KR101733856B1 - Micro Capsule with selective permeability and Method of preparing the same - Google Patents

Abstract

The present invention relates to a method of forming uniform pores of a desired size on a shell using a polymer which is phase-separated and a method of producing microcapsules by the method.
The present invention can form pores uniformly in the shell and can be controlled in size by utilizing the phase separation property between the soluble polymer dispersed in the shell of the thin film and the insoluble polymer.
The microcapsule of the present invention can be used as a drug delivery system or a micro-reactor because the microcapsules are uniform and have pores capable of size control.

Description

TECHNICAL FIELD [0001] The present invention relates to a microcapsule having selective permeability and a method for preparing the microcapsule.

The present invention relates to a method of forming pores in a microcapsule, and more particularly, to a method of forming uniform pores of a desired size in a shell using a polymer that is phase-separated and a method of producing microcapsules .

Microcapsules are not only very efficient in delivering active ingredients, such as pigments, drugs, cells, to specific locations, but also can stably differentiate or store these active ingredients.

Various methods for making such microcapsules have been proposed in the literature. Emulsion drops can be used as a template for capsule manufacturing and form a shell using particle adsorption or interfacial polymerization at the interface to store the internal active material. For example by dispersing the hydrophobic liquid droplets in an aqueous medium containing melamine formaldehyde pre-condensate and reducing the pH of the aqueous medium to produce an impermeable aminoplast resin surrounding the hydrophobic liquid as a shell, It is known to encapsulate liquids.

Recently, double-emulsion drops have been used as a template for producing microcapsules of core-shell structure. Japanese Patent Laid-Open No. 10-965839 discloses a method for producing a polymer capsule using a double droplet.

In order to utilize the microcapsule for various purposes such as a drug delivery system and a microreactor, there is a demand for a technique for storing a substance in a stable state, or for selectively flowing and flowing a substance. There have been attempts to form pores in capsules for this purpose, but until now there has been no technique to control pore size, uniformity, pore and membrane stability.

SUMMARY OF THE INVENTION The present invention provides a method of forming pores in capsules that are uniform and size controllable.

The present invention provides a microcapsule capable of selective permeation or release by controlling the thickness and pore size of a membrane.

The present invention provides a microcapsule which can be used for a drug delivery system or a micro-reactor.

In one aspect,

A second fluid containing two or more different kinds of polymers that are phase separated into an intermediate phase and an organic solvent, and a hydrophilic third fluid containing a surfactant in a continuous phase, ; And

Solidifying the droplet to form a microcapsule of a core-shell structure; And

Wherein the microcapsule is a polymer which is dissolved or decomposed by the solvent or the solution, and the pores are formed in the shell by introducing the microcapsule into a specific solvent or solution, And the pores are formed in the microcapsules formed by selectively removing the polymer dissolved or decomposed.

In another aspect,

A core containing a storage material; And

Wherein the pores are formed by microcapsules formed by selectively removing a soluble polymer or a degradable polymer that is dissolved or decomposed by a specific solvent or solution among two or more different types of polymers that are phase-separated It is related.

According to the present invention, pores having uniform size and controllable in size can be formed on a shell by using the phase separation characteristics of a soluble polymer or a degradable polymer dispersed in a shell of a thin film.

The microcapsule of the present invention can be used as a drug delivery system or a micro-reactor because the microcapsules are uniform and have pores capable of size control.

FIG. 1 shows a conceptual diagram and a manufacturing process of a microcapsule, which is an embodiment of the present invention.
2 shows a conceptual diagram and a manufacturing process of a microcapsule according to another embodiment of the present invention.
Figures 3 and 4 show the microfluidic device used as one device for forming dual droplets.
5 is an SEM photograph of the microcapsules prepared in Example 1. Fig.
6 shows the pore size and the number density of pores according to the PLA content ratios on the basis of Examples 1 and 3.
7 is an SEM photograph of the microcapsules prepared in Example 1. Fig.
Figs. 8 and 9 are images of the results of Experiment 1 and Experiment 2, respectively.

