KR102431191B1 - Microsphere manufacturing devoce and method of manufacturing microsphere - Google Patents

Abstract

The present invention relates to an apparatus for manufacturing a microsphere. The apparatus for manufacturing a microsphere comprises: a first substrate through which a first inlet through which a first raw material is provided and a second inlet through which a second raw material is provided are formed; and a second substrate in contact with the first substrate. The second substrate comprises: a first main flow passage connected to the first inlet; a plurality of first branch flow passages each connected to the first main flow passage; a second main flow passage connected to the second inlet; a plurality of second branch flow passages each connected to the second main flow passage; and a plurality of merging points in which the first raw material and the second raw material meet to continuously form an emulsion including the first raw material of a continuous phase and the second raw material of a dispersed phase. Accordingly, it is possible to mass-produce microspheres of uniform quality.

Description

MICROSPHERE MANUFACTURING DEVOCE AND METHOD OF MANUFACTURING MICROSPHERE

The present invention relates to an apparatus and method for manufacturing microspheres, and more particularly, to an apparatus and method for manufacturing microspheres for mass production of microspheres of uniform quality.

One of the drug delivery systems currently being actively researched, developed and utilized is the so-called Polymeric Drug-Delivery System (“PDDS”), which contains biodegradable, biocompatible and non-toxic polymers, for example, The use of polylactic acid (PLA)/polyglycolic (PGA) polymers allows for controlled release of a quantity of a therapeutic agent over an extended period of time, in circulating dosages, for both hydrophilic or hydrophobic therapeutics.

These biodegradable polymers can be prepared in the form of microspheres by various known techniques. In the production of these biodegradable polymer microspheres, the most frequently used method is dissolving the biodegradable polymer or the material to be encapsulated with the biodegradable polymer (pharmaceutical or other active agent) in a solvent using a known method, and adding a surfactant thereto. It is dispersed or emulsified in an aqueous solution containing it. The solvent is then removed from the microspheres and dried to obtain the microsphere product. Accordingly, efforts have been made to mass-produce high-quality microspheres at low cost.

Accordingly, the technical problem of the present invention has been conceived in this regard, and an object of the present invention is to provide an apparatus for producing microspheres of high quality with high production efficiency.

Another object of the present invention is to provide a method for producing microspheres for producing high quality microspheres with high production efficiency.

A microsphere manufacturing apparatus according to an embodiment for realizing the object of the present invention is a first substrate through which a first inlet through which a first raw material is provided and a second inlet through which a second raw material is provided, and the first and a second substrate in contact with the substrate. The second substrate includes a first main passage connected to the first inlet, a plurality of first branch passages each connected to the first main passage, and a second main passage connected to the second inlet, each of which is 2 A plurality of second branch passages connected to the main passage, and a plurality of the first raw material and the second raw material meet to continuously form an emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase Includes merge points.

In an embodiment of the present invention, the second substrate may further include a plurality of first fine branch passages, each of which is connected to the first branch passage.

In an embodiment of the present invention, the second substrate may further include a plurality of second fine branch passages, each of which is connected to the second branch passage.

In an embodiment of the present invention, the first fine branch passage may include a first portion and a second portion having a cross-sectional area greater than that of the first portion and connected to the merging point.

In an embodiment of the present invention, the second fine branch passage may include a first portion and a second portion having a cross-sectional area greater than that of the first portion and connected to the merging point.

In an embodiment of the present invention, each of the plurality of third fine branch flow paths connected to the first branch flow path is further included, and the first fine branch flow path, the second fine branch flow path, and the third fine branch flow path are further included. A flow path may be connected to the merging point.

In an embodiment of the present invention, the first raw material flowing through the first fine branching passage and the second raw material flowing in the second fine branching passage may flow in opposite directions.

In an embodiment of the present invention, an outlet for discharging the emulsion to the outside of the second substrate may be formed through the second substrate. The second substrate may further include a discharge passage connected to the merging point and connected to the discharge port.

In an embodiment of the present invention, the first branch passage may have a cross-sectional area smaller than that of the first main passage.

In an embodiment of the present invention, the first main flow path and the first branch flow path may be perpendicular to each other on a plane formed by the second substrate.

In one embodiment of the present invention, angles formed by each of the first branch flow paths with the first main flow path may be the same.

In an embodiment of the present invention, a stepped portion may be formed at a portion where the first main flow path and the first branch flow path are connected.

In one embodiment of the present invention, the apparatus for producing microspheres may further include a third substrate in contact with the second substrate and through which an outlet for discharging the emulsion to the outside is formed. The third substrate includes a plurality of first discharge passages each receiving the emulsion formed on the second substrate from the second substrate, and a main discharge connected to the plurality of first discharge passages and connected to the outlet. Euros may be included.

