KR101507408B1 - Apparatus and method for manufacturing microparticles - Google Patents

Abstract

The present invention relates to an apparatus for producing microparticles by filling a water-insoluble polymer solution having a plurality of microwells into a water-insoluble polymer solution, the apparatus comprising: a support for supporting a microwell template; And a pump for injecting a polymer solution into the slot portion so as to be able to pressurize and discharge the polymer solution at a constant pressure, the slot portion being connected to the slot portion and being filled with the polymer solution by discharging the polymer solution into the microwell, .

Description

[0001] APPARATUS AND METHOD FOR MANUFACTURING MICROPARTICLES [0002]

TECHNICAL FIELD The present invention relates to an apparatus and a method for producing microparticles, and more particularly, to an apparatus and a method for manufacturing microparticles for producing microparticles of the same size including physiologically active peptides and chemicals.

It has already become widely known how to manufacture nano- or micro-sized particles and administer them subcutaneously for long-term drug delivery. Although these microparticles are widely and broadly applicable, there are limited products available for clinical use.

One of the reasons for the low clinical efficacy is low loading efficiency, which is mainly caused by loss of most drugs during manufacture. The most common method for producing microparticles is by the emulsion method. When the microparticles are produced by this method, the water-soluble drug in the microparticles is released to the surrounding water before being solidified, resulting in microparticles having low loading efficiency. The emulsion method is difficult to mass-produce and the distribution of micro particle size is very wide. Due to the wide distribution of particle sizes, it is necessary to screen microparticles of suitable size for use in clinical products, which leads to a reduction in production yield.

On the other hand, in order to overcome the technical shortcomings of the emulsion method, a microfabrication technique for producing particles of the same size has been developed. Micro-fabrication techniques have been developed based on lithography, including micro-contact hot-printing (Guan, et al) [US Patent Application Publication 2004/0115279], step and flash imprint lithography (S-FIL) [US Patent Publication 2007/0031505 , A particle replication method in a non-wetting template (PRINT) [US Patent Application Publication No. 2007/0264484], and the like. These methods can produce micro and nanoparticles of uniform size and shape, but they can not be controlled in size or limited in materials used, which limits their application to actual production.

A new method for producing microparticles based on existing lithography methods is disclosed in Korean Patent Publication No. 2010-0075955 entitled "Sol-Gel Phase-Reversible Hydrogel Template and Its Use" and Korean Patent Publication No. 2012-0072463, Microparticles containing an active peptide, a method for producing the same, and a pharmaceutical composition containing the same ", which are different from conventional lithography methods, and are produced by using a water-soluble polymer which is easy to recover microparticles, A template was prepared.

However, in order to manufacture the particles by applying the micro-processing technology proposed in these two patents, a water-insoluble polymer solution containing a physiologically active substance must be efficiently injected into the water-soluble polymer template.

Since the water-soluble polymer template is composed of micro-sized wells, the water-insoluble polymer solution containing the physiologically active substance and the compound is efficiently filled in the microwell, and the formation of the polymer film during the casting is minimized, Can be increased.

The present invention relates to a water-soluble polymer micro-well having a plurality of microwells for filling micro-wells with a solution of water-insoluble polymer in the process of preparing micro-particles, thereby increasing the filling efficiency of microwells and minimizing the formation of polymer membranes An apparatus and a method for manufacturing microparticles.

The present invention relates to an apparatus for preparing a water-soluble polymer micro-well template having a plurality of microwells by filling a water-insoluble polymer solution into micro-particles, the apparatus comprising: a support for supporting the microwell template; A slot part provided on the support part for discharging and filling the polymer solution into the microwell of the microwell template; And a pump connected to the slot part, wherein the slot part pressurizes and injects the polymer solution into the slot part so that the polymer solution can be discharged under a constant pressure.

The slot portion may include: a slot body disposed vertically above the microwell template; An injection port formed at one side of the slot body and connected to the pump by a hose, the injection port through which the polymer solution is injected by the operation of the pump; A space part formed in the slot body to communicate with the injection port and forming a space in which a predetermined volume of the polymer solution injected through the injection port can stay; And an outlet for discharging the polymer solution from the space part, the outlet part being formed at the lower end of the slot part so as to communicate with the space part.

