CN206404046U - A kind of device for preparing double-deck emulsion droplet - Google Patents

Abstract

The utility model is related to a kind of preparation facilities of double-deck emulsion droplet, and the device is composed in series by first order microchannel and second level microchannel；Described first order microchannel is cross microchannel, T-shaped microchannel, Y types microchannel or common flow pattern microchannel；Described second level microchannel includes A classes or the two kinds of microchannel of B classes.The preparation facilities of the utility model bilayer emulsion droplet is simple in construction, adjustment is flexible, emulsion droplet and drug bearing microsphere grain size, the flexible control of ectonexine thickness are easily achieved, preparation cost is low, and obtained double-deck emulsion droplet grain size is controllable, particle diameter adjustable extent is wide.

Description

A device for preparing double-layer emulsified droplets

technical field

The utility model relates to a device for preparing double-layer emulsified droplets, which belongs to the technical field of microfluidic control.

Background technique

Water-in-oil-in-water or oil-in-water-in-oil double-layer emulsified microdroplets, and drug-loaded microspheres prepared using them as templates are widely used in biomedical materials, drug research and development, and other fields. The existing preparation methods mainly adopt traditional large-scale mechanical stirring, emulsification-crosslinking, composite emulsion-solvent volatilization, emulsification-gel, reverse suspension polymerization and other technologies. The first step is to generate double-layer emulsified micro-droplets, and then through Solvent volatilization, drying and other methods to generate microsphere products. The traditional preparation method lacks the precise control of the size of the microspheres. The obtained microspheres have a wide size range and poor particle size uniformity. Products in a specific particle size range are often obtained by sieving; and the loss of the encapsulated drug during the preparation process is relatively low many.

Microfluidic droplet technology can manipulate two-phase immiscible liquids (oil and water) by virtue of the interaction between fluid shear force and surface tension in micro-channels (micro-nanoscale), one of which will form Highly uniform droplets to achieve the preparation of microspheres with controllable size, shape and structure. Microfluidic droplet technology is a bottom-up emulsion preparation method, which can prepare highly monodisperse droplet emulsions with very high throughput, and the formed drug-loaded microspheres have good size uniformity.

However, at present, the devices for preparing double-layer emulsified micro-droplets and drug-loaded microspheres using microfluidic technology have complex structures, many steps in the operation and control process, and are not flexible. higher.

Contents of the invention

In view of the shortcomings of the existing double-layer emulsified droplets and drug-loaded microspheres in the preparation process, the device structure is complicated, the operation is cumbersome, and the cost is high. The utility model provides a device for preparing double-layer emulsified droplets. Flexible combination, low cost, microspheres with a particle size range of 0-1000 microns can be prepared, and the microspheres have good particle size uniformity and high drug loading, which solves the problem of uncontrollable particle size and Unable to synchronize curing, incomplete drug loading and other problems.

The technical scheme of the utility model is as follows:

A preparation device for double-layer emulsified droplets, which is composed of a first-stage microchannel and a second-stage microchannel in series;

The first-level microchannel is a cross-shaped microchannel, a T-shaped microchannel, a Y-shaped microchannel or a co-flow microchannel;

Described second-level microchannel includes two types of microchannels of Class A or Class B;

The Class A second-stage microchannel includes a coaxially connected discrete phase fluid channel, a continuous phase fluid channel and a collection channel, the discrete phase fluid channel and the collection channel are nested in the continuous phase fluid channel, and the discrete phase fluid channel is close to the collection channel. One end of the channel is tapered, and the discrete-phase fluid channel is equally divided into a single-layer emulsified droplet inlet channel and a catalyst or curing agent channel along the central axis;

The second-stage microchannel of Class B includes a single-layer emulsified micro-droplet inlet channel, a catalyst or curing agent channel, a collection channel and a continuous phase fluid channel, and a single-layer emulsified micro-droplet inlet channel, a catalyst or a curing agent channel It is in a Y-shaped communication structure with the collection channel group, and the continuous phase fluid channel is arranged at the intersection of the single-layer emulsified droplet inlet channel, the catalyst or curing agent channel and the collection channel and is vertically connected with the collection channel.

According to the present invention, preferably, the cross-shaped microchannel includes an interphase fluid channel, an internal phase fluid channel and a collection channel connected in a cross-shaped structure.

According to the present invention, preferably, the T-shaped microchannel includes an interphase fluid channel, an internal phase fluid channel and a collection channel connected in a T-shaped structure.

According to the present invention, preferably, the Y-shaped microchannel includes an interphase fluid channel, an internal phase fluid channel and a collection channel connected in a Y-shaped structure.