In one embodiment of the present invention, the first main passage may include a first portion connected to the first inlet and a second portion connected to the first portion. A cross-sectional area of the second portion may be smaller than a cross-sectional area of the first portion.

In an embodiment of the present invention, the first branch flow path may be connected to a portion where the first part and the second part of the first main flow path are connected.

The microsphere manufacturing method according to an embodiment for realizing the object of the present invention is a first inlet, a second inlet, a first main passage connected to the first inlet, each of which is connected to the first main passage A plurality of first branch passages, a second main passage connected to the second inlet, a plurality of second branch passages each connected to the second main passage, and the first raw material and the second raw material meet, continuously An apparatus for making microspheres comprising a plurality of merging points is used to continuously form an emulsion comprising the first raw material of a phase and the second raw material of a dispersed phase. The method for manufacturing the micro-salvage comprises a first and a second raw material supply step of providing a first raw material and a second raw material including a biodegradable polymer, a drug and a solvent to the first inlet and the second inlet, respectively, the first inlet and the first and second raw materials introduced through the second inlet are respectively branched from the first main passage to the plurality of first branch passages, and from the second main passage to the plurality of second branch passages. Including the first branching step to branch to.

In one embodiment of the present invention, the method for producing microspheres further comprises an emulsion forming step in which the branched first raw material and the second raw material meet at the merging point to form an emulsion after the first branching step can

In an embodiment of the present invention, the apparatus for manufacturing microspheres includes a plurality of first fine branch passages each connected to the first branch passage, and a plurality of second fine branch passages each connected to the second branch passage. It may include more Euros. In the microsphere manufacturing method, after the first branching step, the first raw material and the second raw material are respectively branched from the first branching flow path to the first fine branching flow path, and the second branching flow path in the second branching flow path. The method may further include a second branching step of branching into a fine branching passage.

In one embodiment of the present invention, the microsphere manufacturing apparatus may further include a first discharge flow path connected to the plurality of merging points. The microsphere manufacturing method may further include a merging step in which the emulsion formed at the plurality of merging points flows into the first discharge flow path and merges.

In one embodiment of the present invention, the method for preparing microspheres is a solvent extraction and removal step of extracting and removing a solvent from the dispersed phase of the emulsion to form solidified microspheres, and washing to dry the solidified microspheres. and a drying step.

According to embodiments of the present invention, the apparatus for manufacturing microspheres includes a first substrate through which a first inlet through which a first raw material is provided and a second inlet through which a second raw material is provided, and a second substrate in contact with the first substrate includes The second substrate includes a first main passage connected to the first inlet, a plurality of first branch passages each connected to the first main passage, and a second main passage connected to the second inlet, each of which is 2 A plurality of second branch passages connected to the main passage, and a plurality of the first raw material and the second raw material meet to continuously form an emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase Includes merge points. Accordingly, it is possible to mass-produce microspheres of uniform quality.

However, the effects of the present invention are not limited to the above effects, and may be variously expanded without departing from the spirit and scope of the present invention.

1 is a conceptual diagram of a microsphere manufacturing system including a microsphere manufacturing apparatus according to an embodiment of the present invention.
2 is a perspective view of an apparatus for manufacturing microspheres according to an embodiment of the present invention.
3 is a side cross-sectional view for explaining the flow path inside the microsphere manufacturing apparatus of FIG.
FIG. 4 is a view showing a lower surface of a first substrate of the apparatus for manufacturing microspheres of FIG. 2 .
FIG. 5 is a view showing a top surface of a second substrate of the apparatus for manufacturing microspheres of FIG. 2 .
FIG. 6 is a partially enlarged view illustrating in detail the merging points of the microchannels of the second substrate of FIG. 5 .
FIG. 7 is a view showing a top surface of a third substrate of the apparatus for manufacturing microspheres of FIG. 2 .
8 is a flowchart illustrating a method for manufacturing microspheres according to an embodiment of the present invention.
9 is a flowchart illustrating in detail the emulsion forming step of the method for preparing the microspheres of FIG. 8 .
10 is a schematic diagram for explaining a flow formed at a merging point of a microchip.

Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to the drawings.

Since the present invention can have various changes and can have various forms, specific embodiments are illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to the specific disclosed form, it should be understood to include all modifications, equivalents and substitutes included in the spirit and scope of the present invention.

1 is a conceptual diagram of a microsphere manufacturing system including a microsphere manufacturing apparatus according to an embodiment of the present invention.

