CN102068409A - Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology - Google Patents
Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology Download PDFInfo
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Abstract
The invention discloses a method for preparing mono-disperse microemulsion, liposome and microspheres based on a microfluidic technology. The method comprises the following steps: taking aqueous solution (or oily solution) of a hydrophilic medicine (or a lipid-soluble medicine) as a disperse phase; taking an oil phase (or an aqueous phase) as a continuous phase; and respectively conveying the disperse phase and the continuous phase into corresponding micro-channels of a microfluidic chip device, shearing the phases into mono-disperse liquid drops of the encapsulated medicine, then curing the liquid drops by a certain curing method, and finally obtaining the medicine-carrying liposome, microspheres or the biodegradable microspheres with uniform size and dispersion stability. Under an optimum condition, the diameter distribution coefficients of the microemulsion and the microspheres can be less than 5%, and the diameter is 10-500microns. By utilizing the method, the problems such as uneven size, low embedding rate, poor dispersibility, poor targeting property, low bioavailability, low bioactivity of enzyme and cells, immune suppression and the like of the medicine-carrying microemulsion, the liposome and the microspheres prepared by the traditional ultrasonic method, agitation emulsification method and film hydration-dispersion method are solved.
Description
Technical field
The invention belongs to the pharmaceutical engineering field of pharmaceutical preparations, be specifically related to a kind of preparation method of monodispersity microemulsion, liposome and the microsphere based on microflow control technique.
Background technology
Microflow control technique is an important science and technology, and its principal character is exactly integrated and microminiaturized, will play a role in fields such as medical diagnosis on disease, drug screening, environment measuring, food safety, judicial expertise, sports and anti-terrorism, space flight.Micro-fluidic chip mainly is with microchannel network and the integrated characteristics that turn to of various functional unit, and micro-example is controlled on micro-scale and handled, and realizes preparation, reaction, separation and the detection of micro-example.And drop is a kind of brand-new technology of controlling small volume of liquid that grows up on micro-fluidic chip in recent years.As a kind of brand-new technology, the modal application of drop is as microreactor, reaction and process on the research micro-dimension.In these were used, controlled microemulsion, liposome and the biological degradability microsphere of preparation single-size having important use aspect the conveying of medicine.The method for preparing at present microemulsion, liposome and biological degradability microsphere mainly is to adopt the mode of " top-down ", it is traditional ultrasonic, mechanical agitation etc., adopt these methods in preparation emulsion process, because particle diameter heterogeneity, little emulsion can be absorbed by big emulsion, and big emulsion can be destroyed because of the effect of shearing force again simultaneously; In emulsion polymerization process, can form many polymerization condensation products, simultaneously, in the merging and rupture process of emulsion, objects such as interior bag medicine, enzyme and cell escape into the emulsion surface easily, cause the object embedding rate low.Therefore microemulsion, liposome and the biological degradability microsphere of traditional method acquisition exist particle size distribution wide, and form is difficult to control, and the result error that repeats to prepare is bigger, bring many difficulties for the practical application of microemulsion, liposome and biological degradability microsphere.For example, hydrophilic medicament is when adopting film water commonly used to divide arching pushing to prepare liposome, and envelop rate is low, and drug loading is difficult to satisfy the treatment needs.As pharmaceutical carrier, the size of particle diameter determine its in vivo distribution and influence it and the effect of organism organ and cell, the small particle diameter carrier can be reduced to minimum level with the potential stimulus of injection site; If use single dispersible carrier, the release dynamic trait of medicine can be effectively controlled, thereby can more easily construct complicated drug delivery system.In addition as the immobilization and the Separation of Proteins medium of enzyme, because the particle diameter heterogeneity, little microsphere can gather in the gap between the big microsphere, makes separating pressure increase, and can cause when serious separating and can't carry out; As cell culture vector, the particle diameter heterogeneity can cause the inhomogeneous of nutrient and cell density, thereby causes the inhomogeneous of cell growth; As slow releasing carrier of medication, because the emulsion instability can cause the embedding rate of medicine to reduce greatly, in addition because the particle diameter heterogeneity, in being administered systemically, make the targeting of medicine poor, cause medicine bioavailability in vivo to reduce greatly, in addition the preparation batch between difference, cause and can't accurately investigate drug release pattern, its application is restricted greatly.Therefore study novel preparation method, prepare monodispersity microemulsion, liposome and biological degradability microsphere, so as to overcome the not enough of traditional preparation process method and the application that brings thus on restriction.