According to the present invention, preferably, the co-flow microchannel includes a coaxially connected interphase fluid channel, an internal phase fluid channel and a collection channel, the internal phase fluid channel and the collection channel are nested in the interphase fluid channel, The inner phase fluid channel is trapezoidal and the end close to the collecting channel is a small diameter end. The fluid flow direction of the interphase fluid channel is the same as that of the internal phase fluid channel.

According to the present invention, preferably, after the first-stage microchannel and the second-stage microchannel are connected in series, the collection channel in the first-stage microchannel communicates with the single-layer emulsified droplet inlet channel in the second-stage microchannel.

According to the present invention, preferably, the channel diameters of the first-stage microchannel and the second-stage microchannel are 20-1000 microns, more preferably 50-500 microns.

According to the present invention, in the process of using the above-mentioned device to prepare double-layer emulsified droplets, the flow shear force and/or extrusion force of the continuous phase fluid interacts with the interfacial tension between the fluids, and the droplets are separated between the discrete phase fluid and the continuous phase. Generated at the intersection of phase fluid channels. A single-layer emulsified droplet is formed in the first-stage microchannel, and the single-layer emulsified droplet is carried by the interphase fluid into the second-stage microchannel, and a double-layer emulsified droplet is formed at the outlet of the second-stage microchannel, and the double-layer emulsified droplet The droplets are solidified simultaneously to form double-layer microspheres, and the formed drug-loaded microspheres have uniform particle size (size deviation <5%), and the particle size, structure/drug loading are controllable; hydrophilic or lipophilic drugs can be loaded , and the drug loading of each microsphere is consistent.

According to the utility model, the first-level microchannel and the second-level microchannel are glass or quartz capillaries, or microchannels formed by etching methods such as light, chemistry, and laser.

The double-layer emulsified droplet prepared by the above-mentioned device, the droplet is formed by the internal phase fluid and the intermediate phase fluid in the first-stage microchannel to form a single-layer emulsified droplet, and then the single-layer emulsified droplet is mixed with a catalyst or curing agent solution , The continuous phase fluid forms double-layer emulsified droplets at the outlet of the second-stage microchannel.

According to the double-layer emulsified droplet of the present invention, preferably, the internal phase fluid is a biocompatible high molecular polymer solution containing medicine; the high molecular polymer is polylactic acid (PLA), polylactic acid - Glycolic acid copolymer (PLGA) or polyethylene glycol (PEG), the solvent of the polymer solution is methylene chloride, acetone, dimethylformamide, and the mass fraction of the polymer solution is 0.1-10%. .

According to the double-layer emulsified droplet of the present invention, preferably, the interphase fluid is a biocompatible high molecular polymer aqueous solution or a mixed solution of a high molecular polymer aqueous solution and a crosslinking agent aqueous solution, and the high molecular polymer is Sodium alginate, polyvinyl alcohol, chitosan, starch or gelatin, the mass fraction of the polymer aqueous solution is 0.1-10%; the cross-linking agent is glutaraldehyde, glyoxal or formaldehyde, the mass fraction of the cross-linking agent aqueous solution Score 0.5‐80%.

According to the double-layer emulsified droplet of the present invention, preferably, the catalyst is a protonic acid or a biological enzyme aqueous solution, and the protonic acid is used to adjust the pH of the interphase fluid, preferably an organic acid or an inorganic acid, and the protonic acid is preferably an organic acid or an inorganic acid. The pH value of acid is preferably pH1-4; described biological enzyme is preferably able to catalyze the cross-linking between or within protein molecules, the enzyme connecting between protein and amino acid, most preferably transglutaminase, biological enzyme aqueous solution The mass fraction of preferably 0.1-0.3%.

According to the double-layer emulsified droplet of the present invention, preferably, the described curing agent is a divalent water-soluble calcium and barium ion aqueous solution, most preferably calcium chloride or barium chloride aqueous solution, the mass fraction of the curing agent Preferably 0.1-10%.

According to the double-layer emulsified droplet of the present invention, preferably, the continuous phase fluid is an organic solvent immiscible with water, further preferably, the continuous phase fluid contains or does not contain a surfactant ; the surface active Agent is water-soluble or oil-soluble surfactant, more preferably, described water-soluble surfactant selects nonionic surfactant, comprises polyoxyethylene type or polyalcohol type; Described oil-soluble surfactant selects EM90 ( Cetyl Polyethylene Glycol/Polypropylene Glycol-10/1 Dimethicone), Span 80 (Span 80) or DC749 (Dow Corning Silicone XIAMETER RSN‐0749);

The organic solvent is one or a combination of C12-18 liquid alkane, silicone oil, and paraffin.