The microparticle manufacturing apparatus further comprises a guide protrusion protruded in the space portion and guiding the polymer solution injected into the space portion through the injection port so as to be uniformly spread in the space portion. .

Also, the slot part is installed to be reciprocally linearly movable along the longitudinal direction of the microwell template.

Further, the present invention discloses a microparticle-producing apparatus that is provided on an upper part of the support part and further includes a pressing part that presses the slot part with a constant pressure to closely contact the microwell template.

Further, the pressing portion may include: a pressing plate positioned above the slot portion; A driving cylinder connected to the pressure plate and the cylinder rod, for moving the pressure plate up and down to press the slot portion; A pressure sensor positioned between the pressure plate and the slot and sensing a pressure applied to the slot; And a control unit electrically connected to the driving cylinder and the pressure sensor and receiving the pressure information from the pressure sensor and controlling the driving cylinder so that the slot unit maintains a constant pressure on the microwell template. .

The microwell template may be fixed to the upper surface of the microwell template. When the microwell template is moved to fill the polymer solution while pressing the microwell template, elasticity may be applied to the microwell template to relieve a pressure change depending on the degree of bending of the microwell template. Disclosed is an apparatus for producing microparticles comprising an elastic support made of a material.

The present invention also provides a method for producing microparticles by filling a water-soluble polymer micro-well template having a plurality of microwells with a water-insoluble polymer solution, the method comprising the steps of: (a) fixing the microwell template to an elastic support; (b) adhering the slot portion to the microwell template by applying a constant pressure thereto; (c) operating the pump to pressurize the polymer solution to a predetermined pressure in the slot portion; (d) filling the microwell of the microwell template with the polymer solution while moving the slot part when the polymer solution injected into the slot part starts to be discharged through the discharge port of the slot part; (e) solidifying the microparticles by removing the non-aqueous solvent from the polymer solution filled in the microwell; And (f) recovering the microparticles solidified from the microwell template.

Also, in the step (b), a pressure sensor is used to sense the pressure applied to the slot part, and a constant pressure is maintained so that the slot part is in close contact with the microwell template .

The pressure applied to the microwell template by the slot portion is preferably 0.1 to 5 atm.

The pressure when the polymer solution is discharged through the outlet of the slot is preferably 0.1 to 1 atm.

According to the apparatus and method for producing microparticles of the present invention, a water-insoluble polymer solution containing a physiologically active substance and a compound is efficiently filled in a microwell, and the formation of a polymer membrane during the casting is minimized to increase the production yield of microparticles .

1 is a perspective view showing an apparatus for producing microparticles according to a preferred embodiment of the present invention.
2 is a perspective view showing the slot portion shown in Fig.
3 is a cross-sectional view taken along line III-III 'of FIG.
4 is a flowchart illustrating a method of manufacturing microparticles according to a preferred embodiment of the present invention.
5 is a photograph showing the shape of the microparticles produced by Example 1 of the microparticle production method according to the present invention.
FIG. 6 is a photograph showing the shape of the microparticles prepared in Example 2 of the microparticle production method according to the present invention. FIG.
FIG. 7 is a photograph showing the shape of the microparticles prepared in Example 3 of the microparticle production method according to the present invention. FIG.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

Microparticles of the same size, including physiologically active peptides and chemicals, are prepared by filling a water-insoluble polymer solution with a microwell template, which is a water-soluble polymer. Here, the microwell template is a thin film in which microwells having a diameter and height of 100 占 퐉 or less are formed in an infinite number of times.

In order to produce such microparticles, a microwell must be filled with a polymer solution dissolved in a highly volatile solvent such as methylene chloride, which is an organic solvent, in a microwell. However, since the organic solvent volatilizes and hinders the filling during filling, There is a limit. In order to solve this problem, a method of applying a constant pressure to the polymer solution was applied to reduce the phenomenon of volatilization reduction.

