KR20150116485A - Method for preparing Double Emulsion with multiple innermost drops enveloped by ultrathin shell, and Double Emulsion thereof - Google Patents

Abstract

The present invention relates to an apparatus and method for preparing a double liquid drop formed as multiple innermost liquid drops, each of which has its own ultrathin film, touch each other, and to the double liquid drop prepared thereby. The present invention provides the double liquid drop with multiple innermost drops, each of which has its own ultrathin film. A multi-core double liquid drop having its own thin film is capable of delivering a plurality of individual components such as drugs, cosmetics, detergents, and nutrients without contamination/denaturation due to mixing of the components. In the present invention, as photocrosslinkable and biocompatible polymers are used as a material for forming the thin film, the double liquid drop can be used as a microcapsule for in vivo application. In addition, the components contained in the innermost liquid drops can be released in order by using different kinds of materials for the thin film. Furthermore, a non-spherical shell of the double liquid drop can be combined between the innermost liquid drops without destruction of the liquid drop due to a thin film having a volumetric ratio much smaller than that of the innermost drop, thus the double liquid drop of the present invention can be used as a micro membrane encapsulating a reaction product as well as a microreactor.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method of manufacturing a double droplet having a plurality of internal droplets,

The present invention relates to a method for manufacturing a dual droplet having a plurality of internal droplets and a method for manufacturing a double droplet by forming a plurality of internal droplets having their own ultra thin films in contact with each other, And to dual droplets by this.

A double emulsion droplet is one that contains another droplet inside the droplet. This is divided into the case where the oil droplet exists in the water droplet (W / O / W) and the case where there is a water droplet inside the oil droplet (O / W / O). It is very difficult to control the size and the number of internal droplets when using the conventional emulsification apparatus. However, recently, it has become possible to control the size and the number of the internal droplet very finely using the microfluidic device.

In recent years, techniques have been disclosed for forming independent pluralities of internal droplets into one film without mutual contamination (Kim, SH; Shim, JW; Yang, SM Angew. Chem., Int. . Korean Patent No. 10-965839 discloses a dual droplet having a plurality of internal droplets. FIG. 1 shows a double droplet having a plurality of internal droplets generated in the Korean patent. Previous studies, including FIG. 1, have shown that the volume ratio of the mesophase and internal droplet is greater than 0.5 to safely encapsulate the internal droplet, resulting in a low stability of the emulsion and a thick capsule membrane. For this reason, the capsules of previous studies have had problems showing the destruction of the core-shell structure or the low loading rate inside the capsule.

The present invention provides a method of providing a thin film of each of a plurality of inner droplets and a double droplet by the method.

SUMMARY OF THE INVENTION The present invention provides a method for increasing the loading rate that can be contained in an internal droplet by significantly reducing the thickness of the membrane compared to the prior art.

SUMMARY OF THE INVENTION The present invention provides a method of controlling the order and amount of discharge of a plurality of internal droplets.

The present invention provides a double droplet using a plurality of internal droplets and a micro-reactor using the same.

In one aspect,

The present invention relates to a method of manufacturing a dual droplet using an injection capillary having a plurality of parallel channels, the method comprising simultaneously injecting a hydrophilic fluid and a lipophilic fluid into each of the plurality of channels; Wherein the fluids flowing in parallel to the respective channels are dropped into the second hydrophilic fluid from the orifices formed at the ends of the respective channels and are simultaneously emulsified while being in contact with each other.

In yet another aspect, the present invention provides a method of manufacturing a dual droplet with an injection capillary having a plurality of parallel channels, Injecting a fluid into the injection capillary, wherein the step of injecting a hydrophilic fluid and an oleophilic fluid simultaneously into at least one of the plurality of channels and injecting only a lipophilic fluid into at least one of the plurality of channels ; And a step in which the fluids flowing in parallel to the respective channels are dropped into the second hydrophilic fluid from the orifices formed at the ends of the respective channels to meet each other and emulsify at the same time.

In another aspect, the present invention provides a liquid ejection head comprising: a plurality of inner droplets; A thin film surrounding each of the plurality of inner droplets; And a contact interface formed between the plurality of inner droplets.

The present invention provides a double droplet having a plurality of inner droplets each having its own thin film. A multicore, double-droplet with its own thin film can deliver a number of individual components such as drugs, cosmetics, detergents, and nutrients without contamination / denaturation by mixing. In the present invention, microcapsules for in vivo application can be used by using photo-crosslinkable and bioadhesive polymers as a thin film forming material. In addition, the materials contained in the inner droplet can be sequentially discharged using different thin film materials for the inner droplet. Further, since the non-spherical shell of the droplets can be incorporated between the inner droplets without breaking the droplet due to the thin film having a volume ratio smaller than that of the inner droplet, the micro-reactor of the present invention as well as the micro- It can also be used as a membrane.

