Microsphere manufacturing system and microsphere manufacturing method

Abstract

The microsphere manufacturing system includes a first raw material storage section in which a first raw material is stored; a second raw material storage section in which a second raw material containing a solvent, a biodegradable polymer, and a drug is stored; an emulsion forming section that continuously forms an emulsion containing the first raw material as a continuous phase and the second raw material as a dispersed phase; a first solvent extraction and removal section that receives the emulsion formed in the emulsion forming section and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres; and a second solvent extraction and removal section that is separated from the first solvent extraction and removal section and receives the emulsion formed in the emulsion forming section and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres.

Description

[Technical field]

[0001] The present invention relates to a microsphere manufacturing system and a microsphere manufacturing method, and more particularly to a microsphere manufacturing system and a microsphere manufacturing method capable of mass-producing microspheres of uniform quality. [Background technology]

[0002] One of the drug delivery systems currently being actively researched, developed and utilized is the so-called Polymeric Drug-Delivery System (PDDS), which uses biodegradable, biocompatible and non-toxic polymers, such as polylactic acid (PLA) / polyglycolic acid (PGA) polymers, to enable the controllable release of a constant amount of therapeutic agent over an extended period of time at a circulating dose for both hydrophilic and hydrophobic therapeutic agents.

[0003] Such biodegradable polymers can be manufactured in the form of microspheres by various known techniques. In the most frequently used method for manufacturing these biodegradable polymer microspheres, the biodegradable polymer or the biodegradable polymer and the substance to be encapsulated (drug or other active agent) are dissolved in a solvent by a known method, and dispersed or emulsified in an aqueous solution containing a surfactant. The solvent is then removed from the microspheres, which are then dried to obtain a microsphere product. In the manufacturing process of microspheres by known techniques, toxic solvents such as dichloromethane or chloroform are mainly used to dissolve the biodegradable polymer and the active agent, and therefore, sufficient time and effort must be spent to remove the solvent so that the solvent does not remain in the final product, the microsphere product, which increases the time required to obtain the microsphere product and acts as an obstacle to mass production. As a result, efforts have been made to mass-produce high-quality microspheres at low cost. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Korean Patent Registration No. 10-0681213 Summary of the Invention [Problem to be solved by the invention]

[0005] The technical problem of the present invention is therefore to address this issue, and an object of the present invention is to provide a microsphere manufacturing system capable of mass-producing microspheres of uniform quality.

[0006] Another object of the present invention is to provide a method for producing microspheres that allows mass production of microspheres of uniform quality. [Means for solving the problem]

[0007] A microsphere manufacturing system according to one embodiment for achieving the above-mentioned object of the present invention includes a first raw material storage unit in which a first raw material is stored; a second raw material storage unit in which a second raw material containing a solvent, a biodegradable polymer and a drug is stored; an emulsion forming unit that continuously forms an emulsion containing the first raw material in a continuous phase and the second raw material in a dispersed phase; a first solvent extraction removal unit that receives the emulsion formed from the emulsion forming unit and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres; and a second solvent extraction removal unit that is separated from the first solvent extraction removal unit and receives the emulsion formed from the emulsion forming unit and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres.

[0008] In one embodiment of the present invention, the emulsion formation section may include a first flow path through which the first raw material flows, a second flow path through which the second raw material flows, and a third flow path through which the emulsion containing the continuous phase and the dispersed phase flows.

[0009] In one embodiment of the present invention, the emulsion formation section may include a plurality of microchips, and each of the microchips may include the first flow path, the second flow path, and the third flow path.

[0010] In an embodiment of the present invention, the emulsion forming unit may sequentially supply the continuously produced emulsion to the first solvent extraction removal unit and the second solvent extraction removal unit.

[0011] In an embodiment of the present invention, the system for producing microspheres may further include a washing unit for washing the microspheres formed in the first solvent extraction removal unit or the second solvent extraction removal unit with a washing solution.

[0012] In one embodiment of the present invention, the cleaning unit may include a first cleaning unit for cleaning the microspheres formed in the first solvent extraction removal unit, and a second cleaning unit for cleaning the microspheres formed in the second solvent extraction removal unit. The first cleaning unit and the second cleaning unit may be separated from each other.

[0013] In an embodiment of the present invention, the system for manufacturing microspheres may further include a drying unit configured to dry the microspheres formed in the first solvent extraction removal unit or the second solvent extraction removal unit to obtain a microsphere powder.

[0014] In one embodiment of the present invention, the first raw material may include water and a surfactant. The solvent of the second raw material may be one or more selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, or a mixture thereof.

[0015] In one embodiment of the present invention, each of the first and second solvent extraction removal sections can form a fluid flow in the emulsion, extract the solvent of the second raw material, and remove the extracted solvent by evaporation.