The present invention relates to a microcapsule having uniform permeability by forming uniform pores of a desired size on a shell using a polymer which is phase-separated, and a method for producing the same. Embodiments of the present invention will be described in detail.

1 shows a conceptual diagram and a manufacturing process of the microcapsule of the present invention. Referring to Figure 1, the microcapsules of the present invention comprise a core 10 and a shell 20 surrounding it.

The core 10 may be a hydrophilic droplet.

The droplets forming the core 10 may comprise water and a storage material that is dissolved or dispersed in the water. On the other hand, water in the droplets forming the core may be removed later so that only the storage material remains in the core.

The liquid forming the core 10 may include a water-soluble surfactant such as polyvinyl alcohol (PVA) to stabilize the interface.

The storage material can be any material that is soluble or dispersible in water. For example, the storage material may be a water-soluble drug, a water-soluble polymer, or a water-soluble surfactant. More particularly, the storage material may be a drug, cosmetic, nutrient or cell.

In addition, colloidal materials such as particles and droplets dispersed in water can be used without limitation as the storage material.

For example, the metal particles may be dispersed in water in colloidal form with the storage material. More specifically, the storage material may be magnetic nanoparticles, in which case the capsules comprising the magnetic nanoparticles may react to external magnetic forces. On the other hand, the magnetic nanoparticles may be mixed with a lipophilic fluid and injected. In this case, the magnetic nanoparticles may have a lipophilic property and are dispersed in the shell.

The shell 20 surrounds the core and the pores 30 are uniformly formed.

The pores 30 are formed by selectively removing the soluble or degradable polymer 22 for a specific solvent out of two or more different kinds of polymers that are phase-separated. As a result, the microcapsule finally encapsulates the core in which the regularly formed pores of the insoluble or non-degradable polymer 21 are formed.

Wherein one of the two or more kinds of polymers is a polymer dissolving or decomposing in a specific solvent or solution and the other is an insoluble polymer not dissolving. Furthermore, when the polymer is injected into a specific solvent or a solution, the polymer can be used as the soluble polymer or the degradable polymer when any one of the two polymers dissolves or decomposes remarkably faster than the other. A method of uniformly forming the pores in the shell will be described later.

The microcapsules may range in size from 10 to 1000 mu m, preferably from 10 to 200 mu m.

The pore may be in the range of 1 to 100 nm, preferably 1 to 10 nm when the product of the interaction parameter value and the polymer molecular weight is less than 2. When the product of the interaction parameter value and the polymer molecular weight is 2 or more, 10 mu m, preferably 0.1 to 1.0 mu m.

The thickness of the shell may range from 20 to 5000 nm, preferably from 20 to 500 nm.

In another aspect, the present invention relates to a method of forming pores in the microcapsules.

The method includes forming a dual droplet, forming a microcapsule, and forming pores.

The double droplet is a w / o / w (water / oil / water) structure.

The step of forming the double droplet comprises the steps of injecting a hydrophilic first fluid containing a storage material into the inner phase and injecting a lipophilic second fluid containing two or more different kinds of polymers and organic solvents that are phase separated into an intermediate phase , A hydrophilic third fluid containing a surfactant is injected into the continuous phase to form a double droplet.

The double droplets can be prepared by a variety of known methods. For example, droplets can be formed through a microfluidic device or a bulk emulsion production method.

3 and 4 show a microfluidic device used as one device for forming droplets. Further, the droplet can also be formed by a bulk emulsification method in which a single droplet in water / oil phase is formed through the first bulk emulsification and then continuously emulsified (second bulk emulsification) to the second hydrophilic fluid continuously.

The first and third fluid may use a hydrophilic fluid, and the second fluid may use a lipophilic fluid, and vice versa.

The hydrophilic first fluid may include a storage material to form an internal phase, and a material in which a storage material is dissolved in water may be used. At this time, a surfactant may be included if necessary for interfacial stabilization.

The second fluid is a lipophilic mixed liquid containing two or more different kinds of polymers which are phase-separated, and forms an intermediate phase. At this time, a surfactant may be included if necessary for interfacial stabilization.

The present invention can use water, preferably a surfactant-containing water (third fluid), in a continuous phase.