Referring to FIG. 1 , the microsphere manufacturing system includes a raw material storage unit, an emulsion forming unit 30 , a solvent extraction removing unit 40 , a washing unit 50 , and a drying unit 60 . The raw material storage unit may include a first raw material storage unit 10 and a second raw material storage unit 20 .

The first raw material storage unit 10 may store a first raw material. The first raw material may include purified water and a surfactant. For example, the first raw material may be an aqueous solution in which polyvinyl alcohol (“PVA”) is dissolved as a surfactant in pure water.

The type of the surfactant is not particularly limited, and any biodegradable polymer solution may be used as long as it can help the formation of a dispersed phase of stable droplets in an aqueous phase that is a continuous phase. The surfactant is preferably methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivatives, and mixtures thereof. can be selected from

The second raw material storage unit 20 may store a second raw material. The second raw material is an oil-phase solution, and may include an organic solvent, a biodegradable polymer dissolved therein, and a drug. The organic solvent is a solvent used to dissolve the biodegradable polymer, and may have water-immiscible properties. The type of the organic solvent dissolving the biodegradable polymer is not particularly limited, but preferably dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methyl alcohol, At least one may be selected from the group consisting of ethyl alcohol, propyl alcohol, benzyl alcohol, or a mixed solvent thereof.

The type of the biodegradable polymer is not particularly limited, but polyester may be preferably used, and in particular, polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide) Ride) glucose, polycaprolactone, and mixtures thereof.

The type of the drug is not particularly limited, and for example, a dementia treatment agent; Parkinson's disease treatment; anticancer drugs; antipsychotic drugs such as antianxiety drugs, antidepressants, tranquilizers and psychoneurolytics; Cardiovascular therapeutics such as hyperlipidemia, hypertension, hypotension, antithrombotic, vasodilator and arrhythmia; epilepsy treatment; Gastrointestinal treatment agents such as anti-ulcer agents and the like; rheumatoid treatment; antispasmodics; tuberculosis treatment; muscle relaxants; osteoporosis treatment; erectile dysfunction treatment; styptic; hormonal agents such as sex hormones; diabetes treatment; Antibiotic; antifungal agents; antiviral agents; antipyretic analgesic and anti-inflammatory; autonomic modulators; corticosteroids; diuretic; antidiuretics; painkiller; anesthetic; antihistamines; antiprotozoal; anti-anemia; anti-asthma; anticonvulsants; antidote; antimigraine; antiemetic; anti-Parkinson's drugs; antiepileptic drugs; antiplatelet agents; antitussive expectorant; bronchodilator; cardiac; immunomodulators; protein drugs; gene drugs; and mixtures thereof.

Although not particularly limited among the above-mentioned drugs, preferably donepezil, memantine, rivastigmine, entecavir, lamivudine, rotigotine, ropinirole, bupivacaine, ropivacaine, meroxicam, bupre Norphine, fentanyl, nimodipine, granisetron, triamcinolone, cytarabine, carmustine, tamsoleucine, folmacoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, goserelin, leuprolide, tryptic Torrelin, buserellin, naparelin, deslorrelin, octreotide, fasireotide, lanreotide, vapretide, exenatide, liraglutide, lixisenatide, semaglutide and salts thereof and mixtures thereof.

The emulsion forming unit 30 receives the first raw material and the second raw material from the first raw material storage unit 10 and the second fuel storage unit 20 , and supplies the first raw material and the second raw material. An emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase can be continuously formed. The emulsion forming unit 30 may include a microsphere manufacturing device. The apparatus for producing microspheres may be a microchip that forms the emulsion using microfluidics. (The specific principle of forming microspheres using a microchip will be described later in FIG. 10)

The solvent extraction and removal unit 40 receives and receives the emulsion formed from the emulsion generating unit 30, and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres containing the drug. . The solvent extraction and removal unit 40 may include a tank for accommodating the emulsion, a stirrer for stirring the emulsion, and a heater for heating the emulsion.

Specifically, in the solvent extraction and removal unit 40, when the emulsion is maintained or stirred at a temperature below the boiling point of the organic solvent for a certain time, for example, 2 hours to 48 hours, biodegradation in the form of droplets as a dispersed phase An organic solvent can be extracted from the aqueous polymer solution in a continuous phase. A portion of the organic solvent extracted in the continuous phase may be evaporated from the surface. As the organic solvent is extracted and evaporated from the biodegradable polymer solution in the form of droplets, the dispersed phase in the form of droplets may be solidified to form microspheres. At this time, the emulsion may be flowed or heated to accelerate extraction and evaporation. For example, by forming a fluid flow in the emulsion, the solvent of the second raw material may be extracted, and the extracted solvent may be removed by evaporation. By heating the emulsion above the boiling point of the solvent, it can be removed by vaporizing the solvent. By removing a part of the continuous phase containing the organic solvent extracted from the dispersed phase and supplying a new aqueous solution capable of replacing the removed continuous phase, the organic solvent present in the dispersed phase can be sufficiently extracted and evaporated into the continuous phase. At this time, the fresh aqueous solution may optionally further include a surfactant.