Figure 1 shows a double droplet having a plurality of conventionally known internal droplets.
2 shows an apparatus for manufacturing a double droplet according to an embodiment of the present invention.
Fig. 3 (a) is an entrance front view of the apparatus of Fig. 1, Fig. 3 (b) shows an inlet-side front view when three channels and Fig. 3 (c) shows four channels.
FIG. 4 shows one or more internal capillaries formed in FIG. Figure 5 is a schematic diagram showing fluid flowing through each channel.
Figure 6 shows a double droplet produced when using an injection capillary with two channels.
Figure 7 shows a double droplet produced when using an injection capillary having three to four channels.
8 is a schematic view of the case where the injection capillary has two channels, one of the channels is injected with a hydrophilic fluid and the other with a lipophilic fluid, and the other channel is injected with a lipophilic fluid.
9 shows an optical microscope image showing that a double droplet is generated when the doses of two hydrophilic fluids, two lipophilic fluids and one continuous fluid are 300, 200, and 6000 l / h, respectively, and a generated double droplet Focus is on the microscope image.
10 shows an image of generating a double droplet according to the injection flow rate according to the second embodiment.
11A is an optical microscope image of an encapsulated double droplet generated in Example 3, Figs. 11B to 11E are confocal images of a double droplet, and f and g of Fig. 11 are SEM images to be.
Figure 12 shows a plurality of internal droplets merged into a single droplet.
13 shows a double droplet and an image produced in Example 5. Fig.
14 is an optical microscope image of a double droplet generated in Example 6. Fig.

The present invention provides an apparatus and method for providing a dual droplet having a plurality of inner droplets. Embodiments of the present invention will be described in detail.

2 shows an apparatus for manufacturing a double droplet according to an embodiment of the present invention. Referring to FIG. 2, the dual droplet production apparatus of the present invention includes an injection capillary 10, a collection capillary 20, and an outer capillary 30.

The injection capillary 10 may have a plurality of independent channels 11, 12, 13, 14.

The injection capillary may have 2 to 8, preferably 2 to 4 independent channels.

The injection capillary tube is a cylindrical capillary tube, and a plurality of channels are formed inside the tube capillary tube.

Figure 3a is an inlet side front view of the apparatus of Figure 2; FIG. 3B shows an inlet-side front view in the case where three channels and FIG. 3C shows four channels. FIG. 4 shows one or more internal capillaries formed in FIG.

Referring to Figures 2 to 4, the plurality of independent channels are positioned parallel to one another within the injection capillary.

A boundary wall (40) is formed between the plurality of independent channels (11, 12, 13, 14) so that the fluids flowing in the channels are not mixed with each other.

An orifice is formed at the end of each channel of the injection capillary 10.

The diameter of the injection capillary 10 may be 0.1 to 5 mm, preferably 0.5 to 2 mm, and the diameter of the orifice may be 5 to 500 μm, preferably 20 to 200 μm.

An inner capillary (15, 16, 17, 18) of a diameter smaller than the diameter of the inlet channel is formed at the inlet center of each of the plurality of channels. The inner capillary may be one or more, preferably one or two.

The inner capillary may be a microtubule formed on a channel inlet side. The inner capillary may be positioned in contact with or not in contact with the inner wall of the injection capillary and the barrier wall. The diameter of the inner capillary may be 10 to 500 탆, preferably 50 to 200 탆.

The inner wall of the injection capillary tube 10 and the partition wall 40 may exhibit hydrophobicity.

In the present invention, a hydrophilic fluid and an oleophilic fluid may be simultaneously injected into each channel. In this case, an intermittent hydrophilic fluid flows through the center of the channel, and the lipophilic fluid penetrates the inner wall of the channel And flows around the hydrophilic fluid.

More specifically, in the present invention, a hydrophilic fluid may be injected into the inner capillary, a space A between the inner capillary and the inner capillary of the injection capillary, and a lipophilic fluid may be injected into the inner capillary. An intermittent hydrophilic fluid flows through the center of the channel and the lipophilic fluid surrounds and flows around the hydrophilic fluid along the inner wall of the channel. For example, the hydrophilic fluid may be injected into the inner capillary, the lipophilic fluid may be injected through the space (A) between the inner capillary and the inner capillary inner wall, or the lipophilic fluid may be injected into the inner capillary, A hydrophilic fluid can be injected through the space A between the inner capillary and the inner wall of the injection capillary.

If the inner capillary tube has two or more inner capillaries, a hydrophilic fluid is injected into one or more of the inner capillaries, and a lipophilic fluid is injected into at least one of the inner capillaries. In any case, the intermittent hydrophilic fluid flows in the center of the channel, The lipophilic fluid may surround and flow the hydrophilic fluid along the inner wall of the channel.

That is, when the hydrophilic fluid and the lipophilic fluid are injected at the same time in the present invention, the hydrophilic fluid automatically flows to the center of the channel and the lipophilic fluid flows to the inner wall of the channel due to the characteristics of the hydrophobic inner wall.