3, the dual droplet forming apparatus of the w / o / w (water / oil / water) structure includes an injection capillary 210, a collection capillary 220 and an outer capillary 230. The surface of the injection capillary 210 may exhibit hydrophobicity. The surface of the collection capillary 220 may exhibit hydrophilicity. A second fluid (lipophilic fluid) and a third fluid (hydrophilic fluid) interface 240 are formed between the injection capillary and the collection capillary, and a first fluid, a second fluid, and a third fluid A hole 241 through which the droplet can pass is generated.

In the present invention, the first fluid is injected into the injection capillary 210 and the second fluid flows into the gap B between the outer capillary 230 and the injection capillary 210. Also, a third fluid is injected into the outer capillary tube 230 and the collection capillary tube gap C at the opposite side of the first fluid or second fluid.

The first fluid, the second fluid, and the third fluid meet each other to form an interface (240). At the same time, the first fluid is surrounded by the second fluid while flowing through the holes (241) W / o / w double droplets are formed.

Fig. 4 is an example of another apparatus capable of producing a double droplet, which is a mold of a microcapsule of the present invention. Referring to FIG. 4, the dual droplet forming apparatus includes an injection capillary 310, a collection capillary 320, and an outer capillary 330. And an inner capillary 340 inside the injection capillary. The inner wall of the injection capillary may exhibit hydrophobicity.

In the present invention, the first fluid is injected into the inner capillary (340) and the second fluid is injected into the space (B) between the injection capillary (310) and the inner capillary (340). The third fluid is injected into the gap C between the injection capillary 310 and the outer capillary 330 in a continuous phase.

In other words, the intermittent first fluid flows through the center of the injection capillary 310, and the second fluid flows through the inner wall of the injection capillary 310. In other words, And flows around the first fluid. The first fluid and the second fluid are dropped from the orifice formed at the end of the injection capillary 310 into the third fluid to form a w / o / w emulsion.

The core-shell type microcapsules can be formed by solidifying the double droplets.

The droplet solidifying step is a step of phase-separating the polymer by evaporating the organic solvent. More specifically, when the organic solvent is evaporated from the formed double droplet intermediate phase, phase separation of two or more kinds of polymers occurs, and finally a solidified capsule film is formed. For example, the evaporation of the solvent (such as toluene) can be carried out at a temperature of 35 to 45 DEG C for 60 to 120 minutes. 3, a large amount of double droplets are collected in a collecting container such as a chalet containing a collection solution having the same inner and / or osmotic pressure on the downstream side of the collecting capillary, and the collected droplets are placed in an oven at that temperature to evaporate the volatile solvent To obtain solidified microcapsules dispersed in an aqueous solution.

The phase-separable polymer may be a known polymer.

The soluble polymer may be any polymer capable of dissolving in a specific solvent or condition. For example, polylactic acid (PLA), polyglycolic acid (PGA), poly (D, L-lactic-co-glycolic acid), PLGA, But is not limited to, any polymer capable of dissolving under specific conditions, including, but not limited to, PCL, poly (valerolactone), poly (hydroxybutyrate), and poly (hydroxyvalerate).

The insoluble polymer may be, for example, polystyrene (PS), polymethyl methacrylate (PMMA), and ethyl cellulose, but is not limited thereto.

In the step of forming pores in the shell, the microcapsules are put into a specific solvent or solution to dissolve and remove the soluble polymer.

The specific solvent or solution may be appropriately selected depending on the kind of the polymer, and only one kind of solvent and plural kinds of solvent mixtures can be used. For example, when the soluble polymer is polylactic acid, a solution in which 0.5 molar sodium hydroxide is dissolved in a 4 to 6 mixture of methanol and water may be used.

1, when a thin film is formed in the step of preparing a double droplet by an organic mixed solution in which two or more kinds of polymers capable of phase separation are dissolved (FIG. 1 (a)) and the organic solvent is evaporated, the two polymers are phase- And solidified at the same time (FIG. 1 (b)).

Referring to FIG. 1 (c), when the microcapsules are dispersed in a specific solvent or solution, the soluble polymer is selectively removed to form pores 30.