Not have diffusion, stable reaction conditions, monodispersity good because the drop that microflow control technique produces has sample, no cross-contamination and mix characteristics such as rapid, therefore based on microemulsion, liposome and the biological degradability microsphere of the microflow control technique preparation of " bottom up " thought have controllable shapes, size evenly, advantage such as suitable material multiformity.By medicine, enzyme and cell etc. are introduced drop, produce monodispersity microemulsion, liposome and biological degradability microsphere, raising traditional preparation process method size can't be unified, problems such as the object encapsulation ratio is low, poor repeatability, in the hope of make up a kind of can control drug release, improve drug bioavailability, keep enzyme and cell bio-activity, improve the targeting of pharmaceutical carrier, reduce system toxicity and the immunosuppressant in the cell transplantation process and the homologous anaphylaxis etc. of medicine.
Summary of the invention
The present invention is directed to all kinds of hydrophilic medicaments and fat-soluble medicine, microemulsion such as O/W, the W/O of preparation size homogeneous such as enzyme and cell, stably dispersing and W/O/W, liposome and biological degradability microsphere are with conveying, control and the release that is used for medicine; Immobilized and the active maintenance of enzyme; The cultivation of cell, functional expression and targeting transplanting etc.
For achieving the above object, the present invention by the following technical solutions:
A kind of micro flow control chip device for preparing monodispersity microemulsion, liposome and biological degradability microsphere comprises that micro pump, the micro-fluidic chip that produces the different size drop, drop receive and storage capsule; (1) according to the character of preparation microemulsion, chip microchannel is carried out corresponding hydrophobicity or hydrophilic modification; As when preparing the W/O microemulsion, can adopt the inwall of making by PDMS or glass to have hydrophobic microchannel; When preparation O/W microemulsion, need to adopt polymer (as polyvinyl alcohol etc.), to make its inwall show as hydrophilic nmature to carrying out finishing in the PDMS microchannel; Particularly,, adopt the mixed solution of mass concentration 5% glycerol-2% polyvinyl alcohol that the PDMS microchannel is modified, can make the PDMS surface after the modification have Superhydrophilic by absorption self assembly-thermal curing method.(2) hydrophilic medicament (or fat-soluble medicine) being soluble in the aqueous phase (or oil phase), is decentralized photo with water (or oil phase) then, and oil phase (or water) is a continuous phase, cuts into the single or multiple lift microemulsion of monodispersity packaging medicine; (3) be prepared into corresponding solution according to pharmaceutical properties, feed from middle microchannel, the solution of liposome or biocompatible polymer is fed the microchannel, both sides, use the continuous phase opposite with the drop of above-mentioned solution shear then as the monodispersity packaging medicine with above-mentioned SOLUTION PROPERTIES, adopt certain curing that drop is solidified again, obtain the drug-loaded liposome microsphere or the biodegradable microsphere of size homogeneous, stably dispersing.Under optimal conditions, microemulsion and diameter of micro ball breadth coefficient (CV value, define formula as follows) be controlled in 5%, determine (the present invention is an example with 200 microns) under the situation in the microchannel size, can free adjustment realize that microemulsion, liposome or diameter of micro ball are at the 10-500 micron by the flow velocity of regulating decentralized photo concentration, decentralized photo and continuous phase; Medicine embedding rate height, stable storing when being used for pharmaceutical carrier, embedding rate is near 100% under optimal conditions.When being used to wrap up enzyme and cell, the encapsulation ratio height, loss of activity is little.
Above-mentioned diameter Distribution coefficient (Coefficient of Variation, CV)={ [∑ (d
i-d)
2/ N]
1/2/ d} * 100%
In the formula, d
iBe the diameter of each microemulsion, liposome and polymer microballoon, d by the average diameter of research microemulsion, liposome and polymer microballoon, N is microemulsion, liposome and the polymer microballoon number that is used to study diameter, N=100.