 The hydrophilic fluid injected into the channel may comprise a drug, a cosmetic, a nutrient or a polymeric monomer soluble in water. The hydrophilic fluid may contain a water-soluble surfactant such as PVA (polyvinyl alcohol) to stabilize the interface.

 The lipophilic fluid may use a known fluid containing an oil component, and may include polymerizable monomers and polymeric materials dissolved in an organic solvent, for example, ethoxylated trimethylolpropane triacrylate (ETPTA) containing an initiator, Polymerizable monomers such as EGPEA (ethylene glycol phenyl ether acrylate) or HDDA (1,6-hexanediol diacrylate), PLA (poly (lactic acid)), PLGA (poly (lactic-co- glycolic acid) carprolactone), PS (poly styrene), PMMA (poly (methyl methacrylate)) or Ethyl cellulose.

Figure 5 is a schematic diagram showing fluid flowing through each channel. 5, hydrophilic fluids W1 and W2 and lipophilic fluids O1 and O2 may be used for the two channels.

The hydrophilic fluids W1 and W2 flow into the central region of the channel without contacting the inner wall of the hydrophobic channel. The hydrophilic fluids W1 and W2 exhibit intermittent fluid flow.

The lipophilic fluids (O1, O2) flow around the channel inner wall and move around the hydrophilic fluid.

The hydrophilic fluid and the lipophilic fluid may be simultaneously injected into all of the plurality of channels.

The hydrophilic fluid and the lipophilic fluid may be simultaneously injected into any one of the plurality of channels, and only one lipophilic fluid may be injected into any one of the plurality of channels. In this case, only a lipophilic fluid is injected into one channel, so that the shell thickness of the double droplet can be increased.

A second hydrophilic fluid may be injected through the space (B) between the outer surface of the injection capillary and the outer capillary to form a continuous phase. The second hydrophilic fluid may be water, preferably comprising a surfactant.

The collection capillary 20 is arranged coaxially with the injection capillary 10 and has an orifice having a diameter similar to the diameter of the orifice of the injection capillary or having a large diameter, and the diameter of the tube increases toward the downstream side. The collection capillary 20 can be made of a cylindrical glass tube and collects and discharges the generated double droplets.

The outer capillary tube 30 surrounds and supports the injection capillary tube 10 and the collection capillary tube 20. A space is formed at a predetermined distance from the inlet-side outer surface of the injection capillary tube 30 to inject fluid through the space B, can do. As shown in Fig. 3, the continuous phase water is injected through the space B. The outer capillary tube may have a plate-like rectangular shape having a predetermined thickness.  

In another aspect, the present invention relates to a method of manufacturing a dual droplet. The dual droplet of the present invention can use the apparatus of Figs. 2 to 4 described above, but is not necessarily limited thereto.

The present invention includes an injection step and an emulsification step.

The injecting step is a step of simultaneously injecting a hydrophilic fluid and a lipophilic fluid into each of the plurality of channels formed in the injection capillary.

The plurality of channels may be 2 to 8 channels, preferably 2 to 4 channels.

The injecting step may include injecting a hydrophilic fluid into one of the inner capillaries (15, 16, 17, 18) formed at the inlet of each of the plurality of channels and the inner space (A) between the inner capillary and the inner capillary of the injection capillary, On the other hand, a lipophilic fluid can be injected.

When two or more inner capillaries are formed at the entrance of each of the plurality of channels, a hydrophilic fluid may be injected into one or more inner capillaries, and a lipophilic fluid may be injected into any one or more inner capillaries.

Wherein when the hydrophilic fluid and the lipophilic fluid are simultaneously injected into the respective channels, a hydrophilic fluid flows into the channel center and forms a floating flow in each of the channels, and the lipophilic fluid surrounds the hydrophilic fluid along the channel inner wall Thereby forming a flowing mesophase flow.

That is, when the hydrophilic fluid and the lipophilic fluid are injected at the same time in the present invention, the hydrophilic fluid automatically flows to the center of the channel and the lipophilic fluid flows to the inner wall of the channel due to the characteristics of the hydrophobic inner wall.

In the emulsifying step, the fluids that flow in parallel to the respective channels are dropped into the second hydrophilic fluid from the orifices formed at the ends of the respective channels, and are simultaneously emulsified.

A second hydrophilic fluid may be injected through the space (B) between the outer surface of the injection capillary and the outer capillary to form a continuous phase. The second hydrophilic fluid may be water, preferably water containing a water-soluble surfactant such as polyvinyl alcohol (PVA).

Wherein the emulsifying step comprises forming a double droplet containing a plurality of inner droplets, each of the plurality of inner droplets each having its own thin film formed of an intermediate phase.

A plurality of double droplets having their thin films are formed while being dripped from the end of each channel into a continuous phase by simultaneously injecting a hydrophilic fluid and an oleophilic fluid into each of the plurality of channels, The plurality of inner droplets surrounded by the water on the substrate can maintain a single single droplet structure. Here, a single double droplet structure means that a plurality of double droplets are aggregated or brought into contact with each other to show a single physical motion pattern.