According to the double-layer emulsified liquid droplet of the present invention, preferably, the particle diameter of the liquid droplet is 160-650 μm, and the particle diameter deviation is ≤2%.

The drug-loaded microsphere prepared by the above-mentioned device is coated with a drug-containing inner core in the biocompatible macromolecular polymer microsphere.

According to the drug-loaded microsphere of the present invention, preferably, the drug-containing inner core is a hydrophilic or lipophilic drug mixed with a biocompatible polymer;

Preferably, the particle size of the drug-loaded microspheres is 100-1000 μm, and the size deviation is less than 5%; particularly preferably, the particle size of the drug-loaded microspheres is 110-530 μm, and the particle size deviation is ≤4%;

Preferably, the biocompatible polymer is sodium alginate, polyvinyl alcohol, chitosan, starch, gelatin, polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA) or/and poly Ethylene glycol (PEG).

The drug-loaded microspheres of the utility model use double-layer emulsified droplets as a template, add biocompatible polymers and drugs into the inner phase fluid and the intermediate phase fluid, and solidify to form a double-layer structure with inner and outer layers. drug-loaded microspheres. The particle size of the microsphere is uniform, and the thickness of the inner and outer layers is controllable; through the synchronous curing process of the utility model, the surface of the microsphere produced is smooth, the size is uniform, and the drug loading is controllable. The drug-loaded microspheres of the utility model, the inner layer and the outer layer support are both high molecular polymers, the inner layer of the ball is loaded with drugs, and the outer layer provides support while also helping to maintain the activity of the inner layer of drugs to achieve stable release. Drugs, prevent sudden release, and increase safety; by changing the properties of solvents and materials, operating parameters, etc., the size of the microsphere product and the ratio of inner and outer layers can be easily changed to achieve drug loading and drug release controllable.

The method for preparing drug-loaded microspheres using the above-mentioned device, the size of the drug-loaded microspheres is uniform, and the structure/drug-loading amount is controllable, including the following steps:

(1) Preparation of discrete phase fluid and continuous phase fluid

Separately prepare discrete phase fluid and continuous phase fluid;

The discrete phase fluid is composed of internal phase fluid, intermediate phase fluid, and catalyst or curing agent aqueous solution:

The internal phase fluid is a biocompatible high molecular polymer solution containing drugs, and the high molecular polymer is polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA) or polyethylene glycol (PEG ), the solvent of the polymer solution is dichloromethane, acetone, dimethylformamide, and the mass fraction of the polymer solution is 0.1-8%;

The interphase fluid is an aqueous solution of a biocompatible high molecular polymer and/or an aqueous solution of a crosslinking agent, the high molecular polymer is sodium alginate, polyvinyl alcohol, chitosan, starch or/and gelatin, and the high molecular polymer The mass fraction of the aqueous solution is 0.1-10%; the cross-linking agent is glutaraldehyde, glyoxal or formaldehyde, and the mass fraction of the cross-linking agent aqueous solution is 0.5-80%;

Described catalyzer is protonic acid or biological enzyme aqueous solution, and described protonic acid is preferably organic acid or inorganic acid, and the pH value of protonic acid is preferably pH1-4; Described biological enzyme is preferably able to catalyze protein molecules between or within The cross-linking, protein and enzyme connecting between amino acids, most preferably transglutaminase, the mass fraction of biological enzyme aqueous solution is preferably 0.1-0.3%;

The curing agent is a divalent water-soluble calcium and barium ion aqueous solution, most preferably calcium chloride or barium chloride aqueous solution, and the mass fraction of the curing agent is preferably 0.1-10%.

The continuous phase fluid is an organic solvent immiscible with water, and the continuous phase fluid contains or does not contain a surfactant; the organic solvent is one or a combination of C12-18 liquid alkane, silicone oil, paraffin;

(2) Formation of double-layer emulsion droplets

Pass the internal phase fluid and the intermediate phase fluid into the internal phase fluid channel and the intermediate phase fluid channel of the first-stage microchannel respectively, and form a single layer of emulsified droplets at the intersection of the internal phase fluid channel and the intermediate phase fluid channel, and pass through the first The collection channel of the level microchannel collects the monolayer emulsion droplet;

In the second-stage microchannel, the single-layer emulsified droplet is passed into the single-layer emulsified droplet channel, the catalyst or curing agent solution is passed into the catalyst or curing agent channel, and the continuous phase fluid is passed into the continuous phase fluid channel. The emulsified droplets, catalyst or curing agent, and the continuous phase fluid form a double-layered emulsified droplet at the intersection, and the double-layered emulsified droplet is collected through the collection channel of the second-stage microchannel;

(3) Synchronous curing

While forming double-layer emulsified droplets, the catalyst or curing agent is fully mixed with the polymer in the interphase fluid in the second-stage microchannel, and the double-layer emulsified droplets can be solidified synchronously to form microspheres, and then in 20‐ Stand at 80°C for 0.5-24 hours to ensure that the microspheres are completely cross-linked and solidified to obtain drug-loaded microspheres;

(4) Separation of microspheres

Filter the reaction solution after cross-linking and solidification in step (3), collect solid particles, wash with organic solvent and water in sequence, and obtain the drug-loaded microsphere product after drying.