The washing unit 50 may recover and wash the microspheres formed from the solvent extraction and removal unit 40 . A method of recovering and washing the microspheres from the continuous phase containing the microspheres formed from the solvent extraction and removal unit 40 is not particularly limited, and after recovery using a method such as filtration or centrifugation, water is Washing may be performed. Through this, the remaining organic solvent and surfactant (eg, polyvinyl alcohol) can be removed. The washing step may be typically performed using water, and the washing step may be repeated several times.

The drying unit 60 may dry the washed microspheres to obtain a microsphere powder. After the filtration and washing steps, the obtained microspheres can be dried using a conventional drying method to finally obtain a dried microsphere powder. The method for drying the microspheres is not limited. However, the drying method used is not particularly limited, and may be carried out using freeze drying, vacuum drying, or reduced pressure drying method.

Through the drying process of the microspheres, the desired monodisperse biodegradable polymer-based microsphere powder is finally prepared, and then, the obtained microsphere powder is suspended in a suspension and filled in an appropriate container, for example, a disposable syringe, etc. product can be obtained.

2 is a perspective view of an apparatus for manufacturing microspheres according to an embodiment of the present invention. 3 is a side cross-sectional view for explaining the flow path inside the microsphere manufacturing apparatus of FIG. FIG. 4 is a view showing a lower surface of a first substrate of the apparatus for manufacturing microspheres of FIG. 2 . FIG. 5 is a view showing a top surface of a second substrate of the apparatus for manufacturing microspheres of FIG. 2 . FIG. 6 is a partially enlarged view illustrating in detail the merging points of the microchannels of the second substrate of FIG. 5 . FIG. 7 is a view showing a top surface of a third substrate of the apparatus for manufacturing microspheres of FIG. 2 .

2 to 7 , the apparatus for manufacturing microspheres may include a first substrate SB1 , a second substrate SB2 , and a third substrate SB3 . The microsphere manufacturing apparatus has a form in which the third substrate SB3, the second substrate SB2, and the first substrate SB1 are sequentially stacked, and the first raw material and the second raw material are the microspheres. According to the order of flowing, forming, and discharging the emulsion in the sphere manufacturing apparatus, for convenience of description, the first substrate SB1 will be described first.

A first inlet IN1 and a second inlet IN2 passing through the first substrate SB1 may be formed in the first substrate SB1 . A first main flow path MF1 , a first branch flow path DF1 , a second main flow path MF2 , a second branch flow path DF2 , and an alignment mark AL may be formed on a lower surface of the first substrate SB1 . can

The first main flow path MF1 may be connected to the first inlet IN1 and may extend in parallel to a second direction D2 perpendicular to the first direction D1 . The first main flow path MF1 may be formed to have a narrower cross-sectional area in the direction in which the fluid flows. For example, the first main flow path MF1 includes a first portion connected to the first inlet IN1 and a second portion connected to the first portion, and the cross-sectional area of the second portion is the second It may be smaller than the cross-sectional area of 1 part. In this case, the first branch passage DF1 may be connected to a portion where the first portion and the second portion of the first main passage MF1 are connected, that is, a portion where the cross-sectional area is reduced.

The first branch flow path DF1 may be formed in plurality, each of which may be connected to the first main flow path MF1. The first branch flow path DF1 may extend in a direction perpendicular to the first main flow path MF1 , that is, parallel to the first direction D1 . The first branch flow path DF1 may have a cross-sectional area smaller than that of the first main flow path MF1 . A first step (refer to ST1 of FIG. 3 ) may be formed at a point where the first main flow path MF1 and the first branch flow path DF1 meet.

The second main flow path MF2 may be connected to the second inlet IN1 and may extend in parallel to the second direction D2 . The second main flow path MF2 may be formed to have a narrower cross-sectional area toward the flow direction of the fluid. For example, the second main flow path MF2 includes a first portion connected to the second inlet IN2 and a second portion connected to the first portion, and the cross-sectional area of the second portion is the second It may be smaller than the cross-sectional area of 1 part. In this case, the second branch flow path DF2 may be connected to a portion where the first portion and the second portion of the second main flow passage MF2 are connected, that is, a portion having a reduced cross-sectional area.