[0016] In one embodiment of the present invention, each of the first and second solvent extraction removal units may heat the emulsion to a temperature equal to or higher than the boiling point of the solvent, thereby vaporizing and removing the solvent.

[0017] A method for producing microspheres according to one embodiment for achieving the above-mentioned object of the present invention includes the steps of preparing a first raw material and a second raw material containing a biodegradable polymer, a drug, and a solvent; providing the first raw material and the second raw material to an emulsion forming unit, which continuously forms an emulsion containing the first raw material as a continuous phase and the second raw material as a dispersed phase; supplying the emulsion produced from the emulsion forming unit to a first solvent extraction removal unit, which extracts and removes the solvent from the dispersed phase in the first solvent extraction removal unit, to form microspheres; and supplying the emulsion produced from the emulsion forming unit to a second solvent extraction removal unit separated from the first solvent extraction unit, which extracts and removes the solvent from the dispersed phase in the second solvent extraction removal unit, to form microspheres.

[0018] In one embodiment of the present invention, the emulsion may be sequentially supplied to the second solvent extraction removal section after the supply to the first solvent extraction removal section is completed.

[0019] In an embodiment of the present invention, the method for producing microspheres may further include washing and drying the microspheres formed in the first solvent extraction removal unit, or drying the microspheres to obtain a dried microsphere powder.

[0020] In an embodiment of the present invention, the method for producing microspheres may further include the step of recovering the microspheres formed in the first solvent extraction and removal unit, supplying a newly formed emulsion in the emulsion forming unit to the first solvent extraction and removal unit, and extracting and removing the solvent from the second raw material of the dispersed phase of the newly formed emulsion in the first solvent extraction and removal unit to form microspheres.

[0021] In one embodiment of the present invention, the emulsion formation unit may include a microchip including a first flow path through which the first raw material flows, a second flow path through which the second raw material flows, and a third flow path through which the emulsion containing the continuous phase and the dispersed phase flows.

[0022] In one embodiment of the present invention, the method for producing microspheres may further include washing the microspheres formed in the first solvent extraction removal unit in a first washing unit, and washing the microspheres formed in the second solvent extraction removal unit in a second washing unit separated from the first washing unit. Effect of the Invention

[0023] According to an embodiment of the present invention, a microsphere manufacturing system includes an emulsion forming unit which continuously forms an emulsion containing a first raw material for a continuous phase and a second raw material for a dispersed phase, a first solvent extraction removal unit which receives the emulsion formed from the emulsion forming unit and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres, and a second solvent extraction removal unit which is separated from the first solvent extraction removal unit and receives the emulsion formed from the emulsion forming unit and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres. Therefore, the efficiency of the emulsion forming process and the solvent extraction removal process can be maximized, and high quality microspheres can be mass-produced at low cost.

[0024] However, the effects of the present invention are not limited to the above effects, and can be expanded in various ways without departing from the spirit and scope of the present invention. [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention. [Diagram 2] FIG. 2 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG. [Diagram 3] FIG. 3 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention. [Figure 4] FIG. 4 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG. [Diagram 5] FIG. 5 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention. [Figure 6] FIG. 6 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG. [Figure 7] FIG. 7 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention. [Figure 8] FIG. 8 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG. [Figure 9] FIG. 9 is a schematic diagram of a microchip of an emulsion forming section of a system for producing microspheres according to one embodiment of the present invention and a flow formed therein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to the drawings.

[0027] Although the present invention can be modified in various ways and can have various forms, specific embodiments are illustrated in the drawings and described in detail in the text, however, it is not intended to limit the present invention to the specific disclosed forms, and it should be understood that the present invention includes all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention.

[0028] FIG. 1 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention.

[0029] Referring to FIG. 1, the microsphere manufacturing system includes a raw material storage section, an emulsion forming section 200, a solvent extraction removing section, a washing section 400 and a drying section 500.

[0030] The raw material storage unit may include a first raw material storage unit 110 and a second raw material storage unit 120. The solvent extraction removal unit may include a first solvent extraction removal unit 310 and a second solvent extraction removal unit 320.

[0031] The first raw material storage unit 110 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 purified water.

[0032] The type of the surfactant is not particularly limited, and any surfactant can be used as long as it can help the biodegradable polymer solution to form a stable dispersed phase of droplets in the aqueous solution phase of the continuous phase.The surfactant can be preferably selected from the group consisting of methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivatives, and mixtures thereof.

[0033] The second raw material storage unit 120 can store the second raw material. The second raw material may be 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 a property of being immiscible with water. The type of organic solvent for dissolving such a biodegradable polymer is not particularly limited, but may be one or more selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, or a mixture thereof.

[0034] The type of the biodegradable polymer is not particularly limited, but preferably, polyester can be used, and in particular, it can be selected from the group consisting of polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide) glucose, polycaprolactone, and mixtures thereof.