According to the preparation method of the drug-loaded microspheres of the present invention, preferably, when the continuous phase fluid in step (1) contains a surfactant, the surfactant is one or both of water-soluble or oil-soluble surfactants More than mixing; Further preferably, described water-soluble surfactant is nonionic surfactant, comprises polyoxyethylene type and polyalcohol type nonionic surfactant; Described oil-soluble surfactant is EM90 (cetyl wax Polyethylene Glycol/Polypropylene Glycol-10/1 Dimethicone), Span 80 (Span 80) or DC749 (Dow Corning Silicone XIAMETER RSN‐0749).

According to the preparation method of the utility model drug-loaded microspheres, preferably, the solidifying agent described in step (1) is an aqueous calcium chloride solution, and the mass concentration of the solidifying agent aqueous solution is 1-10%, and the particularly preferred mass concentration is 2-10%. 5% calcium chloride solution in water.

According to the preparation method of the drug-loaded microspheres of the present invention, preferably, step (2) controls the flow rate of the mesophase fluid in the second-stage microchannel to be: 0.5-8mL/h, and the flow rate of the catalyst or curing agent aqueous solution to be: 0.05-2.0 mL/h, control the flow rate of the continuous phase fluid: 1‐20mL/h;

Further preferably, step (2) controls the intermediate phase fluid flow rate in the second-stage microchannel to be 2-6mL/h, the catalyst or curing agent aqueous solution flow rate is 0.1-0.5mL/h, and the continuous phase fluid flow rate is 5-6mL /h.

According to the utility model, the formation of double-layer emulsified droplets in the step (2) is in the second-stage microchannel, and the discrete phase fluid is divided into nanoliters and Droplets below the nanoliter level.

According to the preparation method of the drug-loaded microspheres of the present invention, preferably, the cross-linking and curing described in step (3) is: the polymer and the cross-linking agent carry out a conventional cross-linking reaction under the action of a catalyst or a curing agent, for example : Polyvinyl alcohol and aldehyde compounds undergo a conventional crosslinking reaction under the catalysis of an acidic catalyst to form a polyvinyl acetal product, or sodium alginate is solidified under the catalysis of calcium chloride to form calcium alginate; solidified after solidification Particles are then separated, washed, and dried to obtain microsphere products.

According to the preparation method of the drug-loaded microspheres of the present invention, preferably, the organic solvent for washing described in step (4) is selected from one of liquid alkane with a boiling point below 80°C, petroleum ether at 60-90°C, and ethyl acetate. one or a combination of two or more. The washing time is 0.5-3 hours. The drying refers to vacuum drying, freeze drying or spray drying.

The utility model adopts two-stage micro-channels connected in series to prepare double-layer emulsified micro-droplets, forming single-layer emulsified micro-droplets in the first-stage micro-channel, which is wrapped and carried by the intermediate phase (or premixed liquid) into the second stage In the microchannel, while forming double-layer emulsified micro-droplets, the catalyst interacts with the polymer, and the micro-droplets solidify to form microspheres. The basic principle is to prepare double-layer emulsified micro-droplets based on the principle of fluid dynamics, using this as a template, adding polymer monomers, drugs, etc. into the internal phase fluid, and forming drug-loaded microspheres after curing. Since the microspheres are formed one by one, the preparation device and method described in the utility model can precisely control the size of the microspheres, the thickness of the inner and outer layers, and the drug loading amount, and the formed products have good sphericity, uniform size, and structure/ The drug loading is controllable.

The beneficial effects of the utility model are:

1. The device for preparing double-layer emulsified droplets of the present invention has a simple structure and flexible adjustment, and is easy to realize the flexible control of the particle size of the emulsified droplets and drug-loaded microspheres, and the thickness of the inner and outer layers, and the preparation cost is low.