More specifically, the respective inward fl ow flows flowing in the respective channels and the respective intermediate fl ow flows surrounding the fl ow channels are dripped, so that the interfacial fl ow fl ow flows are surrounded by the intermediate fl ow flow to generate internal droplets for each channel, Liquid) is brought into contact with each other and emulsified by continuous water.

FIG. 6 shows a double droplet generated when using an injection capillary having two channels, and FIG. 7 shows a double droplet generated when using an injection capillary having three to four channels.

Referring to FIG. 6, the resulting double droplet 200 includes a plurality of inner droplets 210, 220; A thin film (230, 240) surrounding each of the plurality of inner droplets; And a contact interface 250 formed between the plurality of inner droplets.

The dual droplet 200 exhibits a non-spherical dumbbell shape. A lipophilic fluid is filled in the space between the contact interface of the double droplet (200) and the internal droplets to form a connection (A). The connecting portion (A) enhances the structural stability of the double droplet. Referring to FIG. 7, when the injection capillary has three channels, the double droplet includes three internal droplets, and when four channels include four internal droplets. The dual droplet structure having the plurality of inner droplets maintains its shape with a structure capable of minimizing the interfacial energy between the inner droplets. The four inner droplets form a non-spherical tetrahedral double droplet.

Referring again to FIG. 6, the film surrounding the double droplet has an ultra-thin film thickness. However, in the case of the present invention, a thin film surrounding each inner droplet forms a double droplet film. However, in the present invention, a thin film surrounding each of the inner droplets forms a double droplet film. That is, in the present invention, the thin films 230 and 240 surrounding the droplet and the connecting portion A form a thin film of the double droplet 200. Therefore, unlike FIG. 1, the double droplet of the present invention does not have a separate thick film covering the entire double droplet, and thus can be manufactured as an ultra thin film.

The volume ratio of the interlayer (formed of a thin film, lipophilic fluid) and the internal droplet (formed of a hydrophilic fluid) surrounding the internal droplet may be 0.05 to 0.08.

The diameter of the internal droplet and the thickness of the thin film may be in the range of 1: 0.002 to 0.04, preferably 1: 0.004 to 0.015.

In this method, the volume ratio of the hydrophilic fluid and the lipophilic fluid injected into the channel can be maintained in the range of 0.2 to 5, preferably 1 to 2. In the above range, the internal droplets having the thickness range of the thin film can be formed at a high ratio.

The method may control the relative flow rate of the fluid injected into each channel to adjust the size of a plurality of internal droplets formed in the dual droplet. The size of the internal droplet formed from the channel in which the relatively large flow rate is injected is larger than the size of the internal droplet formed in the other channel.

For example, as shown in FIGS. 2 and 5, when a double droplet is generated by an injection capillary having two channels, the relative diameter ratio D1 / D2 between two internal droplets located inside the double droplet is expressed by the following mathematical expression Can be expressed by Equation (1).

[Equation 1]

D1 / D2 = {(Qi1 + Qm1) / (Qi2 + Qm2)} ^1/3

Qi1 is the flow rate of the hydrophilic fluid forming the internal fl ow flow in any one of the two channels (channel 1), Qm1 is the flow rate of the oleophilic fluid forming the intermediate phase flow in channel 1,

Qi2 is the flow rate of the hydrophilic fluid forming the inward flow at the channel (channel 2), not the channel 1 of the two channels, Qm2 is the flow rate of the oleophilic fluid forming the middle phase flow at channel 2,

D1 is the diameter of the inner droplet generated in channel 1, and D2 is the diameter of the inner droplet generated in channel 2.

The lipophilic fluid injected into the plurality of channels may use the same or different kinds of lipophilic fluid. When different lipophilic fluids are used, the material of the thin film surrounding each internal droplet can be formed differently.

The lipophilic fluids injected into the plurality of channels may be injected at the same flow rate or injected at different flow rates for each channel to form the plurality of thin films forming the inner droplets at the same or different thicknesses.

The hydrophilic fluid and the second hydrophilic fluid may be the same or different types of hydrophilic fluid, and the hydrophilic fluid injected into each channel may contain the same or different materials.

The oleophilic fluid may use a known fluid containing an oil component and may include all hydrophobic polymers that are solid at room temperature. For example, an ethoxylated trimethylolpropane triacrylate (ETPTA) containing an initiator, an ethylene glycol (EGPEA) poly (lactic acid), PLGA (poly (lactic-co-glycolic acid), poly (ε-carprolactone)) and polymerizable monomers such as poly (ether acrylate) or HDDA (1,6-hexanediol diacrylate) , Poly (styrene), PMMA (poly (methyl methacrylate)) or ethyl cellulose dissolved in an organic solvent.

The hydrophilic fluid injected into the channel may comprise a drug, a cosmetic, a nutrient or a polymeric monomer soluble in water.

The method may include irradiating the double droplet generated in the emulsifying step with ultraviolet light to photo-cure the double droplet. For example, the ultraviolet ray irradiation may be performed for 0.1 to 10 seconds at a brightness of 1 to 100 mW / cm 2.

