe intermittently, each 15-20 minute, intermittently 5-10 minute, ultrasonic power was 800-1000W, supersonic frequency is 20-25KHz, then in centrifuge with per minute 10,000 rotary speeds centrifugal 5-8 minute, leave standstill and can make the nanometer liquid crystal particle in 20-30 hour, keep in Dark Place under the 20-30 ℃ of condition;

Step 2, preparation GMO/F127 lysotropic liquid crystal medicine-carried system, under 20 ℃-30 ℃ of steady temperatures, with the nanometer liquid crystal particle for preparing in the step 1 with rotating speed 20-50rmp low speed rotation, and with 5-12 drip/minute speed, ratio in 1.5-2.0mg/ml dropwise adds the medicine that will support, evenly mixed 3-5 hour, make GMO/F127 lysotropic liquid crystal medicine-carried system, be statically placed in 20-30 ℃ and keep in Dark Place;

Step 3, draw the standard solution working curve of medicine to be supported, detect the encapsulation ratio that the GMO/F127 lysotropic liquid crystal supports medicine, configure at first as required the pharmaceutical standards solution of variable concentrations gradient, utilize characteristic absorption peak and the absorbance of the medicine of measurement of ultraviolet-visible spectrophotometer variable concentrations, thereby draw out the standard curve of medicine to be supported, with the absorbance of medicine free in the solution behind the measurement of ultraviolet-visible spectrophotometer GMO/F127 lysotropic liquid crystal packaging medicine, reflect the concentration of medicine with the variation of absorbance;

By the encapsulation ratio computing formula:

In the formula

W _Always---total content of carrier Chinese medicine

W _Trip---the content of the outer free drug of carrier

Calculate the encapsulation ratio of GMO/F127 lysotropic liquid crystal supported carrier medicine;

The counting system of elastically-deformable threshold value occurs in step 4, structure lysotropic liquid crystal under field effect:

The thickness of supposing lysotropic liquid crystal is d, zero is taken at the central authorities of film, get simultaneously the z axle and vow that with sensing n is parallel, be the upper of film, lower interface is in Z=± d/2 position, applying electric field E perpendicular to pointing to the direction X direction of principal axis of vowing n, then electric field will make the arrangement of pointing to arrow n change, from large regional integration, not parallel to each other between the molecule, so, the Emission in Cubic structural equivalents of liquid crystal is in a lot of crooked liquid crystal cells arranged vertically, liquid crystal is subjected under the external electrical field effect deformation to occur, and causing the required energy of deformation is the curvature elastic energy, when the sensing of GMO/F127 lysotropic liquid crystal vows that deformation has occured n, according to liquid crystal continuous elastomeric theory and law of conservation of energy, the Gibbs free energy of liquid crystal system under electric field action:

G=G _el-G _e （1-2）

Then have:

δG=δG _el-δG _e （1-3）

In the formula:

G _El---the elastic energy of deformation of GMO/F127 lysotropic liquid crystal;

G _e---the electric field free energy of GMO/F127 lysotropic liquid crystal;

$G_{\mathrm{el}}=\&Integral;g_{\mathrm{el}}\mathrm{d\&tau;}=\frac{1}{2}\&Integral;[k_{11}{(\&dtri;\&CenterDot;n)}^2+k_{22}{(n\&CenterDot;\&dtri;\&times;n)}^2+k_{33}{(n\&times;\&dtri;\&times;n)}^2]\mathrm{d\&tau;}---(1-4)$

In the formula:

k ₁₁---open up bent elastic constant;

k ₂₂---the distortion elastic constant;

k ₃₃---bend elastic constant,

$G_e=\&Integral;g_e\mathrm{d\&tau;}=\frac{1}{8\mathrm{\&pi;}}\&Integral;E\&CenterDot;\mathrm{Dd\&tau;}---(1-5)$

Wherein electric field strength E is constant, so

When lysotropic liquid crystal reaches poised state, be a kind of steady statue, according to minimum energy principle in the classical physics, G=G _El-G _eHave minima, to the G minimizing:

$G=\&Integral;\frac{1}{2}[k_{11}{(\&dtri;\&CenterDot;n)}^2+k_{22}{(n\&CenterDot;\&dtri;\&times;n)}^2+k_{33}{(n\&times;\&dtri;\&times;n)}^2+k_{33}{(n\&times;\&dtri;\&times;n)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{(n\&CenterDot;E)}^2]\mathrm{d\&tau;}---(1-6)$

In the formula:

k ₁₁---the Splay elastic constant of liquid crystal;

k ₂₂---the distortion coefficient of elasticity of liquid crystal;

k ₃₃---the elasticity of flexure coefficient of liquid crystal,

Under electric field action, be that the sensing at z place vows will be into θ angle with Z axis apart from initial point, and θ be the function of z is θ=θ (z), n then ₁=sin θ (z), n ₂=0, n ₃=cos θ (z), therefore, the free energy density of GMO/F127 lysotropic liquid crystal is:

$g=\frac{1}{2}\underset{\frac{d}{2}}{\overset{\frac{d}{2}}{\&Integral;}}[(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\cos }^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2{\sin }^2\mathrm{\&theta;}]\mathrm{dz}---(1-7)$