[0035] The type of the drug is not particularly limited, and examples thereof include dementia treatments; Parkinson's disease treatments; anticancer drugs; antipsychotic drugs such as antianxiety drugs, antidepressants, neuroleptics, and psychoneurotic drugs; cardiovascular treatments such as hyperlipidemia treatments, hypertension treatments, hypotension treatments, antithrombotic drugs, vasorelaxants, and arrhythmia treatments; epilepsy treatments; digestive treatments such as antiulcer drugs; rheumatism treatments; antispasmodics; tuberculosis treatments; muscle relaxants; osteoporosis treatments; erectile dysfunction treatments; hemostatic agents; hormones such as sex hormones; diabetes treatments; antibiotics; antifungal agents; antiviral agents; antipyretic analgesics and anti-inflammatory agents; autonomic nerve regulators; corticosteroids; diuretics; The therapeutic agent may be selected from antidiuretics; analgesics; anesthetics; antihistamines; antiprotozoal agents; antianemic agents; antiasthmatic agents; anticonvulsants; antidotes; antimigraine agents; antiemetics; antiparkinsonian agents; antiepileptic agents; antiplatelet agents; antitussives and expectorants; bronchodilators; cardiac inotropes; immunomodulators; protein drugs; gene drugs; and mixtures thereof.

[0036] Among the above-mentioned types of drugs, the drug is not particularly limited, but may be preferably selected from the group consisting of donepezil, memantine, rivastigmine, entecavir, lamivudine, rotigotine, ropinirole, bupivacaine, ropivacaine, meloxicam, buprenorphine, fentanyl, nimodipine, granisetron, triamcinolone, cytarabine, carmustine, tamsulosin, polmacoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, goserelin, leuprorelin, triptorelin, buserelin, nafarelin, deslorelin, octreotide, pasireotide, lanreotide, vapreotide, exenatide, liraglutide, lixisenatide, semaglutide, salts thereof, and mixtures thereof.

[0037] The emulsion forming unit 200 can receive the first raw material and the second raw material from the first raw material storage unit 110 and the second fuel storage unit 120. Using the first raw material and the second raw material, an emulsion including the first raw material as a continuous phase and the second raw material as a dispersed phase can be continuously formed.

[0038] According to the present embodiment, the emulsion forming unit 200 can form the emulsion in a continuous process, not in a batch process unit. That is, the emulsion forming unit 200 can be continuously supplied with the first raw material and the second raw material to continuously form the emulsion. For example, the emulsion forming unit 200 includes a microchip including a first flow path through which the first raw material flows, a second flow path through which the second raw material flows, and a third flow path through which the emulsion including the continuous phase and the dispersed phase flows, and a plurality of the microchips are connected in parallel to continuously form a desired amount of emulsion (the specific principle of the microchip will be described later with reference to FIG. 9).

[0039] According to another embodiment, the emulsion forming unit 200 may have a configuration in which a plurality of tanks for mixing the first and second raw materials to form an emulsion may sequentially form an emulsion. For example, while an emulsion is formed in a first tank by mixing, the first and second raw materials are supplied to a second tank, and while an emulsion is formed in the second tank, the first and second raw materials are again supplied to a third tank or to the first tank from which the emulsion formation is completed and the microspheres are collected, and an emulsion is formed again. In this manner, continuous emulsion formation is also possible when an emulsion is formed in a mixing manner.

[0040] The first raw material storage unit 110 and the emulsion forming unit 200 are connected by a first connection path FL1, so that the first raw material can be continuously supplied from the first raw material storage unit 110 to the emulsion forming unit 200. The second raw material storage unit 120 and the emulsion forming unit 200 are connected by a second connection path FL2, so that the second raw material can be continuously supplied from the second raw material storage unit 120 to the emulsion forming unit 200.

[0041] A raw material supply adjusting unit 150 is formed in the first connecting path FL1 and the second connecting path FL2, and the amount of the first raw material and the second raw material required by the emulsion forming unit 200 can be appropriately adjusted and supplied.

[0042] The first solvent extraction and removal unit 310 may receive the emulsion formed from the emulsion forming unit 200, extract and remove the solvent from the dispersed phase of the emulsion, and form microspheres. The first solvent extraction and removal unit 310 may include a tank for receiving the emulsion, a stirrer for stirring the emulsion, and a heater for heating the emulsion.