2. The utility model is used to prepare double-layer emulsified micro-droplets and drug-loaded microspheres based on the principle of fluid dynamics. The inner layer droplets are formed drop by drop under the action of liquid/liquid surface tension and shear force in the first-stage microchannel, and the inner layer droplets are carried by the intermediate phase in the second-stage channel and together with the catalyst or curing agent, are continuously formed. Phase shear encapsulation forms the outer layer of a double-emulsion droplet. Using the double-layer emulsified micro-droplets as a template, adding polymers and drugs to the fluid can be simultaneously cured to form drug-loaded microspheres through the action of a catalyst or a curing agent. The prepared drug-loaded microspheres have uniform particle diameter (the size deviation is less than 5%), and the drug-loaded amount is uniform/controllable.

3. The utility model can adjust the droplet size by adjusting the fluid flow rate and the size of the microchannel. Therefore, by adjusting the fluid flow rate or changing the size of the microchannel, the preparation of drug-loaded microspheres with different particle diameters and inner and outer layer ratios can be achieved. , The advantages of controllable preparation of inner and outer layer thickness.

Description of drawings

FIG. 1A is a schematic structural view of a cross-shaped first-stage microchannel A.

FIG. 1B is a schematic structural diagram of a T-shaped first-stage microchannel B.

FIG. 1C is a schematic structural view of a Y-shaped first-stage microchannel C.

FIG. 1D is a schematic structural view of a co-flow first-stage microchannel D.

Fig. 2A is a schematic diagram of the structure of the Class A second-stage microchannel.

Fig. 2B is a schematic diagram of the structure of the Class B second-stage microchannel.

3 is a schematic structural view of the preparation device for double-layer emulsified micro-droplets in Example 4, that is, a preparation device in which T-shaped first-stage microchannels B and B-type second-stage microchannels are connected in series.

Among them: A1, B1, C1, D1, 13 are interphase fluid channels, A2, B2, C2, D2, 14 are internal phase fluid channels, 3, 8, 15 are single-layer emulsified micro-droplet access channels, 4, 9, 16 are catalyst or curing agent channels, 5, 10, 17 are continuous phase fluid channels, A3, B3, C3, D3, 6, 11, 18 are collection channels, 7, 12, 20 are double-layer emulsion droplets, 19 is a monolayer emulsified droplet.

detailed description

The utility model will be further described below in conjunction with the accompanying drawings and embodiments, but the protection scope of the utility model is not limited thereto.

In the embodiment: the Class A second-level microchannel is a glass or quartz capillary microchannel, and the Type B second-level microchannel is a microchannel formed by optical, chemical, laser and other etching techniques (the channel scale is micron).

The % concentration unit in the application examples is mass percent.

The polyvinyl alcohol used in the application examples has a molecular weight of 13,000‐23,000, and is hydrolyzed over 99%; content: ≥99.0%, white granular.

The molecular formula of sodium alginate used in the application example is (C6H7O6Na)n, the molecular weight is 398.31; the macromolecule is 32,000‐250,000, and it is white granular.

The raw material preparation process in the application example is as follows:

Weigh 10 grams of polyvinyl alcohol solid particles and add 90 grams of distilled water, stir and dissolve evenly under the condition of 75-80 ° C to form a transparent liquid, and obtain a 10% by mass polyvinyl alcohol aqueous solution.

Weigh 5 grams of sodium alginate solid particles and add 95 grams of distilled water, stir evenly at room temperature and dissolve into a transparent liquid to obtain a 5% by mass sodium alginate aqueous solution.

According to the mass fraction, the above aqueous solution of polyvinyl alcohol and sodium alginate was prepared into a mixed aqueous solution of polyvinyl alcohol and sodium alginate with final concentrations of 1% and 0.5%, respectively.

The continuous phase fluid used in the application example is paraffin oil containing 2% EM90. Weigh 98 grams of paraffin oil and add 2 grams of EM90 to obtain a 2% mass percent paraffin oil continuous phase fluid.

The catalyst used in the application example is an aqueous protic acid solution, and the pH value of the aqueous protic acid solution is adjusted to 1-6 to obtain an aqueous catalyst solution.

The cross-linking agent used in the application example is glutaraldehyde aqueous solution, calculate the mass fraction of polyvinyl alcohol aqueous solution and glutaraldehyde aqueous solution, and prepare the cross-linking agent aqueous solution according to the ratio of 3:2.

The curing agent used in the application example is an aqueous solution of calcium chloride. Weigh 10 grams of anhydrous calcium chloride solid and add it to 90 grams of deionized water to obtain a 10% by mass aqueous solution of the curing agent.

The internal phase fluid used in the application example is polylactic acid dichloromethane solution containing medicine, and the mass fraction of the solution is 2%.