The lipophilic fluid may contain a surfactant to maintain a double droplet structure having a plurality of inner droplets. The surfactant may be contained in an amount of 0.01 to 10 wt%, preferably 0.05 to 8 wt%. Examples of the surfactant include hydrophilic liphophilic balance (HLB) values of 2 to 6, such as SPAN 80 (Sorbitan monooleate), ABIL EM90, and PGPR (polyglycerol polyricinoleate)

The method includes allowing the double droplet generated in the emulsifying step to stand for a predetermined time to combine a plurality of droplets into a single droplet. Due to the relatively weak lubrication resistance of the contact interface (250) surface formed between the two inner droplets, the lipophilic component is discharged from the contact interface, and as a result, the contact interface disappears, so that the inner droplets approach each other and coalesce occurs. By this combination, the non-spherical double droplet can be restored into a spherical double droplet.

The allowed time may be several tens of seconds to several hours.

Each of the hydrophilic fluids injected into the plurality of channels may include a reactant capable of reacting with each other when the droplets are combined, or a catalyst necessary for the reaction.

The double droplet may contain a product by reaction of the reactants contained in each inner droplet by the coalescence. That is, the reactants can be used as a micro-reactor by mixing different reactants through the double-droplet coalescence. Micro-picoliter volume reactors, and the reaction product can be encapsulated within the dual droplets without additional processing. For example, a drug that forms crystals and precipitates by reaction can be encapsulated using a combination of the double droplets.

The method may include the step of photo-curing the double-droplet film through ultraviolet irradiation on the double droplet after the coalescence. And after the coalescence, evaporating the organic solvent contained in the thin film of the double droplet to solidify the membrane.

In another aspect, the present invention is a method for producing a dual droplet with an injection capillary having a plurality of parallel channels, wherein only one of the plurality of channels is injected with lipophilic oil.

The method includes injecting a fluid into the injection capillary and an emulsion step.

The injecting step simultaneously injects a hydrophilic fluid and a lipophilic fluid into any one of the plurality of channels and injects only a lipophilic fluid into at least one of the plurality of channels.

In the emulsion step, the fluids that flow in parallel to the respective channels are dropped into the second hydrophilic fluid from the orifices formed at the ends of the channels, and are simultaneously emulsified.

The above emulsion step can be referred to the above description.

8 is a schematic view of the case where the injection capillary has two channels, one of the channels is injected with a hydrophilic fluid and the other with a lipophilic fluid, and the other channel is injected with a lipophilic fluid. Referring to FIG. 8, when the kind of the lipophilic fluid to be injected is different, the generated double droplet has one droplet and two different thin films which are separated to surround the droplet.

Also, referring to Examples described later, when there are one or more channels injecting only lipophilic fluid into three or more channels, the thickness of the thin film can be increased by a relatively increased lipophilic oil. In addition, the flow rate of the lipophilic fluid can be increased to increase the thickness of the thin film.

In another aspect, the invention pertains to a dual droplet comprising internal droplets each having its own film. The above-described double droplet can be referred to the description of FIG. 6 described above.

Referring to FIG. 6, the dual droplet 200 includes a plurality of internal droplets 210, 220; A thin film (230, 240) surrounding each of the plurality of inner droplets; And a contact interface 250 formed between the plurality of inner droplets.

The double droplet in Fig. 7 represents a double droplet of tetrahedral structure formed by four channels and consisting of four droplets each having its own thin film.

Each thin film surrounding the inner droplet can form the thin film of the double droplet.

The double droplet may comprise 2 to 8 internal droplets.

The volume ratio of the thin film to the inner droplet is 0.05 to 0.08.

The diameter of the internal droplet and the thickness of the thin film may be in the range of 1: 0.002 to 0.04, preferably 1: 0.004 to 0.015.

The inner liquid may include a hydrophilic drug, a cosmetic, a nutrient or a polymeric monomer.

The thin film may include photo-curable ETPTA, EGPEA, HDDA and a polymer or lipophilic oil soluble in an organic solvent, such as PLA, PLGA, PCL, PS, PMMA, ethyl cellulose or kerosene.

In this case, since the decomposition rates of the respective thin films are different from each other, the internal droplets may sequentially emit the contained material in accordance with the decomposition sequence of the thin film, have.

The thickness of the thin film surrounding each of the plurality of inner droplets may be different from each other. In this case, the time required for complete decomposition of the thin films is different from each other, .

The thin film may contain a surfactant to maintain the double droplet structure of Figs. 6 and 7 for a long time.

The contact interface may be formed of an oleophilic material forming the thin film.

The double droplet may be incorporated into one internal droplet after a predetermined time.