The method for preparing monodispersity medicine carrying microemulsion provided by the present invention comprises the steps: with the aqueous solution (oil solution) that contains water solublity (fat-soluble) medicine as decentralized photo; With the oil solution (aqueous solution) that contains w/o type (O/W type) emulsifying agent as continuous phase; Described decentralized photo and continuous phase are transported to the respective microchannels of micro flow control chip device respectively, prepare W/O (O/W) microemulsion, microemulsion is collected in the container that continuous phase or cross-linking agent solution are housed, obtain the medicine carrying microemulsion by described micro flow control chip device.
The method for preparing the monodispersity drug-loaded liposome provided by the present invention comprises the steps: with the aqueous solution (oil solution) that contains water solublity (fat-soluble) medicine and blank liposome (promptly not pastille liposome) as decentralized photo; With the oil solution (aqueous solution) that contains w/o type (O/W type) emulsifying agent as continuous phase; Described decentralized photo and continuous phase are transported to the respective microchannels of micro flow control chip device respectively, prepare W/O (O/W) microemulsion by described micro flow control chip device, the microemulsion lyophilization with producing obtains drug-loaded liposome.
The method for preparing the monodispersity medicine carrying microballoons provided by the present invention comprises the steps: with the aqueous solution (oil solution) that contains water soluble drug (fat-soluble) and biodegradable polymer as decentralized photo; With the oil solution (aqueous solution) that contains w/o type (O/W type) emulsifying agent as continuous phase 5; Described decentralized photo and continuous phase are transported to the respective microchannels of micro flow control chip device respectively, prepare W/O (O/W) microemulsion by described micro flow control chip device, microemulsion is collected in the container that continuous phase or cross-linking agent solution are housed, adopt different curing mode (as: lyophilization, add the heat abstraction solvent, add cross-linking agent polymerization etc.) to be cured according to described biodegradable polymerization character, obtain medicine carrying microballoons.
The method of microemulsion, liposome and the microsphere of preparation monodispersity parcel enzyme provided by the present invention and cell, identical with said method, just when selecting decentralized photo and continuous phase, should note using biocompatible substances, reduce enzyme and cell activity influence.
In the microemulsion of the present invention's preparation, the concentration of institute's packaging medicine (enzyme or cell) can be regulated by the flow of decentralized photo and continuous phase in the adjusting fluid channel.
When preparation drug-loaded liposome or medicine carrying microballoons, the size of liposome or microsphere, can regulate by the concentration of liposome in the decentralized photo or biodegradable polymer (when other condition fixedly the time, liposome or polymer concentration are big more, then liposome of Chan Shenging or microsphere size are big more), regulate by the flow of decentralized photo and continuous phase perhaps that (when decentralized photo flow fixedly the time, continuous phase flow more little (big more) produces microsphere size big more (more little); The continuous phase flow is fixedly the time, and decentralized photo flow big more (more little) produces microsphere size big more (more little)).
In the method for microemulsion, liposome or the microsphere of above-mentioned preparation medicine carrying or parcel enzyme and cell, the mass concentration of surfactant can be 0.5%-10% in the continuous phase, and preferable range is 0.5%-4%.In the method for the microemulsion, liposome or the microsphere that prepare parcel enzyme and cell, should select the surfactant of good biocompatibility.
Among the present invention, described water soluble drug comprises water-soluble anticancer medicine, nucleic acid, RNA, interferon, various albumen, enzyme and polypeptide drugs etc., can be soluble in the aqueous phase together or separately as required; Fat-soluble medicine comprises fat-soluble anticarcinogen, hormone and other various fat-soluble medicines etc.Employed emulsifying agent generally uses non-ionic surface active agent.