Embodiment 1,

A preparation device for double-layer emulsified droplets, which is composed of a first-stage microchannel and a second-stage microchannel in series;

The first-stage microchannel is a cross-shaped microchannel A, a T-shaped microchannel B, a Y-shaped microchannel C or a co-flow microchannel D;

Described second-level microchannel includes two types of microchannels of Class A or Class B;

The Class A second-stage microchannel includes a coaxially connected discrete phase fluid channel, a continuous phase fluid channel 5 and a collection channel 6, the discrete phase fluid channel and the collection channel 6 are nested in the continuous phase fluid channel 5, and the discrete phase One end of the fluid channel close to the collection channel 6 is tapered, and the discrete phase fluid channel is equally divided into a single-layer emulsified micro-droplet inlet channel 3 and a catalyst or curing agent channel 4 along the central axis;

Described B type second-stage microchannel comprises single-layer emulsified micro-droplet leading channel 8, catalyst or curing agent channel 9, collection channel 11 and continuous phase fluid channel 10, single-layer emulsified micro-droplet leading channel 8, Catalyst or solidifying agent channel 9 and collecting channel 11 groups are Y-shaped communication structure, and described continuous phase fluid channel 10 is arranged at the junction of single-layer emulsified microdroplet inlet channel 8, catalyst or curing agent channel 9 and collecting channel 11 and communicates vertically with the collection channel 11.

After the first-stage microchannel and the second-stage microchannel are connected in series, the collection channel in the first-stage microchannel communicates with the single-layer emulsified microdroplet inlet channel in the second-stage microchannel.

The cross-shaped microchannel A includes an interphase fluid channel A1, an internal phase fluid channel A2 and a collection channel A3 connected in a cross-shaped structure.

The T-shaped microchannel B includes an interphase fluid channel B1, an internal phase fluid channel B2, and a collection channel B3 connected in a T-shaped structure.

The Y-shaped microchannel C includes a Y-shaped interphase fluid channel C1, an internal phase fluid channel C2, and a collection channel C3.

The co-flow microchannel D includes a coaxially connected mesophase fluid channel D1, an internal phase fluid channel D2 and a collection channel D3, the internal phase fluid channel D2 and the collection channel D3 are nested in the mesophase fluid channel D1, and the internal The phase fluid channel D2 is trapezoidal and the end close to the collecting channel D3 is a small diameter end. The fluid flow direction of the interphase fluid channel D1 is the same as the fluid flow direction of the internal phase fluid channel D2.

Embodiment 2,

A device for preparing double-layer emulsified droplets, which is composed of a first-stage microchannel and a second-stage microchannel connected in series.

The first-level microchannel selects the cross-shaped first-level microchannel shown in Figure 1A for use, and the diameter of the inner phase fluid channel A2 is 150 microns, and the diameter of the interphase fluid channel A1 is 200 microns; the second-level microchannel is selected for use as shown in Figure 2A Class A second-stage microchannels, the diameter of the discrete phase fluid channel is 250 microns, and the diameter of the continuous phase fluid channel 5 is 300 microns.

Application Example 1. Using the preparation device in Example 2 to prepare double-layer emulsified droplets and drug-loaded microspheres.

The mass percentage concentration of the mixed aqueous solution of polyvinyl alcohol and sodium alginate is 1.5% and 0.5% respectively, and the aqueous solution of the crosslinking agent is 50% by mass of glutaraldehyde aqueous solution. The polyvinyl alcohol aqueous solution and the glutaraldehyde aqueous solution are premixed according to the mass ratio of solute polyvinyl alcohol:crosslinking agent=3:2, and the aqueous catalyst solution is hydrochloric acid aqueous solution with pH=2.0.

The mixed solution of polyvinyl alcohol, sodium alginate and cross-linking agent, and the internal phase fluid were pumped into the first-stage microchannel at a constant flow rate of 0.3mL/h and 3mL/h, respectively, and the formed single-layer emulsified microdroplets were passed through The single-layer emulsified micro-droplet is carried into the second-stage microchannel (Fig. 2A) through channel 3, while the catalyst aqueous solution is pumped into the catalyst channel 4 with a constant flow rate of 0.8mL/h, and the liquid paraffin is pumped into the catalyst channel 4 with a constant flow rate of 6mL/h. h is pumped into the continuous phase fluid channel 5, double-layer emulsified micro-droplets 7 are formed at the junction, and collected through the collection channel 6.