[0043] Specifically, when the emulsion is maintained or stirred at a temperature below the boiling point of the organic solvent for a certain period of time, for example, 2 hours to 48 hours, in the first solvent extraction and removal unit 310, the organic solvent can be extracted in the continuous phase from the droplet-shaped biodegradable polymer solution, which is the dispersed phase. A part of the organic solvent extracted in the continuous phase can evaporate from the surface. As the organic solvent is extracted and evaporated from the droplet-shaped biodegradable polymer solution, the dispersed phase in the droplet form can be solidified to form microspheres. In this case, the extraction and evaporation can be accelerated by causing a flow or heating the emulsion. For example, the solvent of the second raw material can be extracted by forming a fluid flow in the emulsion, and the extracted solvent can be evaporated and removed. The emulsion can be heated at a temperature above the boiling point of the solvent to vaporize and remove the solvent. The organic solvent present in the dispersed phase can be fully extracted and evaporated as the continuous phase by removing a part of the continuous phase containing the organic solvent extracted from the dispersed phase and supplying a new aqueous solution to replace the removed continuous phase. In this case, the new aqueous solution may optionally further contain a surfactant.

[0044] The second solvent extraction and removal unit 320 may receive the emulsion formed from the emulsion forming unit 200, extract and remove the solvent from the dispersed phase of the emulsion, and form microspheres.

[0045] The second solvent extraction removal unit 320 is a separate component separated from the first solvent extraction removal unit 310, and specific functions and components may be substantially the same as those of the first solvent extraction removal unit 320.

[0046] The first solvent extraction removal unit 310 and the emulsion forming unit 200 may be connected by a third connecting line FL3. The second solvent extraction removal unit 320 and the emulsion forming unit 200 may be connected by a fourth connecting line FL4.

[0047] An emulsion supply control unit 250 is formed in the third connecting line FL3 and the fourth connecting line FL4, and the emulsion can be selectively supplied to the first solvent extraction removal unit 310 or the second solvent extraction removal unit 320 as needed.

[0048] The washing unit 400 may collect and wash the microspheres formed from the first solvent extraction and removal unit 310 or the second solvent extraction and removal unit 320. The method of collecting and washing the microspheres from the continuous phase containing the microspheres formed from the first or second solvent extraction and removal unit 310, 320 is not particularly limited, and the microspheres may be collected using a method such as filtration or centrifugation, and then washed with water. Through this, the remaining organic solvent and surfactant (e.g., polyvinyl alcohol) may be removed. The washing step may be generally performed using water, and the washing step may be repeated several times.

[0049] The drying unit 500 can dry the washed microspheres to obtain a microsphere powder. After the filtering and washing steps, 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. However, the drying method used is not particularly limited, and can be performed using freeze drying, vacuum drying, or reduced pressure drying. Although the washing unit 400 is illustrated as being separate from the first or second solvent extraction and removal unit 310, 320, it can be formed integrally within the first or second solvent extraction and removal unit 310, 320, and the washing step of the washing unit 400 can be performed within the first or second solvent extraction and removal unit 310, 320.

[0050] The microspheres are dried to produce the desired monodisperse biodegradable polymer-based microsphere powder. The microsphere powder is then suspended in a suspension and filled into a suitable container, such as a disposable syringe, to obtain the final product.

[0051] Fig. 2 is a diagram for explaining a method for producing microspheres using the microsphere production system of Fig. 1. In the drawing, the horizontal axis is the time axis, which indicates the duration of a corresponding step.

[0052] 1 and 2, a first raw material and a second raw material are prepared (S10). The first raw material may be stored in a first raw material storage unit 110, and the second raw material may be stored in a second raw material storage unit 120.

[0053] The first raw material and the second raw material are supplied to the emulsion forming unit 200 (S20). The first raw material and the second raw material may be continuously supplied to the emulsion forming unit 200 from the first and second raw material storage units 110 and 120.

[0054] The emulsion forming unit 200 continuously forms an emulsion (S21). The emulsion can be continuously formed using the first and second fuels continuously supplied from the first and second raw material storage units 110 and 120.

[0055] The emulsion formed initially is supplied to the first solvent extraction and removal section 310 (S30). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the first solvent extraction and removal section 310 (S31).

[0056] The emulsion formed in the latter stage is supplied to the second solvent extraction and removal section 320 (S40). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the second solvent extraction and removal section 320 (S41).

[0057] The microspheres formed by removing the solvent in the first and second solvent extraction / removal units 310 and 320 can be finally obtained as a microsphere powder through a washing step (S50) and a drying step (S60).

[0058] According to this embodiment, even after forming the emulsion to be supplied to the first solvent extraction removal unit 310, the emulsion forming unit 200 can continue to form an emulsion and provide it to the second solvent extraction removal unit 320, which is separate from the first solvent extraction removal unit 310. That is, the amount of "additional production" in the drawing can be produced in a larger amount than the conventional batch size, thereby enabling mass production.