Monodispersity microemulsion, liposome or the microsphere drug carrier of the present invention's preparation, and the liposome or the microsphere of parcel enzyme and cell have the following advantages: (1) method provided by the invention can be used for preparing all kinds microemulsion, liposome and polymer microballoon, can be used for multiple hydrophilic of embedding and fat-soluble medicine, for example embedding paclitaxel, pirarubicin, 5-fluorouracil etc.; Also can be used for the cultivation, transplanting of enzyme immobilization and cell etc., be used for treatment of diabetes as immobilized insulinase, the cell of parcel reorganization urase gene is used to study the decomposition to harmful substance in the body, for certain basis is established in uremic treatment; The size of regulation and control microemulsion, liposome and microsphere can be used for subcutaneous injection, intravenous injection, oral, arterial thrombosis etc.
(2) microemulsion provided by the invention, liposome or microsphere are as pharmaceutical carrier, because size homogeneous and controlled, good reproducibility between batch, therefore the relation between research drug release kinetics and different pharmaceutical and therapeutic effect thereof seems more accurate and simple.As pharmaceutical carrier, there is certain relation its size and its distributing position and time in vivo, and the different medicine curative effect of diverse location generation in vivo also is not quite similar; Therefore the microemulsion, liposome or the microsphere that different pharmaceutical are prepared a series of monodispersity packaging medicines, and medication respectively, thus can find out the medication effect of different pharmaceutical at different size, thus find out the required optimum size scope of different pharmaceutical.If, then can't carry out correlational study effectively as microemulsion, liposome or the microsphere size heterogeneity of pharmaceutical carrier.
(3) preparation method provided by the invention, mild condition is expected to keep the high activity of biologically active drugs such as polypeptide, albumen.
(4) microemulsion provided by the invention, liposome or microsphere size homogeneous are expected to realize medicine sustained release stable, favorable reproducibility.
(5) liposome provided by the invention or microsphere can be used for immobilized and cell culture, the transplanting use of enzyme, and mild condition is expected to keep enzyme and cell activity, realizes the functional of the two.
Method of the present invention has solved stirring and emulsifying, conventional art such as ultrasonic and has prepared inhomogeneous such as particle size distribution in medicine carrying microemulsion, liposome and the polymer microballoon, and form is difficult to control, and the medicine embedding rate is low, has than defectives such as big-differences between batch.And the release behavior of the method affect medicine of traditional preparation process microsphere and its targeting of reduction can't be investigated the relation between particle diameter and various disease and the therapeutic effect clinically, and its application is restricted greatly.Can utilize the homogeneous characteristic of microemulsion, liposome and the microspherulite diameter of micro-fluidic preparation, reach stable controlled release medicine, accurately investigate drug release behavior, releasing mechanism and kinetic model, for certain basis is established in clinical practice.Simultaneously, be expected to solve the blood drug level big problem that rises and falls, reduce medicine toxic and side effects, prolong drug action time, improve medicine utilization rate and therapeutic effect in vivo.This preparation method technology is simple, the operating condition gentleness, and good reproducibility amplifies easily.
Description of drawings
Fig. 1 prepares the micro-fluidic chip sketch map of monodispersity microemulsion, liposome or microsphere for the present invention; Wherein, Figure 1A is the simplest a kind of micro-fluidic chip sketch map, introduces decentralized photo by import 1, and continuous phases are introduced in import 2 and 3, and microemulsion or liposome, polymer drop are drawn in outlet 4; Figure 1B is a kind of micro-fluidic chip sketch map for preparing monodispersity multifunction microemulsion, liposome or microsphere, continuous phase is introduced in import 1, import 2-4 can introduce multicomponent pharmaceutical, magnetic nano-particle, liposome and multicomponent polymeric etc. respectively, thereby realize multifunction microemulsion, liposome or microspheres such as medicine, polymer multicomponent and magnetic, drop is drawn in outlet 5.
Fig. 2 is the micro-fluidic preparation sketch map of embodiment 1 polylactic acid microsphere; Wherein, the chloroformic solution that is dissolved with polylactic acid is introduced in import 1, and import 2-3 introduces the aqueous solution of 2% polyvinyl alcohol (PVA), produces the monodispersity drop.
Fig. 3 is the light micrograph that drop produces among the embodiment 1; Wherein, Fig. 3 (b) is the light micrograph that drop produces the zone; Fig. 3 (c) is the light micrograph (Q of drop at the microchannel afterbody
1=0.20mL/h, Q
2=Q
30.15mL/h; Q
1Expression decentralized photo flow velocity; Q
2=Q
3Expression continuous phase flow velocity, down together).