The double droplet may contain a product by reaction of the reactants contained in each inner droplet by the coalescence.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  One

The apparatus of FIG. 2 was used to prepare a double droplet having two internal droplets. In the 10% PVA solution, dyes (red dye of sulforhodamine B and green dye of fluorescein) were mixed and injected through microtubules into each channel. ETPTA monomer, 8% Of a kerosene solution containing a PGPR surfactant, and a chloroform solution containing 20% of PLA, respectively. A continuous phase was formed by injecting 10 wt% of PVA aqueous solution into the B space.

9 shows an optical microscope image showing that a double droplet is generated when the doses of two hydrophilic fluids, two lipophilic fluids and one continuous fluid are 300, 200, and 6000 l / h, respectively, and a generated double droplet Is a confocal microscope image (Fig. 9 (b), (c)). Referring to FIG. 9, it can be seen that two droplets contact and a single droplet is generated.

Example  2

The procedure of Example 1 was repeated except that the flow rate of each fluid to be injected was changed as follows.

(A) 300, 200, 300, and 200 (a) flow rates of the hydrophilic fluid Qi1, the lipophilic fluid Qm1, the hydrophilic fluid Qi2, and the lipophilic fluid Qm2 in one channel, H, (b) 200, 150, 300 and 200 μl / h, (c) 100, 75, 300 and 200 μl / h, and (d) 50, 35, 300 and 200 μl / h, respectively.

10A to 10D, the relative diameters of the internal droplets according to the injection flow rates a, b, c, and d are indicated by dotted lines in FIG. 10, The curve is shown in Equation (1).

Referring to FIG. 10, when the same flow rate is supplied to each channel, a symmetric internal droplet is formed. However, when the ratio of the flow rate to be injected, that is, (Qi1 + Qm1) / (Qi2 + Qm2) is decreased from 1 to 0.7 and 0.35 b, c, an asymmetric dumbbell is generated as a double droplet. If the ratio is reduced further than 0.17, asymmetric double droplets of different shapes are alternately generated, such as 10d.

Example  3

The ETPTA monomer containing the red dye of Nile red and the silica particles of 500 nm was injected into a channel as a lipophilic fluid in intermediate phase and the ETPTA monomer containing Coumarin 540 green dye and 200 nm silica particles was mixed with the intermediate lipophilic fluid , And the hydrophilic fluid injected into each channel was not mixed with the dye. The double droplets generated in the apparatus were irradiated with UV for 10 seconds in a collecting container to prepare microcapsules having a dual structure. The other conditions were the same as in Example 1.

11A shows an optical microscope image of the encapsulated double droplet generated in Example 3. Fig. 11B to 11E are confocal images obtained by photographing a double droplet, and f and g in FIG. 11 are SEM images of the contact interface.

Referring to FIG. 11, it can be seen that a double droplet of a stable structure can be generated due to photopolymerization, and referring to FIGS. 11 to 11, it can be seen that it is surrounded by two separated green and red thin films, It can be seen that the droplet does not have a separate shell but the thin film surrounding each internal droplet constitutes a double droplet shell. In addition, it can be visually recognized that the volume or thickness of the thin film is very small or thin compared to the diameter or volume of the internal droplet.

Referring to FIGS. 11F and 11G, since 500 nm and 200 nm silica particles are separated from each other at the contact interface, the internal droplets have their own thin films separated from each other, and two thin films are separated even at the contact interface .

Example  4

Chloroform containing 20 wt% of PLA as a lipophilic fluid was injected into each of the two channels through a space, and a dye (sulforhodamine B red dye, fluorescein green dye used) was mixed with 10% PVA aqueous solution And injected into each channel via microtubules. The resulting double droplets were allowed to stand for several minutes without being light-cured. The other conditions were the same as in Example 1.

Figure 12 shows a plurality of internal droplets merged into a single droplet.

FIG. 12A shows that the droplet is changed into a single droplet through the double droplet merging process with the plurality of inner droplets generated. Fig. 12 (b) is an optical microscope photograph taken by time showing that the generated double droplets are incorporated. 12C and 12D are images showing monodispersed double droplets before and after the coalescence, respectively.

Referring to FIG. 12, a plurality of internal droplets generated in the absence of a surfactant or photopolymerization are combined into a spherical double droplet within a few minutes. The green and red images of the internal droplets are represented by the mixed colors of the combined droplets. Also, even when such a plurality of internal droplets are combined, the double droplet can be maintained in a stable shape without being broken.

Example  5

ETPTA monomer (Qm1) containing Nile red red dye and silica particles of 500nm, green dye of Coumarin 540 and ETPTA monomer (Qm2) containing silica particles of 200nm were injected into the channel as lipophilic fluid, , But a hydrophilic fluid (10% PVA aqueous solution) (Qi2) was injected into only one side of the channel. Qi2, Qm1 and Qm2 were injected at a flow rate of 300, 30 and 200 μl / h, respectively, and the continuous phase fluid was injected at 6000 μl / h as in Example 1. The resulting double droplets were photopolymerized.