In addition, the slot for filling the polymer solution should be designed so that there is no gap between the microwell templates. If there is a gap between the microwell template and the slot, the polymer solution flows out between the gap and the leaked polymer solution The polymer membrane is formed. In order to prevent this, the gap between the slot and the microwell template should be minimized to prevent the separation of the microparticles into individual microparticles by connecting the respective microparticles in the step of recovering the microparticles. .

Therefore, in order to solve the two constraints, volatilization of the volatile solvent and reduction of the filling efficiency due to the formation of the polymer membrane, the slot part for microwell filling was designed in the present invention, and the shape of the microparticles after filling was observed under various conditions The manufacturing conditions were set.

FIG. 1 is a perspective view showing an apparatus for producing microparticles according to a preferred embodiment of the present invention, FIG. 2 is a perspective view showing a slot part shown in FIG. 1, and FIG. 3 is a cross- to be.

1 to 3, an apparatus 100 for manufacturing microparticles according to a preferred embodiment of the present invention includes a support 110, a slot 120, a pump 130, and a presser 140 Soluble polymer micro-well template 10 having a plurality of microwells is filled with a water-insoluble polymer solution to prepare microparticles.

The support 110 includes a base 111, a flat support 113 and an elastic support 115 to support the microwell template 10. The base 111 is formed in a rectangular shape, preferably a rectangular shape. The plane support 113 is fixed to the upper surface of the foundation 111 and is made of a rectangular prism having a width smaller than the width of the foundation 111. [ The elastic supporter 115 is formed on the upper surface of the plane support 113 in the form of a thin plate so that the microwell template 10 is attached to the upper surface. The elastic support 115 is made of an elastic material including any one of polydimethylsiloxane, rubber, and Teflon. When the elastic supporter 115 is made of an elastic material, when the slot 120 moves to fill the polymer solution while pressing the microwell template 10, the pressure variation according to the degree of bending of the microwell template 10 is alleviated So that the amount of the polymer solution filled in the microwell can be kept constant.

The slot 120 is provided on the elastic support 115 of the support 110 to discharge and fill the polymer solution into the microwell of the microwell template 10. The slot part 120 is installed to be movable in a reciprocating linear motion along the longitudinal direction of the microwell template 10 by a moving block 118 moving along a rail 117 provided on the base 111.

The slot portion 120 may include a slot body 121, an inlet 123, an outlet 125, a space 127, and a guide protrusion 129.

The slot body 121 is a slot die for filling the microwell, which is vertically disposed on the microwell template 10 to fill the microwell with the polymer solution. The slot body 121 may be integrally formed by assembling two parts made of a metal material, for example, a left slot body 121a and a right slot body 121b with bolts 122. [ The slot body 121 forms an entire portion with a uniform cross section of a rectangle and forms a cross-sectional shape of a polymer solution discharge portion at a lower portion thereof.

The injection port 123 is formed in the shape of a circular hole so as to be connected to the one side of the slot body 121 by the pump 130 and the hose 131. By the operation of the pump 130, And is injected into the body 121.

The discharge port 125 is formed in a slit shape so as to communicate with a space 127 to be described later at a lower end of the slot 120. The polymer solution pressurized in the space 127 is discharged through the discharge port 125 . The outlet 125 is designed to maintain the slit spacing of the outlet 125 in the range of 10 to 500 탆, preferably 10 to 300 탆, in order to prevent the natural solution of the polymer solution due to gravity.

The space 127 is formed in the slot body 121 so as to communicate with the injection port 123 and the discharge port 125 so that a certain volume of the polymer solution injected through the injection port 123 can stay in a pressurized state Thereby forming a space.

The guide protrusion 129 is protruded in the space 127 slightly below the injection port 123 so that the polymer solution injected into the space 127 through the injection port 123 flows in the space 127 It serves as a guide to spread uniformly. The protrusion height of the guide protrusion 129 is preferably smaller than the width of the space 127.

The pump 130 is connected to the injection port 123 of the slot 120 by the hose 131 and operates to pump the polymer solution to the slot 120 by pressing the pump 130 at a constant pressure .

The pressing part 140 is installed on the upper part of the supporting part 110 and presses the slot part 120 at a constant pressure to come into close contact with the microwell template 10 to generate a polymer film in the microwell template 10 And the like.