Fig. 4 is the contact angle photo (contact angle is to adopt the PDMS thin slice of modifying with the same method of modifying of microfluidic channel to be surveyed numerical value among the figure) that adopts after absorption self assembly-thermal curing method is modified PDMS, and wherein, Fig. 4 (a) is the contact angle (120 °, hydrophobic) of PDMS; Fig. 4 (b) is the contact angle (52 °, hydrophilic) of the PDMS of PVA modification; Fig. 4 (c) is the contact angle (5 °, super hydrophilic) of the PDMS of PVA/ glycerol (Gly) modification.
Fig. 5 is a light micrograph; Wherein, figure (a-c) is the array of polylactic acid drop on the microscope slide; Figure (d) is polylactic acid drop solidification process in container, and color is deeply felt bright and solidified, and color is more shallow is indicated as drop or semi-solid preparation (achromatic map); Figure (e-f) is for solidifying polylactic acid microsphere.Flow conditions: (a) Q
1=0.15mL/h; Q
2=Q
3=0.35mL/h; (b) Q
1=0.20mL/h; Q
2=Q
3=0.15mL/h; (c) Q
1=0.25mL/h; Q
2=Q
3=0.45mL/h; (d)-(f) Q
1=0.10mL/h, Q
2=Q
3Scale is 100 microns among the=0.15mL/h. figure.
Fig. 6 is the light micrograph (a-b) and the size distribution plot (c) of medicine carrying polylactic acid microsphere of the different-grain diameter of embodiment 2 preparation.Flow conditions: (a) Q
1=0.15mL/h, Q
2=Q
3=0.35mL/h; (b) Q
1=0.20mL/h, Q
2=Q
3=0.15mL/h, scale are 50 microns, and the scale of interpolation picture is 25 microns.
Fig. 7 is the paclitaxel-polylactic acid microsphere vitro drug release figure of the different drug loading of different size of embodiment 2 preparations, wherein, a) is paclitaxel cumulative release figure, b) is the logarithmic chart of burst size and release time; S a-b explanation: S represents sample, a representative diameter (31 microns of 1 expressions, 2-represents 50 microns), b representation theory drug loading (1 milligram of 1 expression, 2 milligrams of 2 expressions).
Fig. 8 is the polylactic acid drop light micrograph of the parcel pirarubicin of embodiment 3 preparations.
Fig. 9 is the polylactic acid microsphere light micrograph of the parcel pirarubicin of embodiment 4 preparations.
Figure 10 is the pirarubicin-polylactic acid microsphere vitro drug release figure of the different drug loading of different size of embodiment 4 preparations.
Figure 11 is the drop and the microsphere optical microphotograph of the polylactic acid-hydroxide acetic acid of embodiment 5 preparations.
Figure 12 is the chitosan microball light micrograph of the different amplification of embodiment 6 preparations.
Figure 13 is the calcium alginate microsphere light micrograph of the different amplification of embodiment 7 preparations.
Figure 14 is the micro fluidic device sketch map that is used to produce in batches.
The specific embodiment
Below by specific embodiment method of the present invention is described, but the present invention is not limited thereto.
Experimental technique described in the following embodiment if no special instructions, is conventional method; Described reagent and biomaterial if no special instructions, all can obtain from commercial channels.
The present invention includes the microfluidic control Preparation Method of microemulsion, liposome or the microsphere of monodispersity packaging medicine, enzyme or cell.This method can prepare various microemulsion, liposome and microspheres such as O/W, W/O, the O/W/O of occluded water dissolubility, fat-soluble medicine; Also can prepare the liposome or the microsphere that wrap up functional enzyme; The microsphere of preparation parcel cell is similar with the method for preparing the hydrophilic medicament microsphere.
The microsphere preparation of fat-soluble medicine is by step preparation shown in Figure 2, and concrete grammar and step are described as follows:
(1) modification of micro-fluidic chip passage: PDMS chip Cement Composite Treated by Plasma after 90 seconds, is led to the mixed solution of full mass concentration 5% glycerol-2% polyvinyl alcohol, and room temperature was placed 20 minutes; Subsequently redundant solution is used the vacuum pump sucking-off, placed 2 hours with heat-curable coating at 60 ℃, above-mentioned steps obtains solidifying 20 minutes at 110 ℃ behind the passage of multiple modification repeatedly, and it is standby to naturally cool to room temperature.