[0059] In addition, the process for solvent extraction removal, which is a time-consuming process in the production of microspheres, i.e., steps S31 and S41, is performed as a separate configuration and is performed simultaneously for the "reduced time" in the drawing, so that the time for further processing of the "additional production" can be reduced and the efficiency of the emulsion formation process and the solvent extraction removal process can be maximized. Through this, high-quality microspheres can be mass-produced. In particular, compared to the conventional manufacturing technology based on the batch process, more microspheres can be produced with the same process equipment size, and therefore the load on cleaning, sterilization, and quality control (QC) that should be performed for each batch is reduced, and as a result, high-quality microspheres can be mass-produced at low cost.

[0060] FIG. 3 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention.

[0061] 3, the microsphere manufacturing system includes a raw material storage section, an emulsion forming section 200, a solvent extraction removal section, a washing section, and a drying section. The raw material storage section may include a first raw material storage section 110 and a second raw material storage section 120. The solvent extraction removal section may include a first solvent extraction removal section 310 and a second solvent extraction removal section 320. The washing section may include a first washing section 410 and a second washing section 420. The drying section may include a first drying section 510 and a second drying section 520.

[0062] 1, except that the cleaning unit includes the first cleaning unit 410 and a second cleaning unit 420 spaced apart from the first cleaning unit 410, and the drying unit includes the first drying unit 510 and a second drying unit 520 spaced apart from the first drying unit 510. Therefore, repeated description will be omitted.

[0063] The first cleaning unit 410 may collect and clean the microspheres formed in the first solvent extraction removal unit 310. The second cleaning unit 420 may collect and clean the microspheres formed in the second solvent extraction removal unit 320. The second cleaning unit 420 may be a separate component separated from the first cleaning unit 410, and specific functions and components may be substantially the same as those of the first cleaning unit 410.

[0064] The first drying unit 510 may dry the microspheres washed in the first washing unit 410 to obtain a microsphere powder. The second drying unit 520 may dry the microspheres washed in the second washing unit 420 to obtain a microsphere powder. The second drying unit 520 is a separate component separated from the first drying unit 510, and specific functions and components may be substantially the same as those of the first drying unit 510.

[0065] FIG. 4 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG.

[0066] 3 and 4, a first raw material and a second raw material are prepared (S10). The first raw material may be stored in a first raw material storage unit 110, and the second raw material may be stored in a second raw material storage unit 120.

[0067] The first raw material and the second raw material are supplied to the emulsion forming unit 200 (S20). The first raw material and the second raw material may be continuously supplied to the emulsion forming unit 200 from the first and second raw material storage units 110 and 120.

[0068] The emulsion forming unit 200 continuously forms an emulsion (S21). The emulsion can be continuously formed using the first and second fuels continuously supplied from the first and second raw material storage units 110 and 120.

[0069] The emulsion formed initially is supplied to the first solvent extraction and removal section 310 (S30). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the first solvent extraction and removal section 310 (S31).

[0070] The emulsion formed in the latter stage is supplied to the second solvent extraction and removal section 320 (S40). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the second solvent extraction and removal section 320 (S41).

[0071] The microspheres formed by removing the solvent in the first solvent extraction and removal unit 310 are washed in the first washing unit 410 (S32) and dried in the first drying unit 510 (S33), and finally obtained as a microsphere powder.

[0072] The microspheres formed by removing the solvent in the second solvent extraction and removal unit 320 are washed in the second washing unit 420 (S42) and dried in the second drying unit 520 (S43), and finally obtained as a microsphere powder.

[0073] According to this embodiment, even after forming the emulsion to be supplied to the first solvent extraction removal unit 310, the emulsion forming unit 200 can continue to form an emulsion and provide it to the second solvent extraction removal unit 320, which is separate from the first solvent extraction removal unit 310. That is, the amount of "additional production" in the drawing can be produced in a larger amount than the conventional batch size, thereby enabling mass production.

[0074] In addition, the process for solvent extraction removal, which is a time-consuming process in the production of microspheres, i.e., steps (S31) and (S41), is performed as a separate component, and washing and drying are also performed separately (S32 and S42, S33 and S43) and are performed simultaneously for the "reduced time" shown in the drawing, so that the time required for further processing of the "additional production" can be reduced and the efficiency of the emulsion formation process and the solvent extraction removal process can be maximized, thereby enabling mass production of high-quality microspheres.

[0075] FIG. 5 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention.

[0076] 5, the microsphere manufacturing system includes a raw material storage section, an emulsion forming section 200, a solvent extraction removal section, a washing section, and a drying section. The raw material storage section may include a first raw material storage section 110 and a second raw material storage section 120. The solvent extraction removal section may include a first solvent extraction removal section 310, a second solvent extraction removal section 320, and a third solvent extraction removal section 330. The washing section may include a first washing section 410, a second washing section 420, and a third washing section 430. The drying section may include a first drying section 510, a second drying section 520, and a third drying section 530.