After standing the double-layer emulsified micro-droplet 7 at room temperature of 25° C. for 24 hours, a white solid was obtained. It was then filtered to collect a white solid. The white solid was washed with ethyl acetate, and then washed with water for 24 hours through a Soxhlet extractor, and dried under vacuum at 4° C. to obtain white microspheres. The particle size of the outer layer is 500 microns, the particle size of the inner layer is 100 microns, and the size deviation of the microspheres is 3%.

Embodiment 3,

A device for preparing double-layer emulsified droplets, which is composed of a first-stage microchannel and a second-stage microchannel connected in series.

The first-stage microchannel selects the T-shaped first-stage microchannel shown in Figure 1B, the diameter of the internal phase fluid channel B2 is 100 microns, and the diameter of the interphase fluid channel B1 is 200 microns; the second-stage microchannel selects B shown in Figure 2B Similar to the second-stage microchannel, the diameter of the discrete phase fluid channel is 200 microns, and the diameter of the continuous phase fluid channel 10 is 300 microns. After the first-stage microchannel and the second-stage microchannel are connected in series, as shown in FIG. 3 .

Application Example 2. The preparation device of Example 3 was used to prepare double-layer emulsified droplets and drug-loaded microspheres.

The concentration of polyvinyl alcohol aqueous solution is 2%, the aqueous solution of cross-linking agent is 40% glutaraldehyde aqueous solution, and the aqueous solution of polyvinyl alcohol and the aqueous solution of cross-linking agent are premixed according to the mass ratio of solute polyvinyl alcohol:cross-linking agent=3:2 , the catalyst aqueous solution is a sulfuric acid aqueous solution with pH=1.5. The mixed solution of polyvinyl alcohol and cross-linking agent and the internal phase fluid are pumped into the first-stage microchannel at a constant flow rate of 0.5mL/h and 2mL/h respectively, and the formed single-layer emulsified micro-droplets 19 are emulsified by a single layer The micro-droplet is passed into channel 15 and enters the second-stage microchannel, while the catalyst aqueous solution is pumped into the catalyst channel 16 with a constant flow rate of 0.8mL/h, and dodecane is pumped into the continuous phase fluid channel with its constant flow rate of 8mL/h 17 in. Double-layer emulsified droplets 20 are formed at the junction and collected through the collection channel 18 .

A white solid was obtained after the double-layer emulsified micro-droplet 20 was left to stand at room temperature of 25° C. for 24 hours. It was then filtered to collect a white solid. The white solid was washed with ethyl acetate, and then washed with water for 24 hours through a Soxhlet extractor, and dried under vacuum at 4° C. to obtain white microspheres. The particle size of the outer layer is 300 microns, the particle size of the inner layer is 120 microns, and the size deviation of the microspheres is 3%.

Embodiment 4,

A device for preparing double-layer emulsified droplets, which is composed of a first-stage microchannel and a second-stage microchannel connected in series.

The first-stage microchannel selects the Y-shaped first-stage microchannel shown in Figure 1C, the internal phase fluid channel C2 has a diameter of 80 microns, and the interphase fluid channel C1 has a diameter of 100 microns; the second-stage microchannel selects B shown in Figure 2B Similar to the second-stage microchannel, the diameter of the discrete phase fluid channel is 150 microns, and the diameter of the continuous phase fluid channel 10 is 200 microns.

Application Example 3. The preparation device of Example 4 was used to prepare double-layer emulsified droplets and drug-loaded microspheres.

The mass percentage concentration of the sodium alginate aqueous solution is 2%, and the curing agent aqueous solution is 4mol/L calcium chloride aqueous solution. The sodium alginate aqueous solution and the intermediate phase were pumped into the first-stage microchannel at a constant flow rate of 0.5mL/h and 3mL/h, respectively, and the formed monolayer emulsified microdroplets entered the second-stage microchannel through channel 8 ( FIG. 2B ), at the same time the curing agent aqueous solution is pumped into the curing agent channel 9 at a constant flow rate of 0.5 mL/h, and toluene is pumped into the continuous phase fluid channel 10 at a constant flow rate of 10 mL/h. Double-layer emulsified micro-droplets 12 are formed at the junction and collected through the collection channel 11 .

The double-layer emulsified micro-droplet 12 was left standing at room temperature of 25°C for 24 hours to obtain a white solid. It was then filtered to collect a white solid. The white solid was washed with petroleum ether, and then washed with water for 24 hours through a Soxhlet extractor, and dried under vacuum at 4° C. to obtain white microspheres. The particle size of the outer layer is 120 microns, the particle size of the inner layer is 95 microns, and the size deviation of the microspheres is 4%.

Embodiment 5,

A device for preparing double-layer emulsified droplets, which is composed of a first-stage microchannel and a second-stage microchannel connected in series.