(2) preparation of decentralized photo and continuous phase: fat-soluble medicine paclitaxel and polylactic acid are dissolved in chloroform (oil phase), as decentralized photo; With polyvinyl alcohol or other water soluble emulsifier (water) soluble in water, as continuous phase; In micro flow control chip device shown in Figure 1 (passage is through hydrophilic modification), decentralized photo is fed passage 1 through pump, continuous phase feeds passage 2 and 3, through the fluid focus zone, obtains monodispersity O/W microemulsion (or drop); When wanting the occluded water soluble drug, can be with water soluble drug solution as decentralized photo 1, the chloroformic solution of polylactic acid is sheared 1 one-tenth W/O microemulsion of decentralized photo as decentralized photo 2 with decentralized photo 2, the continuous phase that will be dissolved with hydrophilic emulsifier is again sheared decentralized photo 2 once more, forms the W/O/W microemulsion.
(3) preparation of polylactic acid microsphere
Above-mentioned steps (2) gained microemulsion is positioned in the room-temperature water bath, stirs gently, remove chloroform; The bag medicine microsphere that is cured is filtered washing, room temperature vacuum drying or lyophilizing.
Micro flow control chip device is assembled as shown in Figure 1.The chloroformic solution of the polylactic acid (molecular weight 10000) of preparation 30mg/mL; The preparation mass concentration is that (model: average degree of polymerization 1750 ± 50) solution is as continuous phase for 2% PVA.Decentralized photo and continuous phase are transported to the micro-fluidic chip (see figure 2) by micro pump, in chip,, make decentralized photo form monodispersed drop (see figure 3) by the shear action of continuous phase; The hydrophilic that chip channel is modified characterizes sees Fig. 4.
The drop of collecting is placed room-temperature water bath, remove organic solvent, become ball material to separate out, be solidified into microsphere; The medicine carrying microballoons that is cured is filtered washing, room temperature vacuum drying or lyophilizing.The size of drop and microsphere can be regulated by the flow of decentralized photo and mobile phase, and the size of microsphere can also be regulated by the concentration of polylactic acid.Get 100 drops or microsphere and carry out the measurement of size, average.Accompanying drawing 5 (a-c) is the array optical displaing micro picture of the polylactic acid drop of different in flow rate generation, and its CV value shows very homogeneous of particle diameter all less than 1.5%; Figure (d) is polylactic acid drop solidification process in container, and figure (e-f) is for solidifying polylactic acid microsphere.Flow conditions: (a) Q
1=0.15mL/h; Q
2=Q
3=0.35mL/h; (b) Q
1=0.20mL/h; Q
2=Q
3=0.15mL/h; (c) Q
1=0.25mL/h; Q
2=Q
3=0.45mL/h; (d)-(f) Q
1=0.10mL/h, Q
2=Q
3=0.15mL/h.
The polylactic acid microsphere of embodiment 2, preparation parcel paclitaxel
Micro flow control chip device is assembled as shown in Figure 1.The chloroformic solution of polylactic acid (molecular weight 10000) of preparation 30mg/mL, other takes by weighing a certain amount of paclitaxel and is dissolved in the above-mentioned solution, be prepared into respectively contain paclitaxel 1mg/mL and 2mg/mL solution as decentralized photo; The PVA solution of preparation mass concentration 2% is as continuous phase.Decentralized photo and continuous phase are transported to micro-fluidic chip by micro pump, form monodispersed drop; The drop of collecting is placed 40 ℃ of water-baths, remove organic solvent; The medicine carrying microballoons that is cured is filtered washing, room temperature vacuum drying or lyophilizing.