The second branch flow path DF2 may be formed in plurality, and each may be connected to the second main flow path MF2. The second branch flow path DF2 may extend in a direction perpendicular to the second main flow path MF2 , that is, parallel to the first direction D1 . The second branch flow path DF2 may have a cross-sectional area smaller than that of the second main flow path MF2 . A step may be formed at a point where the second main flow path MF2 and the second branch flow path DF2 meet.

The alignment mark AL may be formed on an edge portion of the first substrate SB1 in which a flow path is not formed, and the alignment mark AL is also formed on the second substrate SB2 and the third substrate SB3 . is formed, and may be used as an alignment mark to determine an accurate position when the first to third substrates SB1, SB2, and SB3 are laminated to be in contact with each other.

The first main flow path MF1 , the first branch flow path DF1 , the second main flow path MF2 , and the second branch flow path DF2 may be formed on an upper surface of the second substrate SB2 . . A first fine branch flow path 110 , 130 , a second fine branch flow path 120 , a merging point JP, and an exhaust flow path 150 may be further formed on the upper surface of the second substrate SB2 . An outlet H passing through the second substrate SB2 may be formed in the second substrate SB2 .

A plurality of first minute branch passages 110 and 130 may be formed, and each of the first minute branch passages 110 and 130 may be connected to the first branch passage DF1. The first minute branch passages 110 and 130 may extend in a direction perpendicular to the first branch passage DF1 , that is, parallel to the second direction D2 . The first fine branch passages 110 and 130 may have a cross-sectional area smaller than that of the first branch passage DF1. A second step (refer to ST2 of FIG. 3 ) may be formed at a point where the first branch passage DF1 and the first fine branch passages 11 and 130 meet.

A plurality of second fine branch passages 120 may be formed, and each of the second fine branch passages 120 may be connected to the second branch passage DF2. The first minute branch passages 110 and 130 may extend in a direction perpendicular to the first branch passage DF1 , that is, parallel to the second direction D2 . The first fine branch passages 110 and 130 may have a cross-sectional area smaller than that of the first branch passage DF1. A second step (refer to ST2 of FIG. 3 ) may be formed at a point where the first branch flow path DF1 and the first fine branch flow path 11 and 130 meet.

The two first minute branch passages 110 and 130 and the second minute branch passage 120 may be connected to each other at the merging point JP. At the merging point, the first raw material and the second raw material may be mixed to continuously form an emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase. A plurality of such merging points JP are formed in the microsphere manufacturing apparatus, which is a single microchip, so that microspheres of uniform quality can be manufactured more efficiently.

The discharge passage 150 may be connected to the merging point JP, and may be connected to the discharge port H. The discharge flow path 150 may have a relatively large cross-sectional area compared to the first fine branch flow path 110 and 130 or the second fine branch flow path 120 .

The first fine branch passages 110 and 130 have a cross-sectional area greater than that of the first portions 112 and 132 and the first portions 112 and 132, and a second portion ( 114, 134).

In this case, the first raw material flowing through the first minute branch passages 110 and 130 and the second raw material flowing through the second minute branch passage 120 may flow in opposite directions. At the merging point JP, the first minute branch passages 110 and 130 and the second minute branch passage 120 may vertically meet each other.

An outlet OUT passing through the third substrate SB3 may be formed in the third substrate SB3 . A first discharge passage OF, a main discharge passage MO, and an alignment mark AL may be formed on an upper surface of the third substrate SB3 .

A plurality of the first discharge passages OF may be formed, and each of them may be connected to the main discharge passage MO. The first discharge channel OF may receive the emulsion formed on the second substrate SB2 through the outlet H. The first discharge flow path OF may extend in a direction perpendicular to the main discharge flow path MO, that is, parallel to the first direction D1 . The first discharge passage OF may have a cross-sectional area smaller than that of the main discharge passage MO.

The main discharge flow path MO may be connected to the outlet OUT and may extend in parallel to the second direction D2 . The emulsion may be discharged to the outside of the microsphere manufacturing apparatus 1000 through the first discharge passage MO, the main discharge passage MO, and the outlet OUT.

The flow path inside the microsphere manufacturing apparatus is branched from a flow path having a large cross-sectional area in the flow direction of the fluid to a flow path having a plurality of small cross-sectional areas, and the flow of the fluid through a plurality of branch passages in which the traveling direction is changed, a stepped structure, etc. It generates resistance and acts as a buffer. Accordingly, the deviation between the plurality of branched fluid flows can be reduced and a uniform flow can be formed, so that the dispersed phase of the droplets formed at the plurality of merging points is uniform and mass-produced at the same time.