13 shows the production of the double droplet of Example 5. Fig. 13A and 13B are a schematic diagram for generating a double droplet and an optical microscope image showing that a double droplet is generated. FIG. 13C shows a photopolymerized double droplet, and FIG. 13D is an image showing a hemispherical membrane (membrane) having different colors. Figs. 13 (e) and 13 (f) are SEM images obtained by imaging the boundaries of the separated films and their cross sections.

Referring to FIG. 13, in the present invention, the surface of the droplet can be formed into two separate thin films.

Example  6

As shown in FIG. 3C, the fluid is injected into the apparatus having four channels. All the hydrophilic fluids use 10% PVA aqueous solution. However, the hydrophilic fluid injected into each channel is injected with different dye to divide the internal droplet into a fluorescent color. As the lipophilic fluid, ETPTA monomers were injected equally into all channels.

Figs. 14 (a) to 14 (c) are optical microscope images obtained by photographing the double droplets generated in Example 6. Fig. FIG. 14 (a) shows hydrophilic fluid and lipophilic fluid injected into three channels out of the four channels, FIG. 14 (b) shows that hydrophilic fluid and lipophilic fluid are respectively injected into three channels out of the four channels, And only the lipophilic fluid is injected into the channel, and FIG. 14C shows the case where hydrophilic fluid and lipophilic fluid are injected into all four channels.

As shown in FIG. 14 (b), a single droplet of triangular or tetrahedral structure having a relatively thick shell can be produced by flowing only oil to one channel. As shown in FIG. 14C, four divided inner droplets are combined into one double droplet.

14f to 14f are confocal images showing the double droplets generated in Example 6. Fig. Referring to Figs. 14 to 14 and 14, the droplets represented by red, green, and mixed colors of the double droplet of the present invention are formed into a triangular structure or a tetrahedral structure. Since the lipophilic fluid of each channel blocks the direct contact between the droplets, the core-shell structure can be maintained during the emulsion, and the four parallel flows into the plate-like diamond structure while being dripped into the continuous phase in each channel, It seems to be rapidly converted into a tetrahedral shape to minimize interfacial energy. 14 and 7, the dual droplet of the present invention is produced as a double droplet in which four internal droplets come into contact with each other and exhibit a single behavior, and the thin film surrounding the double droplet is formed of each thin film Respectively.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments.

10: injection capillary 11, 12, 13, 14: channel
15, 16, 17, 18: inner capillary 20: collection capillary
30: outer capillary tube 40:
A, B: Fluid injection space

Claims (39)