Accompanying drawing 6 (a-b) is the light micrograph of medicine carrying polylactic acid microsphere of the different-grain diameter of preparation, flow conditions: (a) Q
1=0.15mL/h, Q
2=Q
3=0.35mL/h; (b) Q
1=0.20mL/h, Q
2=Q
3=0.15mL/h; Fig. 6 (c) is a distribution of sizes.Get 100 microspheres and carry out the measurement of size, average, two kinds of microspherulite diameters are respectively about 31 and 50 microns, and the CV value shows very homogeneous of particle diameter all less than 4.0%.
Get dried microsphere 1mg and be dissolved in the 1mL chloroform, ultrasonic 2 minutes, adding 2mL acetonitrile/water (1: 1, v/v), vortex carries out after 2 minutes leaving standstill in 15 minutes, and the back that is separated feeds nitrogen and removes chloroform; Add subsequently acetonitrile/water (1: 1, v/v) make cumulative volume keep 2mL constant; 4000rpm is centrifugal 10 minutes after ultrasonic 5 minutes, the supernatant efficient liquid phase chromatographic analysis.Chromatographic condition: the C of 25 centimeter length
18Chromatographic column, and the mobile phase acetonitrile/water (1: 1, v/v), flow velocity 1mL/ minute, detect wavelength 227nm, sampling volume 20 microlitres.The embedding rate that records all is higher than 93%.
Fig. 7 is the vitro drug release figure of the microsphere of four kinds of different-grain diameter sizes and theoretical drug loading, as seen from the figure, paclitaxel release behavior from polylactic acid microsphere was divided into for two steps: at first be prominent faster releasing the stage of first three hour, be subsequently one gradually and the dispose procedure that continues.And, prominent release phenomenon and slightly increase along with the increase of microsphere size and theoretical drug loading.
The polylactic acid microemulsion of embodiment 3, preparation parcel pirarubicin
As embodiment 1, no curing schedule only changes decentralized photo into contain pirarubicin polylactic acid chloroformic solution, and the microemulsion light micrograph of collection is seen Fig. 8.
The polylactic acid microsphere of embodiment 4, preparation parcel pirarubicin
As embodiment 2, only change decentralized photo into contain pirarubicin 1mg/mL polylactic acid chloroformic solution, the polylactic acid microsphere light micrograph of the parcel pirarubicin of collection is seen Fig. 9.The release in vitro figure of different size pirarubicin-polylactic acid microsphere sees Figure 10.As seen from the figure, the small size microsphere all is slow release in whole dispose procedure, and does not have the significantly prominent phenomenon of releasing.The large scale microsphere shows certain prominent phenomenon of releasing, and the later stage shows as slow release equally.
As embodiment 1, only decentralized photo is changed into the chloroformic solution of PLGA (poly-(lactic-co-glycolic acid)), the light micrograph of drop and microsphere is seen Figure 11.
Embodiment 6, preparation hydrophilic medicament chitosan microball
The mass concentration that preparation contains 1mg/mL hydrophilic medicament 5-fluorouracil is that 2% chitosan aqueous acetic acid is as decentralized photo, the mineral oil (or soybean oil) that contains mass concentration 5%Span80 is as continuous phase, under certain flow velocity, produce the monodispersity drop, it is in the 10% sodium polyphosphate container of (containing a small amount of isopropyl alcohol) that the drop access is filled mass concentration, solidify after 2 hours, filter, secondary water washing is washed, and lyophilizing or low temperature dry.The mean diameter of microsphere is 44 microns, light micrograph as shown in figure 12, uniform particle diameter.
Embodiment 7, preparation calcium alginate microsphere
As embodiment 6, it is 2% sodium alginate aqueous solution that decentralized photo changes mass concentration into, and firming agent uses 10% calcium chloride solution, solidifies after 1 hour, filters gently, and washing is dried.The light micrograph of drop and microsphere is seen Figure 13.
Adopt the design of Figure 14 can produce various microspheres in batches.