The pressing portion 140 may include a pressure plate 141, a driving cylinder 143, a pressure sensor 145, and a controller (not shown).

The pressure plate 141 is a rectangular plate member which is positioned at an upper portion of the slot unit 120 and vertically moves up and down so as to be brought into close contact with the microwell template 10 by applying a predetermined pressure to the upper end of the slot unit 120.

The driving cylinder 143 is located on both sides of the slot 120 and is connected to the pressure plate 141 by a cylinder rod and moves up and down the pressure plate 141 to press the slot 120. In this embodiment, the driving cylinder 143 may be a hydraulic cylinder that generates driving force by using oil, or an air cylinder that generates driving force by using air. Preferably, the driving cylinder 143 generates a large pressing force, This easy-to-use hydraulic cylinder is used. The hydraulic cylinder and the air cylinder can be understood by a known technique, and a detailed description thereof will be omitted.

The driving cylinder 143 is installed on the upper portion of the moving block 118 which moves along the rail 117 provided on the base 111 so that the slot 120 is aligned with the longitudinal direction of the microwell template 10 And moves in conjunction with the slot part 120 when moving linearly and reciprocally.

The pressure sensor 145 is disposed between the pressure plate 141 and the slot 120 and senses the pressure applied to the slot 120. Since the pressure sensor 145 can be understood by a known technique, detailed description is omitted.

The control unit is electrically connected to the driving cylinder 143 and the pressure sensor 145 and receives the pressure information from the pressure sensor 145 so that the slot unit 120 maintains a constant pressure on the microwell template 10. [ 143).

A method of manufacturing microparticles according to a preferred embodiment of the present invention includes the steps of filling a water-insoluble polymer micelle template (10) having a plurality of microwells with a solution of a water-insoluble polymer, To solidify the microparticles, and recovering the solidified microparticles from the microwell template (10). Particularly, the present invention proposes a method of manufacturing microparticles which can increase the filling efficiency and minimize the formation of polymer films at the stage of filling the polymer solution into the microwell template 10.

Hereinafter, a method of manufacturing microparticles according to a preferred embodiment of the present invention will be described in detail with reference to FIG.

4, the water-soluble polymer micro-well template 10 having a plurality of microwells is fixed on the upper surface of the elastic support 115 of the support 110 (S10).

Next, a constant pressure (0.1 to 5 atmospheric pressure) is applied to the slot portion 120 (S20), and the slot portion 120 is completely brought into close contact with the microwell template 10 (S30).

Next, the pump 130 is operated in a state in which the slot 120 is pressed against the microwell template 10 (S40), and the water-insoluble polymer solution is injected into the slot 120 at a constant pressure S50).

Next, when the polymer solution injected into the slot part 120 starts to be discharged through the discharge port 125 of the slot part 120 (S60), the slot part 120 is moved in the longitudinal direction of the microwell template 10 The microwell of the microwell template 10 is filled with the polymer solution (S70). At this time, the polymer solution is adjusted to be discharged through the discharge port 125 while being pressurized in the space 127 in the slot part 120 at a constant pressure, for example, 0.1 to 1 atm, preferably 0.1 to 0.5 atm . Since the height of the slot 120 may vary according to the degree of bending of the microwell template 10 while the slot 120 is in close contact with the microwell template 10, The pressure in the microwell template 10 is maintained at a constant pressure by using the pressure sensor 145 that senses the pressure applied to the microwell template 10. Otherwise, there arises a problem that a polymer solution is applied to an area other than the microwell existing in the microwell template 10 to form a polymer film. In addition, in order to continuously perform the filling process, an automatic device can be added to move the filled slot 120 in a short time. In one casting, the polymer solution may not be completely filled in the microwell. Therefore, the same operation is repeated several times, preferably 2 to 10 times, more preferably 3 to 7 times, most preferably 4 to 6 times .

Next, when the casting is completed, the non-aqueous solvent (organic solvent) is removed from the polymer solution filled in the microwell at room temperature or warmed state to solidify the microparticles (S80).

Finally, the microwell template 10 is dissolved in water to dissolve the water-soluble polymer, and the solidified microparticles are recovered from the microwell template 10 by centrifugation or sieving (S90).