In the present embodiment, the first main flow path MF1 , the first branch flow path DF1 , the second main flow path MF2 , and the second branch flow path DF2 include the first substrate SB1 and the second branch flow path DF2 . Since it is formed on the second substrate SB2, and the first minute branch passages 110 and 130, the first minute branch passage 120, and the merging point JT are formed only on the second substrate SB2, It is possible to form flow passages of different heights. In this case, each flow path may be formed to have a small cross-sectional area in the flow direction of the fluid, and each flow path may be formed on either or both of the first substrate SB1 and the second substrate SB2 . In addition, the cross-sectional area of the flow path, the presence or absence of a step, and the height of the flow path may be designed in various forms. (See (a) and (b) of FIG. 3)

As the first to third substrates SB1, SB2, and SB3, various substrates capable of forming a flow path pattern, such as a glass substrate, a plastic substrate, and a silicon substrate, may be used. Various known methods such as , imprint method, photolithography method, etc. may be used, and various known methods such as a laser bonding method, a thermocompression bonding method, an adhesion method, a lamination method, etc. may be used for bonding of a plurality of substrates.

8 is a flowchart illustrating a method for manufacturing microspheres according to an embodiment of the present invention. 9 is a flowchart illustrating in detail the emulsion forming step of the method for preparing the microspheres of FIG. 8 .

8 and 9 , the method for preparing the microspheres may include a raw material preparation step (S100), an emulsion forming step (S200), a solvent extraction and removal step (S300), and a washing and drying step (S400).

In the raw material preparation step (S100), a first raw material may be prepared, and a second raw material including a biodegradable polymer, a drug, and a solvent may be prepared.

In this case, the first raw material may include purified water and a surfactant. The second raw material is an oil-phase solution, and the second raw material may include an organic solvent, a biodegradable polymer dissolved therein, and a drug.

In the emulsion forming step (S200), an emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase may be formed using the first raw material and the second raw material.

An emulsion may be formed through various known methods using the first raw material and the second raw material. For example, using the microsphere manufacturing apparatus shown in FIGS. 2 to 7, a microfluidic method of forming microsphere droplets through the flow of a microchannel may be used. The emulsion includes the first raw material in a continuous phase and the second raw material in a dispersed phase.

Specifically, the emulsion forming step (S200) may include a first and second raw material supply step (S210), a branching step (S220), an emulsion forming step (S230) and a merging step (S240).

In the first and second raw material supply step ( S210 ), the first raw material and the second raw material are supplied to the microsphere manufacturing apparatus. A first raw material may be prepared, and a second raw material including a biodegradable polymer, a drug, and a solvent may be introduced through the first inlet IN1 and the second inlet IN2 of the microsphere manufacturing apparatus, respectively.

The branching step S200 may include a first branching step S222 and a second branching step S224.

In the first branching step S222 , the first and second raw materials introduced through the first inlet IN1 and the second inlet IN2 are respectively transferred from the first main flow path MF1 to the first branch flow path. It may branch to DF1 , and branch from the second main flow path MF2 to the second branch flow path DF2 .

In the second branching step ( S224 ), the first branching of the first raw material and the second raw material are respectively branched from the first branching passage DF1 to the first fine branching passages 110 and 130 , respectively, and , may be branched from the second branch flow path DF2 to the second fine branch flow path 120 .

Through this branching step, the flow of the fluid flowing through the microchannel can be homogenized. In particular, since the flow paths are branched at a predetermined angle (90 degrees in this embodiment) at the point where the fluid is branched, the flow of the fluid in the plurality of branched branch flow paths may be more uniform and stable than before the branching. In addition, since the cross-sectional area of the flow path is discontinuously or rapidly reduced at the point where the branching of the fluid occurs (a step, a decrease in the flow path width, or a decrease in the flow path height), the flow of the fluid in the plurality of branched branch flow paths is reduced before the branching. Contrast may be uniform and stable.

In the emulsion forming step ( S230 ), the first raw material and the second raw material flowing through the first fine branch passages 110 and 130 and the second minute branch passage 120 meet at a merging point JT and are continuous An emulsion including the first raw material of the phase and the second raw material of the dispersed phase may be formed.

In the merging step (S240), the emulsions formed at the plurality of merging points (JT) are merged to form a large-capacity emulsion in a short time. The merging step ( S240 ) may include a primary merging step ( S242 ) and a secondary merging step ( S244 ).

In the first merging step ( S242 ), the emulsions formed at the plurality of merging points (JT) may be merged by flowing into the first discharge passage (OF). In the secondary merging step (S244), the plurality of first discharge passages OF are connected to the main discharge passage MO, so that the emulsions flowing through the plurality of first discharge passages OF are separated into the main discharge passage ( MO) can be incorporated.