The co-flow first-stage microchannel shown in Figure 1D is selected as the first-stage microchannel, the diameter of the internal phase fluid channel D2 is 150 microns, and the diameter of the interphase fluid channel D1 is 130 microns; the second-stage microchannel is selected as shown in Figure 2A Class A second-stage microchannels, the diameter of the discrete phase fluid channel is 150 microns, and the diameter of the continuous phase fluid channel 5 is 400 microns.

Application Example 3. The preparation device of Example 5 was used to prepare double-layer emulsified droplets and drug-loaded microspheres.

The gelatin aqueous solution has a mass concentration of 2%, and the crosslinking agent aqueous solution has a mass concentration of 0.2% transglutaminase aqueous solution. The mixture of gelatin and cross-linking agent (gelatin: cross-linking agent = 3:2 mass ratio) and the intermediate phase were pumped into the first-stage microchannel at a constant flow rate of 1 mL/h and 6 mL/h to form a single A layer of emulsified micro-droplets enters the second-stage micro-channel through the single-layer emulsified micro-droplet channel 3 (Figure 2A), and at the same time, a constant flow rate of 0.8 mL/h of the cross-linking agent aqueous solution is pumped into the catalyst or curing agent channel 4 , the liquid paraffin is pumped into the continuous phase fluid channel 5 at a constant flow rate of 8mL/h. Double-layer emulsified micro-droplets 7 are generated near the outlet of the discrete-phase fluid channel and collected through the collection channel 6 .

The double-layer emulsified micro-droplet 12 was left standing at room temperature of 25°C for 24 hours to obtain a white solid. It was then filtered to collect a white solid. The white solid was washed with ethyl acetate, and then washed with water for 24 hours through a Soxhlet extractor, and dried under vacuum at 4° C. to obtain white microspheres. The particle size of the outer layer is 290 microns, the particle size of the inner layer is 90 microns, and the size deviation of the microspheres is 3%.

Claims (7)

1. a kind of preparation facilities of double-deck emulsion droplet, it is characterised in that the device is micro- logical by first order microchannel and the second level Road is composed in series；

Described first order microchannel is cross microchannel, T-shaped microchannel, Y types microchannel or common flow pattern microchannel；

Described common flow pattern microchannel includes interphase fluid passage, internal phase fluid passage and the collection channel of coaxial connection, interior Phase fluid passage and collection channel are socketed in interphase fluid passage, and internal phase fluid passage is trapezoidal and close to collection channel One end be smaller diameter end；

Described second level microchannel includes A classes or the two kinds of microchannel of B classes；

Discrete phase fluid passage, continuous phase fluid passage and the collection that described A classes second level microchannel includes coaxial connection are logical Road, discrete phase fluid passage and collection channel are socketed in continuous phase fluid passage, and discrete phase fluid passage is close to collection channel One end it is tapered, discrete phase fluid passage along central shaft be bisected into individual layer emulsification microlayer model be passed through passage and catalyst or solidification Agent passage；

Described B classes second level microchannel includes individual layer emulsification microlayer model and is passed through passage, catalyst or curing agent passage, collects logical Road and continuous phase fluid passage, individual layer emulsification microlayer model are passed through passage, catalyst or curing agent passage and collection channel composition Y types Connectivity structure, described continuous phase fluid passage is arranged on individual layer emulsification microlayer model and is passed through passage, catalyst or curing agent passage With the intersection of collection channel and with collection channel vertical connection.

2. the preparation facilities of double-deck emulsion droplet according to claim 1, it is characterised in that described cross microchannel Including the interphase fluid passage connected in cross-shaped configuration, internal phase fluid passage and collection channel.

3. the preparation facilities of double-deck emulsion droplet according to claim 1, it is characterised in that described T-shaped microchannel bag Include interphase fluid passage, internal phase fluid passage and the collection channel of T-shaped fabric connectivity.

4. the preparation facilities of double-deck emulsion droplet according to claim 1, it is characterised in that described Y types microchannel bag Include interphase fluid passage, internal phase fluid passage and the collection channel connected in y-type structure.

5. the preparation facilities of double-deck emulsion droplet according to claim 1, it is characterised in that first order microchannel and second After the series connection of level microchannel, the individual layer emulsification microlayer model in the collection channel and second level microchannel in first order microchannel is passed through logical Road is connected.

6. the preparation facilities of double-deck emulsion droplet according to claim 1, it is characterised in that described first order microchannel Channel diameter with second level microchannel is 20-1000 microns.

7. the preparation facilities of double-deck emulsion droplet according to claim 1, it is characterised in that described first order microchannel Channel diameter with second level microchannel is 50-500 microns.