Hereinafter, the microparticle production method of the present invention will be described in detail with reference to examples. It should be understood, however, that the following examples are presented for the purpose of promoting understanding of the present invention, and are not to be construed as limiting the scope of the present invention.

Example  One

A microwell template 10 of 14 cm in length and 28 cm in length prepared using polyvinyl alcohol as a water-soluble polymer was completely adhered to the upper surface of the elastic support 115 of the device 100, and then fixed with tape so as not to move during casting. 10 g of poly (lactide-co-glycolide) was dissolved in 40 g of methylene chloride to prepare a 20% poly (lactide-co-glycolide) (PLGA, RG502H, EVONIK) solution. As shown in Table 1 below, the slot 120 was operated so as to apply a pressure of 0.5 atm through the pump 130 while applying a pressure of 0.1 to 5 atm to the microwell template 10. When the polymer solution was observed at the portion where the microwell template 10 and the slot portion 120 contacted, the polymer solution was filled in the microwell while moving the slot portion 120 at a rate of 1 cm / s. When the slot part 120 arrived at the end of the microwell template 10, the process of reversing the advancing direction of the slot part 120 and filling the microwell again under the same conditions was repeated five times. The reason for repeating the process of filling the microwell in this way is that the space in which the methylene chloride, which is an organic solvent used in the polymer solution, volatilizes and can be refilled in the microwell occurs, so that a complete filling can not be obtained It is because.

After completion of the 5 repetitions, the microwell template 10 was dried at room temperature for 1 day and then further dried at 37 캜 for 30 minutes. After completely drying, the microwell template (10) was placed in water and ethanol solution to dissolve the water-soluble polymer, and the microparticles were recovered using a sieve and freeze-dried. The morphology of the microparticles was observed using an electron microscope. FIG. 5 shows the microparticle shape at a slot pressure of 0.1 atm and a polymer solution discharge pressure of 0.5 atm.

In order to measure the production yield of the microparticles, the difference between the weight of the polymer solution before the preparation and the weight of the recovered microparticles was used, and the yields of the products were as follows.

Slot pressure (atmospheric pressure) Polymer solution discharge pressure (atmospheric pressure) yield(%) 0.1 0.5 1.2 One 0.5 4.4 3 0.5 8.9 5 0.5 16.4

Example  2

Except that the slot section 120 was operated so as to apply a pressure of 0.1 to 0.8 atm through the pump 130 while applying a pressure of 2 atm to the microwell template 10 as shown in Table 2 below , The microparticles were prepared in the same manner as described in Example 1 above. 6 shows the microparticle shape when the pressure of the slot part is 2 atm and the discharge pressure of the polymer solution is 0.5 atm.

Slot pressure (atmospheric pressure) Polymer solution discharge pressure (atmospheric pressure) yield(%) 2 0.1 3.2 2 0.2 9.8 2 0.5 14.3 2 0.8 0.5

Example  3

Goserelin acetate was dissolved in purified water to a concentration of 10 mg / ml, and polylactic acid (number average molecular weight of 1,500 daltons) was dissolved in purified water to give a concentration of 30 mg / ml. Each of the above aqueous solutions was mixed at a weight ratio of 1: 1 so as to make up to 6 ml to form precipitates, followed by lyophilization for 24 hours. 10 g of poly (lactide-co-glycolide) was dissolved in 40 g of methylene chloride to prepare a 20% poly (lactide-co-glycolide) (PLGA, RG502H, EVONIK) solution.

The freeze-dried product of goserelin acetate was added to the poly (lactide-co-glycolide) solution to completely dissolve or disperse homogeneously. The microwell template 10 was attached to the upper surface of the elastic supporter 115 of the device 100 and the polymer solution containing goserelin was filled into the microwell at 0.2 atm for the slot 120 and 0.5 atm for the polymer solution. After drying, the microwell template (10) was dissolved in water to collect the microparticles, freeze-dry the microparticles, and examine the shape of the microparticles using an electron microscope. As a result, the microparticle shape as shown in FIG. 7 was observed.