In the solvent extraction and removal step (S300), the solvent may be extracted and removed from the dispersed phase of the emulsion to form microspheres. A method for obtaining the microspheres from the emulsion may use various known methods. For example, the emulsion can be accommodated in a solvent evaporation tank and stirred to accelerate extraction of the solvent from the dispersed phase of the emulsion to the continuous phase and evaporation of the extracted solvent. Through this, the dispersed phase in the form of droplets may be solidified to form microspheres.

The washing and drying step (S400) is a step of washing and drying the solidified microspheres, and may be performed as needed. For example, the solidified microspheres may be recovered using a method such as filtration or centrifugation, and then washed with water. After filtration and washing, the obtained microspheres can be dried using a conventional drying method to finally obtain a dried microsphere powder. The method of drying the microspheres is not limited, and may be carried out using freeze drying, vacuum drying, or reduced pressure drying method.

Through the drying process of the microspheres, the desired monodisperse biodegradable polymer-based microsphere powder is finally prepared, and then, the obtained microsphere powder is suspended in a suspension and filled in an appropriate container, for example, a disposable syringe, etc. product can be obtained.

10 is a schematic diagram for explaining a flow formed at a merging point of a microchip.

Referring to FIG. 10 , the microchip includes three microchannels (channel 1, channel 2, and channel 3 in the drawing). One of the micro-channels becomes a passage through which the biodegradable polymer solution flows (flow 2), and the remaining two micro-channels become a passage through which the aqueous-phase solution flows (flow 1, flow 3). The micro-channels for receiving the flow of the biodegradable polymer solution are positioned between the micro-channels for receiving the flow of the aqueous-phase solution. The micro-channels receiving the flow of the aqueous-phase solution merge with the micro-channels receiving the flow of the biodegradable polymer-phase solution at an angle Ψ at the merging point (15). Due to the interaction of the solutions flowing through the microchannels and the immiscibility of the solutions meeting at the merging point, biodegradable polymer-based microsphere droplets are formed at the merging point. The micro-channels for receiving the flow of the aqueous-phase solution include introduction passages 11 and 13, respectively, through which the solution is introduced into the micro-channel. The micro flow path for receiving the flow of the biodegradable polymer-phase solution includes an inlet passage 12 and an outlet passage 14 . The solution containing the biodegradable polymer-based microsphere droplets is discharged from the microchip via the discharge path 14 . The number of microchannels in the microchip for accommodating the flows of solutions may vary according to the required values for the final product. A solution comprising biodegradable polymer-based microsphere droplets will hereinafter be referred to as a dispersed phase solution.

In the present invention, the aqueous-phase solution is introduced into the microchip through the introduction passages 11 and 13, respectively, to form a flow 1 and a flow 3 in the micro passages 1 and 3, respectively, so that it is biodegradable. The flow ( 2 ) of the polymer-phase solution meets at an angle at the point of merging ( 15 ). Here, by the water-phase solution, i.e. the flow (1) and the stream (3), the biodegradable polymer solution, i.e. the stream (2), is segmented and due to the immiscibility of the two solutions, microspheres Droplets are formed. Thereby, a dispersed phase solution is formed, and the microsphere droplets formed at the merging point 15 are discharged out of the microchip through the discharge path 14 .

Meanwhile, in the embodiments of the present invention, the case in which the dispersed phase of the emulsion includes an oil-phase solution and the continuous phase includes an aqueous-phase solution has been described, but the present invention is not limited thereto. It is also possible that the dispersed phase of the emulsion comprises an aqueous-phase solution and the continuous phase comprises an oil-phase solution, in which case the drug contained in the microspheres may comprise a hydrophilic therapeutic agent.

Although it has been described with reference to the above embodiments, it will be understood by those skilled in the art that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention as set forth in the claims below. will be able

SB1: first substrate SB2: second substrate
SB3: third substrate IN1, IN2: first and second inlets
OUT: outlets MF1, MF2: first and second main flow paths
DF1, DF2: flow path 1st and 2nd branch JT: merge point
110, 130: first fine branch flow path 120: second fine branch flow path