[0077] 3, except that the solvent extraction removal unit further includes the third solvent extraction removal unit 330, the cleaning unit further includes the third cleaning unit 430, and the drying unit further includes the third drying unit 530. Therefore, repeated description will be omitted.

[0078] The third solvent extraction and removal unit 330 may receive the emulsion formed from the emulsion forming unit 200, extract and remove the solvent from the dispersed phase of the emulsion, and form microspheres. The third solvent extraction and removal unit 330 and the emulsion forming unit 200 may be connected to each other by a fifth connecting line FL5.

[0079] The third solvent extraction removal section 330 is a separate structure separated from the first and second solvent extraction removal sections 310 and 320, and specific functions and components may be substantially the same as those of the first solvent extraction removal section 320 or the second solvent extraction removal section 330.

[0080] The third cleaning unit 430 may collect and clean the microspheres formed in the third solvent extraction removal unit 310. The third cleaning unit 430 is a separate component separated from the first and second cleaning units 410 and 420, and specific functions and components may be substantially the same as those of the first cleaning unit 410 or the second cleaning unit 420.

[0081] The third drying unit 530 may obtain a microsphere powder by drying the microspheres washed in the third washing unit 430. The third drying unit 530 may be a separate component separated from the first and second drying units 510 and 520, and specific functions and components may be substantially the same as those of the first drying unit 510 or the second drying unit 520.

[0082] An emulsion supply control unit 250 is formed in the third connecting line FL3, the fourth connecting line FL4 and the fifth connecting line FL5, and the emulsion can be selectively supplied to the first solvent extraction removal unit 310, the second solvent extraction removal unit 320 or the third solvent extraction removal unit 330 as needed.

[0083] FIG. 6 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG.

[0084] 5 and 6, a first raw material and a second raw material are prepared (S10). The first raw material may be stored in a first raw material storage unit 110, and the second raw material may be stored in a second raw material storage unit 120.

[0085] The first raw material and the second raw material are supplied to the emulsion forming unit 200 (S20). The first raw material and the second raw material may be continuously supplied to the emulsion forming unit 200 from the first and second raw material storage units 110 and 120.

[0086] The emulsion forming unit 200 continuously forms an emulsion (S21). The emulsion can be continuously formed using the first and second fuels continuously supplied from the first and second raw material storage units 110 and 120.

[0087] The emulsion formed initially is supplied to the first solvent extraction and removal section 310 (S30). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the first solvent extraction and removal section 310 (S31).

[0088] The emulsion formed in the middle stage is supplied to the second solvent extraction and removal section 320 (S40). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the second solvent extraction and removal section 320 (S41).

[0089] The emulsion formed in the latter stage is supplied to the third solvent extraction and removal section 330 (S50). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the third solvent extraction and removal section 330 (S51).

[0090] The microspheres formed by removing the solvent in the first solvent extraction and removal unit 310 are washed in the first washing unit 410 (S32) and dried in the first drying unit 510 (S33), and finally obtained as a microsphere powder.

[0091] The microspheres formed by removing the solvent in the second solvent extraction and removal unit 320 are washed in the second washing unit 420 (S42) and dried in the second drying unit 520 (S43), and finally obtained as a microsphere powder.

[0092] The microspheres formed by removing the solvent in the third solvent extraction and removal unit 330 are washed in the third washing unit 430 (S52) and dried in the third drying unit 530 (S53), and finally obtained as a microsphere powder.

[0093] According to this embodiment, even after forming the emulsion to be supplied to the first solvent extraction removal unit 310, the emulsion forming unit 200 can continue to form emulsion and provide it to the second or third solvent extraction removal unit 320, 330, which is separate from the first solvent extraction removal unit 310. That is, the amount of "additional production" in the drawing can be produced in a larger amount than the conventional batch size, thereby enabling mass production.

[0094] In addition, the process for solvent extraction removal, which is a time-consuming process in the production of microspheres, i.e., steps (S31), (S41) and (S51), is performed as a separate configuration, and thus, only "reduced time 1" and "reduced time 2" are performed simultaneously, thereby reducing the time required for further processing of the "additional production" and maximizing the efficiency of the emulsion formation process and the solvent extraction removal process, thereby enabling mass production of high-quality microspheres.

[0095] FIG. 7 is a schematic diagram of a system for producing microspheres according to one embodiment of the present invention.

[0096] 7, the microsphere manufacturing system includes a raw material storage section, an emulsion forming section 200, a solvent extraction removal section, a washing section, and a drying section. The raw material storage section may include a first raw material storage section 110 and a second raw material storage section 120. The solvent extraction removal section may include a first solvent extraction removal section 310, a second solvent extraction removal section 320, and a third solvent extraction removal section 330. The washing section may include a first washing section 410 and a second washing section 420. The drying section may include a first drying section 510 and a second drying section 520.