Claims (5)
1. method for preparing monodispersity medicine carrying microemulsion, according to the difference of pharmaceutical properties, be divided into following a) and b) two kinds of methods;
Described a) method comprises the steps: with the aqueous solution that contains water soluble drug to be designated as decentralized photo 1 as decentralized photo; As continuous phase, be designated as continuous phase 1 with the oil solution that contains the w/o type emulsifying agent; Described decentralized photo 1 and continuous phase 1 are transported to the respective microchannels of micro-fluidic chip respectively by micro pump, prepare the W/O microemulsion by described micro-fluidic chip, the W/O microemulsion is collected in the container that continuous phase 1 or cross-linking agent solution are housed, obtains carrying the water-soluble pesticide microemulsion; Wherein, the microchannel inner wall surface of described micro flow control chip device has hydrophobicity;
Described b) method comprises the steps: with the oil solution that contains fat-soluble medicine as decentralized photo 2; With the aqueous solution that contains O/W type emulsifying agent as continuous phase 2; Described decentralized photo 2 and continuous phase 2 are transported to the respective microchannels of micro flow control chip device respectively, prepare the O/W microemulsion, the O/W microemulsion is collected in described continuous phase 2 solution, obtain carrying a fat-soluble medicine microemulsion by described micro flow control chip device; Wherein, the microchannel inner wall surface possess hydrophilic property of described micro flow control chip device.
2. a method for preparing the monodispersity drug-loaded liposome or carry the enzyme liposome according to the difference of pharmaceutical properties, is divided into following c) and d) two kinds of methods;
Described c) method comprises the steps: with the aqueous solution that contains blank liposome and water soluble drug as decentralized photo 3, or with the aqueous solution that contains blank liposome and enzyme as decentralized photo 3; With the oil solution that contains the w/o type emulsifying agent as continuous phase 3; Described decentralized photo 3 and continuous phase 3 are transported to the respective microchannels of micro flow control chip device respectively, prepare the W/O microemulsion,, obtain drug-loaded liposome or carry the enzyme liposome the W/O microemulsion lyophilization that produces by described micro flow control chip device; Wherein, the microchannel inner wall surface of described micro flow control chip device has hydrophobicity;
Described d) method comprises the steps: with the oil solution that contains fat-soluble medicine and blank liposome as decentralized photo 4; With the aqueous solution that contains O/W type emulsifying agent as continuous phase 4; Described decentralized photo 4 and continuous phase 4 are transported to the respective microchannels of micro flow control chip device respectively, prepare the O/W microemulsion by described micro flow control chip device, the W/O microemulsion lyophilization with producing obtains drug-loaded liposome; Wherein, the microchannel inner wall surface possess hydrophilic property of described micro flow control chip device.
3. one kind prepares the monodispersity medicine carrying microballoons or carries the enzyme microsphere or the method for the microsphere of parcel cell, according to the difference of pharmaceutical properties, is divided into following e) and f) two kinds of methods;
Described e) method comprises the steps: with the aqueous solution that contains biodegradable polymer and following any one material as decentralized photo 5: water soluble drug, enzyme and cell; With the oil solution that contains the w/o type emulsifying agent as continuous phase 5; Described decentralized photo 5 and continuous phase 5 are transported to the respective microchannels of micro flow control chip device respectively, prepare the W/O microemulsion by described micro flow control chip device, the W/O microemulsion is collected in the container that continuous phase 5 or cross-linking agent solution are housed, solidify, obtain medicine carrying microballoons or carry the enzyme microsphere or the microsphere of parcel cell; Wherein, the microchannel inner wall surface of described micro flow control chip device has hydrophobicity;
Described f) method comprises the steps: with the oil solution that contains fat-soluble medicine and biodegradable polymer as decentralized photo 6; With the aqueous solution that contains O/W type emulsifying agent as continuous phase 6; Described decentralized photo 6 and continuous phase 6 are transported to the respective microchannels of micro flow control chip device respectively, prepare the O/W microemulsion by described micro flow control chip device, the O/W microemulsion is collected in the container of described continuous phase 6 or cross-linking agent solution, solidified, obtain medicine carrying microballoons; Wherein, the microchannel inner wall surface possess hydrophilic property of described micro flow control chip device.
4. according to each described method among the claim 1-3, it is characterized in that: described microemulsion, liposome and diameter of micro ball breadth coefficient are all smaller or equal to 5%.
5. according to each described method among the claim 1-4, it is characterized in that: the mass concentration of surfactant is 0.5%-10% in the described continuous phase, is preferably 0.5%-4%.
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