As shown in the above embodiments, when the slot part 120 is filled with a low pressure applied to the microwell template 10, the shape of the microparticles is not perfect and the inside of the particles is not filled. Therefore, when filling was performed by increasing the pressure of the slot part 120 so as to be completely in close contact with the microwell template 10, no polymer film was formed and the shape of the microparticles was kept constant.

While the present invention has been described in connection with certain exemplary embodiments, it will be understood by those skilled in the art that various changes may be made without departing from the scope of the present invention. In addition, the description in parentheses in the description of the claims is intended to prevent obscuration of the description, and the scope of the claims of the claims should be construed to include all the items in parentheses.

100: Microparticle production apparatus
110: Support
111: foundation stand
113: plane support
115: elastic support
120:
121: Slot body
123: inlet
125: Outlet
127:
129: Guide protrusion
130: pump
140:
141: pressure plate
143: drive cylinder
145: Pressure sensor

Claims (11)

An apparatus for producing microparticles by filling a water-insoluble polymer solution with a water-soluble polymer micro-well template having a plurality of microwells,
A support for supporting the microwell template;
A slot part provided on the support part for discharging and filling the polymer solution into the microwell of the microwell template; And
And a pump connected to the slot part, wherein the slot part pressurizes and injects the polymer solution into the slot part so that the polymer solution can be pressurized and discharged at a constant pressure. The apparatus of claim 1,
A slot body disposed vertically above the microwell template;
An injection port formed at one side of the slot body and connected to the pump by a hose, the injection port through which the polymer solution is injected by the operation of the pump;
A space part formed in the slot body to communicate with the injection port and forming a space in which a predetermined volume of the polymer solution injected through the injection port can stay; And
And a discharge port formed at a lower end of the slot to communicate with the space and discharging the polymer solution from the space. The apparatus of claim 2,
And a guide projection protruding from the inside of the space and guiding the polymer solution injected into the space through the injection port so as to be uniformly spread in the space. The method according to claim 1,
Wherein the slot portion is provided so as to be reciprocally linearly movable along the longitudinal direction of the microwell template. 2. The microparticle-producing apparatus according to claim 1,
And a pressing part installed on the upper part of the supporting part to press the slot part with a constant pressure to adhere to the microwell template. 6. The apparatus according to claim 5,
A platen positioned above the slot;
A driving cylinder connected to the pressure plate and the cylinder rod, for moving the pressure plate up and down to press the slot portion;
A pressure sensor positioned between the pressure plate and the slot and sensing a pressure applied to the slot; And
And a control unit electrically connected to the driving cylinder and the pressure sensor and receiving the pressure information from the pressure sensor and controlling the driving cylinder so that the slot unit maintains a constant pressure on the microwell template. 6. The method of claim 5,
The support portion may be made of an elastic material to relieve a pressure change according to the degree of bending of the microwell template when the microwell template is fixed on the upper surface and the slot portion moves to fill the polymer solution while pressing the microwell template And an elastic support formed on the support. A method for producing microparticles by filling a water-insoluble polymer solution with a water-soluble polymer microwell template having a plurality of microwells,
(a) fixing the microwell template to an elastic support;
(b) adhering the slot portion to the microwell template by applying a constant pressure thereto;
(c) operating the pump to pressurize the polymer solution to a predetermined pressure in the slot portion;
(d) filling the microwell of the microwell template with the polymer solution while moving the slot part when the polymer solution injected into the slot part starts to be discharged through the discharge port of the slot part;
(e) solidifying the microparticles by removing the non-aqueous solvent from the polymer solution filled in the microwell; And
(f) collecting the microparticles solidified from the microwell template. 9. The method of claim 8, wherein step (b)
Wherein a pressure is applied to the slot portion to maintain a constant pressure such that the slot portion is in close contact with the microwell template using a pressure sensor that senses a pressure applied to the slot portion. 10. The method of claim 8 or 9, wherein the slotted portion is applied to the microwell template at a pressure of 0.1-5 atm. The microparticle manufacturing method according to claim 8 or 9, wherein the pressure when the polymer solution is discharged through the outlet of the slot portion is 0.1 to 1 atm.

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