The pore size can be controlled by the polymer content.

The present invention can control the pore size by controlling the phase separation characteristics between the two kinds of polymers.

The phase separation characteristic may be determined by an interaction parameter between the phase-separated polymers, a molecular weight, and a thickness of the polymer membrane.

The interaction parameter is a variable indicating the affinity between two kinds of polymers. When the Flory-Huggins theory is used, the interaction parameter (χ) is a function of the Gibbs energy, enthalpy, It is a variable indicating the contribution of entropy. For example, the interaction parameter value of polystyrene and polylactic acid is about 0.2 at 40 ° C.

Generally, when the interaction parameter value and the molecular weight are large, for example, when the product of the interaction parameter value and the molecular weight of the polymer is 2 or more, the affinity between the polymers is low, so that macrophase separation phenomenon occurs. However, as shown in FIG. 1 (b), when the thickness of the shell is very thin in nanosize, macrophase separation does not proceed and local phase separation appears. Further, the phase separation phenomenon of the present invention (when both the soluble polymer and the non-soluble polymer are lipophilic fluids), when the soluble polymer is more hydrophilic than the non-soluble polymer, the structure of the soluble polymer / insoluble polymer / It is phase separated. In this case, removal of the soluble polymer can result in uniform formation of relatively large pores on the shell surface (c in Fig. 1).

When the product of the interaction parameter value and the molecular weight of the polymer is 2 or more, pores of 0.1 to 10 mu m, preferably 0.1 to 1.0 mu m, can be formed.

Referring to FIG. 2, it is shown that the thin film and pores are formed when the product of the interaction parameter and the molecular weight is less than 2. Fig. 2 (a) shows that an organic mixed solution in which two or more kinds of polymers are dissolved as shown in Fig. 1 (a) forms a thin film in the step of producing a double droplet. FIG. 2 (b) shows that since the affinity between the polymers is high, the homogeneous mixing of the polymers is achieved throughout the shell, while the degree of phase separation is remarkably decreased. When the soluble polymer is selectively removed, nano-sized very fine pores can be uniformly formed throughout the shell (FIG. 2 (c)).

That is, when the product of the interaction parameter value and the polymer molecular weight is less than 2, the phase separation between the polymers can be suppressed and homogeneous mixing can be induced. In this case, pores of 1 to 100 nm, preferably 1 to 10 nm, can be formed in the shell by the method of the present invention.

As described above, factors affecting the phase separation characteristics include interaction parameters between polymers, molecular weight of the polymer, thickness of the double droplet interlayer, and the like. More specifically, the larger the interaction parameter, the larger the thickness of the double-droplet interlayer, the larger the phase separation occurs, and the effect of the polymer molecular weight is more complex.

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

Microcapsules were prepared using the apparatus of Fig.

A injection tube was filled with 10 wt% polyvinyl alcohol aqueous solution and 9 wt% polystyrene (molecular weight 785, 400) and 1 wt.% Polylactic acid (PLA, molecular weight 15,000) 10 wt% aqueous solution of polyvinyl alcohol was injected to form a continuous phase. The continuous phase solution in which the double droplets were dispersed was collected in the collection container containing the collection solution at the downstream of the collection capillary, and the toluene was evaporated in an oven at 40 DEG C to obtain microcapsules having a shell thickness of about 100 nm.

Then, the microcapsules were placed in a solution of 0.5 molar sodium hydroxide dissolved in a 4 to 6 mixture of methanol and water to decompose and remove the polylactic acid in the microcapsule membrane to obtain microcapsules with pores formed therein.

5 is a scanning electron microscope (SEM) photograph of the microcapsules prepared in Example 1. Fig. Referring to FIG. 5, it can be confirmed that pores having a size of about 0.4 μm are uniformly dispersed on the surface of the shell.

Example  2 to 3

Except that the content ratio of polystyrene (PS): polylactic acid (PLA) injected into the injection tube was adjusted to 7: 3 (Example 2) and 5: 5 (Example 3) Respectively.

6 shows the pore size and the number density of pores according to the PLA content ratios based on Examples 1 to 3.