[0097] The microsphere manufacturing system is substantially the same as the microsphere manufacturing system of Fig. 3, except that the solvent extraction removal unit further includes the third solvent extraction removal unit 330. Therefore, repeated description will be omitted.

[0098] The third solvent extraction and removal unit 330 may receive the emulsion formed from the emulsion forming unit 200, extract and remove the solvent from the dispersed phase of the emulsion, and form microspheres. The third solvent extraction and removal unit 330 and the emulsion forming unit 200 may be connected to each other by a fifth connecting line FL5.

[0099] The third solvent extraction removal section 330 is a separate structure separated from the first and second solvent extraction removal sections 310, 320, and its specific functions and components may be substantially the same as those of the first solvent extraction removal section 320 or the second solvent extraction removal section 330.

[0100] In this embodiment, the solvent extraction removal unit is composed of three units, and the cleaning unit and drying unit are composed of two units. However, only the solvent extraction removal unit, which requires a relatively long time, is composed of three units, and the cleaning unit or drying unit that has completed its operation is appropriately alternately used to maximize the production efficiency. In addition, the solvent extraction removal unit that has completed its operation is alternately used to maximize the production efficiency. This will be described in detail later with reference to FIG. 8.

[0101] FIG. 8 is a diagram for explaining a method for producing microspheres using the microsphere production system of FIG.

[0102] 7 and 8, a first raw material and a second raw material are prepared (S10). The first raw material may be stored in a first raw material storage unit 110, and the second raw material may be stored in a second raw material storage unit 120.

[0103] The first raw material and the second raw material are supplied to the emulsion forming unit 200 (S20). The first raw material and the second raw material may be continuously supplied to the emulsion forming unit 200 from the first and second raw material storage units 110 and 120.

[0104] The emulsion forming unit 200 continuously forms an emulsion (S21). The emulsion can be continuously formed using the first and second fuels continuously supplied from the first and second raw material storage units 110 and 120.

[0105] The emulsion formed in the first stage is supplied to the first solvent extraction and removal section 310 (S30). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the first solvent extraction and removal section 310 (S31).

[0106] The emulsion formed in the second stage is supplied to the second solvent extraction and removal section 320 (S40). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the second solvent extraction and removal section 320 (S41).

[0107] The emulsion formed in the third stage is supplied to the third solvent extraction and removal section 330 (S50). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the third solvent extraction and removal section 330 (S51).

[0108] At this time, the microspheres formed by removing the solvent in the first solvent extraction / removal unit 310 are washed in the first washing unit 410 (S32). Thus, the first solvent extraction / removal unit 310 can further receive emulsion and become ready to extract and remove the solvent.

[0109] The emulsion formed in the fourth stage is further supplied to the first solvent extraction and removal section 310 (S60). Thereafter, the solvent of the dispersed phase of the emulsion is extracted and removed in the first solvent extraction and removal section 310 (S61).

[0110] The microspheres formed by removing the solvent in the first solvent extraction and removal unit 310 are washed in the first washing unit 410 (S32) and dried in the first drying unit 510 (S33), and finally obtained as a microsphere powder.

[0111] The microspheres formed by removing the solvent in the second solvent extraction and removal unit 320 are washed in the second washing unit 420 (S42) and dried in the second drying unit 520 (S43), and finally obtained as a microsphere powder.

[0112] The microspheres formed by removing the solvent in the third solvent extraction and removal unit 330 are washed in the first washing unit 410 (S52) and dried in the first drying unit 510 (S53), and finally obtained as a microsphere powder. At this time, the first washing unit 410 and the first drying unit 510 have already washed and dried the microspheres supplied from the first solvent extraction and removal unit 310, respectively, and are therefore ready to receive more microspheres from the third solvent extraction and removal unit 330.

[0113] The microspheres formed by removing the solvent in the second solvent extraction / removal unit 310 are washed in the second washing unit 420 (S62) and dried in the second drying unit 520 (S63), and finally obtained as microsphere powder. At this time, the second washing unit 420 and the second drying unit 520 have already washed and dried the microspheres supplied from the second solvent extraction / removal unit 320, respectively, and are therefore ready to receive more microspheres from the first solvent extraction / removal unit 330.

[0114] According to the present embodiment, even after forming the emulsion to be supplied to the first solvent extraction and removal unit 310, the emulsion forming unit 200 can continue to form emulsion and provide it to the subsequent process. That is, the amount of "additional production" in the drawing can be produced in a larger amount than the conventional batch size, thereby enabling mass production. Although the first solvent extraction and removal unit 310 is used twice, and the first and second cleaning units 410, 420 and the first and second drying units 510, 520 are each used twice, the present invention is not limited thereto. That is, according to the same principle, emulsions are continuously formed, and a desired amount of microspheres can be obtained by continuously and repeatedly using each of the components that have completed their work.