A method for producing a dual droplet with an injection capillary having a plurality of parallel channels,
Simultaneously injecting a hydrophilic fluid and a lipophilic fluid into each of the plurality of channels; And
Wherein the fluids flowing in parallel to the respective channels are simultaneously emulsified while being dropped into the second hydrophilic fluid from an orifice formed at the end of each channel. The method of claim 1, wherein the plurality of channels are two to eight channels. The method according to claim 1, wherein the simultaneously injecting step includes injecting a hydrophilic fluid into either the inner capillary tube formed at the inlet of each of the plurality of channels and the inner space (A) between the inner capillary tube and the inner capillary tube, Characterized in that a lipophilic fluid is injected into the droplet. [2] The method of claim 1, wherein, when the at least two inner capillaries are formed at the inlet of each of the plurality of channels, the hydrophilic fluid is injected into the at least one inner capillary, Wherein the fluid is injected. The method of claim 1, wherein when the hydrophilic fluid and the lipophilic fluid are simultaneously injected into the respective channels, the hydrophilic fluid flows into the channel center to form a flotation flow, and the lipophilic fluid forms the hydrophilic fluid along the channel inner wall To form a surrounding, intermediate stream flow. The method of claim 1, wherein the emulsifying step comprises forming a double droplet containing a plurality of inner droplets, wherein each of the plurality of inner droplets comprises a thin film of the inner droplet itself formed as a middle phase . 7. The method of claim 6, further comprising the steps of: dropping a plurality of internal fl ow streams containing a plurality of internal droplets and a plurality of intermediate fl ow streams flowing therethrough, the plurality of internal droplets generated by the inter- Wherein the first and second droplets are formed while being in contact with each other. 7. The method according to claim 6, wherein the volume ratio of the thin film to the inner droplet is 0.02 to 0.1. The method according to claim 6, wherein the diameter of the inner droplet and the thickness of the thin film have a range of 1: 0.008 to 0.014. 2. The method of claim 1, wherein the volume ratio of the hydrophilic fluid and the lipophilic fluid injected into the channels is in the range of 1.3 to 2. The method of claim 1, wherein the method controls the relative flow rate of fluid injected into each channel to adjust the size of a plurality of internal droplets formed within the dual droplet. 12. The method of claim 11, wherein, in the case of producing a double droplet with an injection capillary having two channels, a relative diameter ratio (D1 / D2) between two internal droplets positioned inside the double droplet is expressed by the following equation Wherein the first droplet is a droplet.
[Equation 1]
D1 / D2 = {(Qi1 + Qm1) / (Qi2 + Qm2)} ^1/3
Qi1 is the flow rate of the hydrophilic fluid forming the internal fl ow flow in any one of the two channels (channel 1), Qm1 is the flow rate of the oleophilic fluid forming the intermediate phase flow in channel 1,
Qi2 is the flow rate of the hydrophilic fluid forming the inward flow at the channel (channel 2), not the channel 1 of the two channels, Qm2 is the flow rate of the oleophilic fluid forming the middle phase flow at channel 2,
D1 is the diameter of the inner droplet generated in channel 1, and D2 is the diameter of the inner droplet generated in channel 2. The method of claim 1, wherein the lipophilic fluid injected into the plurality of channels can use the same or different types of lipophilic fluid. The method of claim 1, wherein the lipophilic fluid injected into the plurality of channels is injected at the same flow rate or injected at a different flow rate for each channel to form a plurality of thin films forming the inner droplets at the same or different thicknesses By weight. The method of claim 1, wherein the hydrophilic fluid and the second hydrophilic fluid are the same or different types of hydrophilic fluid. The dual droplet manufacturing method according to claim 1, wherein the lipophilic fluid injected into the plurality of channels is at least one selected from the group consisting of ETPTA, EGPEA, HDDA, PLA, PLGA, PCL, PS, PMMA and ethyl cellulose . The method of claim 1, wherein the hydrophilic fluid injected into the channel comprises a drug, cosmetic, nutrient or polymeric monomer that is soluble in water. The method according to claim 1, wherein the method comprises irradiating the double droplet generated in the emulsifying step with ultraviolet light to photo-cure the double droplet. The method of claim 1, wherein the oleophilic fluid comprises a surfactant to maintain a double droplet structure with a plurality of inner droplets. The method of claim 1, wherein the dual droplet generated in the emulsifying step is allowed to stand for a predetermined time to combine a plurality of droplets into a single droplet. 21. The method of claim 20, wherein the leaving time is from a few seconds to several hours. 21. The method of claim 20, wherein each hydrophilic fluid injected into the plurality of channels comprises a reactant capable of reacting with each other when the droplets are combined, or a catalyst required for the reaction. 21. The method of claim 20, wherein the method comprises irradiating ultraviolet light to the double droplet after it is incorporated into the single droplet and photo-curing the double droplet. A method for producing a dual droplet with an injection capillary having a plurality of parallel channels,
Injecting a fluid into the injection capillary, wherein the step of injecting a hydrophilic fluid and an oleophilic fluid simultaneously into at least one of the plurality of channels and injecting only a lipophilic fluid into at least one of the plurality of channels ; And
Wherein the fluids flowing in parallel to the respective channels are simultaneously emulsified while being dropped into the second hydrophilic fluid from an orifice formed at the end of each channel. 25. The method of claim 24, wherein if the injection capillary has two channels and the types of lipophilic fluids to be injected are different, the resulting double droplet may contain one droplet and two distinct thin films surrounding the droplet Wherein the first droplet is formed by a droplet ejection method. 25. The method of claim 24, wherein the method further comprises increasing the channel for injecting only the lipophilic fluid into the plurality of channels or increasing the film thickness of the resulting double droplet by increasing the flow rate of the lipophilic fluid. Way. A plurality of inner droplets;
A thin film surrounding each of the plurality of inner droplets; And
A dual droplet comprising a contact interface formed between a plurality of inner droplets. 28. The dual droplet of claim 27, wherein each thin film surrounding the inner droplet forms the thin film of the double droplet. 28. The dual droplet of claim 27, wherein the double droplet comprises 2 to 8 internal droplets. 28. The dual droplet as claimed in claim 27, wherein the volume ratio of the thin film to the inner droplet is 0.05 to 0.08. 28. The dual droplet of claim 27, wherein the diameter of the inner droplet and the thickness of the thin film are in the range of 1: 0.008 to 0.014. 28. The dual droplet of claim 27, wherein the inner droplet comprises a hydrophilic drug, cosmetic, nutrient or polymeric monomer. 28. The dual droplet as claimed in claim 27, wherein the thin film is at least one selected from the group consisting of ETPTA, EGPEA, HDDA, PLA, PLGA, PCL, PS, PMMA and ethyl cellulose. 28. The method of claim 27, wherein the material forming the thin film surrounding each of the plurality of inner droplets is a different dual droplet, the double droplet having different rates of decomposition of the thin film surrounding each droplet, Containing material. ≪ / RTI > 28. The method of claim 27, wherein the thin film surrounding each of the plurality of inner droplets has a different thickness, wherein the thin film surrounding the respective droplets has a different decomposition rate, Of the first droplet. 28. The dual droplet of claim 27, wherein the thin film comprises a surfactant. 28. The dual droplet of claim 27, wherein the contact interface comprises a material that forms the thin film. 28. The dual droplet of claim 27, wherein the dual droplet is a plurality of internal droplets merged into one internal droplet after a predetermined time. 39. The dual droplet of claim 38, wherein the double droplet contains a product by reaction of reactants contained in each inner droplet by the coalescent.

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