Claims (20)

a first substrate having a first inlet through which a first raw material is provided and a second inlet through which a second raw material is provided; and
a second substrate in contact with the first substrate;
the second substrate
a first main flow passage connected to the first inlet and having a first cross-sectional area;
a plurality of first branch passages, each of which is connected to the first main passage and has a second cross-sectional area smaller than the first cross-sectional area;
a second main passage connected to the second inlet;
a plurality of second branch passages each connected to the second main passage; and
and a plurality of merging points where the first raw material and the second raw material meet to continuously form an emulsion comprising the first raw material in a continuous phase and the second raw material in a dispersed phase;
a plurality of first minute branch passages, each of which is connected to the first branch passage; and
The first fine branch flow path includes a first portion having a third cross-sectional area smaller than the second cross-sectional area, and a second portion having a cross-sectional area greater than the first portion and connected to the merging point. Sphere manufacturing apparatus. delete delete delete According to claim 1,
The second main flow passage has a fourth cross-sectional area, and the second branch passage has a fifth cross-sectional area smaller than the fourth cross-sectional area;
Further comprising a plurality of second fine branch passages, each of which is connected to the second branch passage,
The second fine branch flow path includes a first portion having a sixth cross-sectional area smaller than the fifth cross-sectional area, and a second portion having a larger cross-sectional area than the first portion and connected to the merging point. Sphere manufacturing apparatus. 6. The method of claim 5,
Further comprising a plurality of third fine branch passages, each of which is connected to the first branch passage, wherein the first minute branch passage, the second fine branch passage, and the third fine branch passage are connected to the merging point An apparatus for producing microspheres, characterized in that 6. The method of claim 5,
The apparatus for producing microspheres, characterized in that the first raw material flowing through the first fine branching flow path and the second raw material flowing through the second fine branching flow path flow in opposite directions. The method of claim 1,
An outlet for discharging the emulsion to the outside of the second substrate is formed through the second substrate,
The second substrate is connected to the merging point, the microsphere manufacturing apparatus characterized in that it further comprises a discharge passage connected to the outlet. delete According to claim 1,
The first main flow path and the first branch flow path are microsphere manufacturing apparatus, characterized in that perpendicular to each other on a plane formed by the second substrate. According to claim 1,
The apparatus for manufacturing microspheres, characterized in that the angles formed by each of the first branch flow paths with the first main flow path are the same. According to claim 1,
The apparatus for manufacturing microspheres, characterized in that a stepped portion is formed at a portion where the first main flow path and the first branch flow path are connected. The method of claim 1,
Further comprising a third substrate in contact with the second substrate and through which an outlet for discharging the emulsion to the outside is formed,
The third substrate may include a plurality of first discharge channels each receiving the emulsion formed on the second substrate from the second substrate; and
and a main discharge passage connected to the plurality of first discharge passages and connected to the outlet. The method of claim 1,
The first main flow path includes a first portion connected to the first inlet and a second portion connected to the first portion,
and a cross-sectional area of said second portion is smaller than a cross-sectional area of said first portion. 15. The method of claim 14,
The apparatus for producing microspheres, characterized in that the first branch passage is connected to a portion where the first portion and the second portion of the first main passage are connected. A first inlet, a second inlet, a first main passage connected to the first inlet, a plurality of first branch passages each connected to the first main passage, a second main passage connected to the second inlet, respectively a plurality of second branch passages connected to the second main passage, and a plurality of first and second raw materials meeting to continuously form an emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase In the microsphere manufacturing method using the microsphere manufacturing apparatus comprising the merging point of
a first and second raw material supply step of providing the first raw material and the second raw material including the biodegradable polymer, drug and solvent to the first inlet and the second inlet, respectively; and
The first and second raw materials introduced through the first inlet and the second inlet are respectively branched from the first main flow path to the plurality of first branch flow paths, and the plurality of the plurality of first branch flow paths from the second main flow path a first branch step of branching into second branch flow paths;
After the first branching step, further comprising an emulsion forming step in which the branched first raw material and the second raw material meet at the merging point to form an emulsion,
The apparatus for manufacturing microspheres further includes a plurality of first fine branch passages each connected to the first branch passage, and a plurality of second fine branch passages each connected to the second branch passage,
After the first branching step, the first raw material and the second raw material are respectively branched from the first branch flow path to the first fine branch flow path, and branch from the second branch flow path to the second fine branch flow path. further comprising a second branching step;
The first main flow passage has a first cross-sectional area, and the first branch passage has a second cross-sectional area smaller than the first cross-sectional area;
The first fine branch flow path includes a first portion having a third cross-sectional area smaller than the second cross-sectional area, and a second portion having a cross-sectional area greater than the first portion and connected to the merging point. A method for making spheres. delete delete 17. The method of claim 16,
The microsphere manufacturing apparatus further comprises a first discharge flow path connected to the plurality of merging points,
Method for producing microspheres, characterized in that it further comprises a merging step in which the emulsion formed at the plurality of merging points is merged by flowing into the first discharge passage. 17. The method of claim 16,
a solvent extraction and removal step of extracting and removing a solvent from the dispersed phase of the emulsion to form solidified microspheres; and
Method for producing microspheres, characterized in that it further comprises a washing and drying step of washing and drying the solidified microspheres.

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