Referring to FIG. 6, it can be seen that the pore size gradually increases when the PLA content increases from 10 to 50% (PLA: PS = 1 to 5: 9 to 5). However, even when the PLA content is 50%, it is considered that the pore size does not increase sharply because the polymers are phase-separated into PLA / PS / PLA in the ultra-thin shell as described above.

Example  4

Except that a toluene solution in which 9 wt% polymethyl methacrylate (PMMA, molecular weight: 606,000) and 1 wt.% Polylactic acid (PLA, molecular weight: 15,000) were dissolved was injected into the microcapsule .

7 is an SEM photograph of the microcapsules prepared in Example 1. Fig. Referring to FIG. 5, pores are not seen even though they were photographed at the same magnification as in FIG. Unlike Examples 1 to 3, which had a pore size of 0.4 to 0.6 탆, microcapsules of Example 4 had pore sizes of several nanoseconds as shown in the experimental results described later.

Experiment 1

The microcapsules obtained in Example 1 were placed in a solution in which 1 占 퐉 PS (coated with a red dye) and 100 nm PS (coated with green) were dispersed for one day, and observed with a confocal microscope.

Experiment 2

The microcapsules obtained in Example 4 were placed in a solution in which dextran (molecular weight: 20,000) with fluorescein isothiocyanate (FITC) attached and red fluorescent pigment sulfoladin B (molecular weight: 558.67) And then observed with a confocal microscope.

Figs. 8 and 9 are images of the results of Experiment 1 and Experiment 2, respectively. Referring to FIG. 8, PS (coated with red dye) having a size of 1 탆 is present only on the outer surface of the microcapsule, and 100 nm of PS (coated with green) have. Since the average pore size in the microcapsules prepared in Example 1 is 400 nm and the largest size is 710 nm, the 100 nm PS particles are easily dispersed through the membrane while the 1 탆 PS particles remain on the outside.

FIG. 9 shows that a red fluorescent dye having a size of 2 nm is present inside the microcapsule membrane while the green fluorescent dye having a size of about 6.6 nm is present only outside the microcapsule because the capsule can not be permeated. That is, the microcapsules prepared in Example 4 have a pore size ranging from about 2 to about 6.6 nm.

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.

Claims (15)

A second fluid containing two or more different kinds of polymers that are phase separated into an intermediate phase and an organic solvent, and a hydrophilic third fluid containing a surfactant in a continuous phase, ; And
Solidifying the droplet to form a microcapsule of a core-shell structure; And
Wherein the microcapsule is a polymer which is dissolved or decomposed by the solvent or the solution, and the pores are formed in the shell by introducing the microcapsule into a specific solvent or solution, Wherein the polymer to be dissolved or decomposed is selectively removed,
Wherein the pore size of the microcapsules is controlled by controlling the content of the two or more kinds of polymers or controlling the phase separation characteristics between the polymers. The method of claim 1, wherein the droplet solidifying step comprises phase separation of the polymer by evaporating the organic solvent. delete The microcapsule according to claim 1, wherein the phase separation characteristic is determined by at least one of an interaction parameter, a molecular weight and a thickness of the polymer membrane between the phase-separated polymers. How to. The method of claim 1, wherein the thickness of the shell is controlled in the range of 20 to 5000 nm. 5. The method of claim 4, wherein the step of adjusting the product of the interaction parameter value and the molecular weight of the polymer to at least 2 to induce local phase separation within the shell. The method of claim 6, wherein the pore size of the microcapsule is 0.1 to 10 μm. 5. The method of claim 4, wherein the method further comprises controlling the product of the interaction parameter value and the polymer molecular weight to less than 2 to inhibit phase separation and induce homogeneous mixing. The method of claim 8, wherein the pore size of the microcapsule is 1 to 100 nm. The method of claim 1, wherein the solvent or the solution dissolves only the soluble polymer in the two or more kinds of polymers, or dissolves the soluble polymer at a higher rate than the non-soluble polymer. delete delete The method of claim 1, wherein the microcapsules have a size ranging from 10 to 1000 mu m.



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