(1-7) in the formula, only there is k ₁₁And k ₃₃, do not have k ₂₂, show that the GMO/F127 lysotropic liquid crystal is merely able to produce exhibition song and Bending Deformation under electric field action, can not produce twist distortion; Free energy density should have minima under the equilibrium state, then can derive following formula:

$\frac{d[(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\cos }^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2-\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2{\sin }^2\mathrm{\&theta;}]}{\mathrm{dz}}=0---(1-8)$

In (1-8), because integrand is and x ₃, θ,

Relevant function, therefore the Euler-Lagrange equation of free energy density g is:

$\frac{(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\cos }^2\mathrm{\&theta;})d^2\mathrm{\&theta;}}{d{z}^2}+(k_{11}-k_{33})\sin \mathrm{\&theta;}\cos \mathrm{\&theta;}{\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{{\mathrm{\&epsiv;}}_a{E}^2\sin \mathrm{\&theta;}\cos \mathrm{\&theta;}}{4\mathrm{\&pi;}}=0---(1-9)$

(1-9) formula both sides are multiplied by respectively , then have:

$\frac{d(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\cos }^2\mathrm{\&theta;})}{\mathrm{dz}}{\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{{\mathrm{\&epsiv;}}_a{E}^{2}d\left({\sin }^2\mathrm{\&theta;}\right)}{4\mathrm{\&pi;dz}}=0---(1-10)$

(1-10) formula both sides z is carried out integration from 0 to d/2, notice that there is θ=0 in the z=d/2 place, at the largest deformation angle of z=0 place lysotropic liquid crystal θ _MHave

, can get:

$(k_{11}{\sin }^2\mathrm{\&theta;}+k_{33}{\cos }^2\mathrm{\&theta;}){\left(\frac{\mathrm{d\&theta;}}{\mathrm{dz}}\right)}^2+\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2{\sin }^2\mathrm{\&theta;}=\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2{\sin }^2{\mathrm{\&theta;}}_M---(1-11)$

Work as z〉0, θ increases progressively θ with z and reduces gradually, can get:

$-\frac{\mathrm{d\&theta;}}{\mathrm{dz}}={\left[\frac{\frac{1}{4\mathrm{\&pi;}}{\mathrm{\&epsiv;}}_a{E}^2({\sin }^2{\mathrm{\&theta;}}_M-{\sin }^2\mathrm{\&theta;})}{k_{33}+(k_{11}-k_{33}){\sin }^2\mathrm{\&theta;}}\right]}^{\frac{1}{2}},---(1-12)$

If k=sin is θ _M, ,

, sin θ=ksin λ can get:

$[\frac{1+\frac{\mathrm{\&eta;}}{2}}{\sqrt{1-k^2{\sin }^2\mathrm{\&lambda;}}}-\frac{\mathrm{\&eta;}}{2}\sqrt{1-k^2{\sin }^2\mathrm{\&lambda;}}]\mathrm{d\&lambda;}=-\frac{\mathrm{dz}}{\mathrm{\&xi;}}---(1-13)$

Note boundary condition z=0 place, θ=θ _M, λ=pi/2; At the z=d/2 place, θ=0, λ=0; With (1-13) formula both sides x ₃Be integrated to d/2 from 0 respectively, can get:

$(1+\frac{\mathrm{\&eta;}}{2})F\left(k\right)-\frac{\mathrm{\&eta;}}{2}E\left(k\right)=\frac{d}{2\mathrm{\&xi;}}---(1-14)$

In the formula:

F (k)---complete elliptic integral of the first kind;

E (k)---complete elliptic integral of the second kind,

Work as θ _M=0, k=0 then, and F (0)=E (0)=pi/2 can get π=d/ ξ by (1-14) formula, substitution

, can obtain intensity threshold:

$E_c=\frac{2\mathrm{\&pi;}}{d}\sqrt{\frac{{\mathrm{\&pi;k}}_{33}}{{\mathrm{\&epsiv;}}_a}}---(1-15)$

Can try to achieve threshold current density by threshold field strength is:

jc=σE （1-16）

In the formula:

σ---liquid crystal molecule electrical conductivity,

Step 5, GMO/F127 lysotropic liquid crystal medicine-carried system realize that under impulse electric field control control discharges,

The GMO/F127 lysotropic liquid crystal system that supports medicine is placed impulse electric field, and the intensity of regulating impulse electric field is when electric field strength surpasses threshold value E _cOr the electric current density that flows through liquid crystal molecule is greater than threshold value jc, to cause GMO/F127 lysotropic liquid crystal Emission in Cubic membrane structure generation deformation, cause structure and the character of pharmaceutical carrier to change, with drug release out, will cause that like this concentration difference and the driving force of medicine in carrier changes; When electric field strength is lower than threshold value E _cOr the electric current density that flows through liquid crystal molecule is less than threshold value jc, and the GMO/F127 lysotropic liquid crystal system that supports medicine will stop to discharge medicine, thereby realizes pulse control drug release; Control simultaneously the elastic deformation ability that electric field strength can not be higher than the GMO/F127 lysotropic liquid crystal, otherwise excessive electric field intensity has surpassed the elastic deformation ability of GMO/F127 lysotropic liquid crystal, can destroy its structure, the effect of impact control drug release.

Images