[0115] In addition, the process for solvent extraction removal, which is a time-consuming process in the production of microspheres, is performed separately, and therefore, only "reduced time 1", "reduced time 2" and "reduced time 3" are performed simultaneously, thereby reducing the time required for further processing of the "additional production" and maximizing the efficiency of the emulsion formation process and the solvent extraction removal process. Through this, high-quality microspheres can be mass-produced.

[0116] FIG. 9 is a schematic diagram of a microchip of an emulsion forming section of a system for producing microspheres according to one embodiment of the present invention and a flow formed therein.

[0117] Referring to FIG. 9, the microchip includes three microchannels (channel 1, channel 2, and channel 3 in the figure). One of the microchannels is a passage through which the biodegradable polymer solution flows (flow 2), and the other two microchannels are passages through which the aqueous phase solution flows (flow 1 and flow 3). The microchannels containing the flow of the biodegradable polymer solution are located between the microchannels containing the flow of the aqueous phase solution. The microchannels containing the flow of the aqueous phase solution merge with the microchannels containing the flow of the biodegradable polymer phase solution at a Ψ angle at a merging point 15. The interaction of the solutions flowing through the microchannels and the immiscibility of the solutions meeting at the merging point form the biodegradable polymer-based microsphere droplets at the merging point. The microchannels containing the flow of the aqueous phase solution include inlet channels 11 and 13, respectively, through which the solutions are introduced into the microchannels. The microchannels containing the flow of the biodegradable polymer phase solution include an inlet channel 12 and an outlet channel 14. The solution containing the biodegradable polymer-based microspherical droplets leaves the microchip via the outlet 14. The number of microchannels in the microchip to accommodate the solution flow can vary depending on the requirements of the final product. The solution containing the biodegradable polymer-based microspherical droplets is referred to below as the dispersed phase solution.

[0118] In the present invention, the aqueous phase solution flows into the microchip through the inlet channels 11 and 13, respectively, and forms flows 1 and 3 in the microchannels 1 and 3, respectively, and meets flow 2 of the biodegradable polymer phase solution at a predetermined angle at a merging point 15. Here, the aqueous phase solutions, i.e., flows 1 and 3, cause segmentation of the biodegradable polymer solution, i.e., flow 2, and due to the immiscibility of the two solutions, microspherical droplets are formed. This forms a dispersed phase solution, and the microspherical droplets formed at the merging point 15 are discharged outside the microchip through the outlet channel 14.

[0119] When an emulsion is formed using a microchip, the quality of the microspheres produced can be improved compared to the case of the stirring method. However, in the case of continuous production using a microchip, after a product is produced using a one batch process, the microchip cannot be reused, and a new microchip must be used after disposal, which is disadvantageous for mass production.

[0120] According to an embodiment of the present invention, a microsphere manufacturing system includes an emulsion forming unit which continuously forms an emulsion containing a first raw material for a continuous phase and a second raw material for a dispersed phase, a first solvent extraction removal unit which receives the emulsion formed from the emulsion forming unit and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres, and a second solvent extraction removal unit which is separated from the first solvent extraction removal unit and receives the emulsion formed from the emulsion forming unit and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres. Therefore, the efficiency of the emulsion forming process and the solvent extraction removal process can be maximized, and high quality microspheres can be mass-produced at low cost.

[0121] In the embodiment of the present invention, the dispersed phase of the emulsion contains an oil phase solution, and the continuous phase contains an aqueous phase solution, but the present invention is not limited to this. The dispersed phase of the emulsion may contain an aqueous phase solution, and the continuous phase may contain an oil phase solution, and in this case, the drug contained in the microspheres may contain a hydrophilic therapeutic agent.

[0122] Although the above description has been given with reference to the embodiments, it will be understood that those skilled in the art can make various modifications and variations of the present invention without departing from the spirit and scope of the present invention as set forth in the claims below. [Explanation of symbols]

[0123] 110 First raw material storage section 120 Second raw material storage section 200 Emulsion forming section 310 First Solvent Extraction Removal Section 320 Second Solvent Extraction Removal Section 400 Cleaning section 500 Drying section

Claims

1. a first raw material storage section in which a first raw material is stored; a second raw material storage section in which a second raw material including a solvent, a biodegradable polymer, and a drug is stored; an emulsion forming section for continuously forming an emulsion including the first raw material of a continuous phase and the second raw material of a dispersed phase; a first solvent extraction removal unit that receives the emulsion formed from the emulsion forming unit, and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres; and a second solvent extraction removal unit that is separated from the first solvent extraction removal unit, receives the emulsion formed from the emulsion forming unit, and extracts and removes the solvent from the dispersed phase of the emulsion to form microspheres.

2. 2. The system for producing microspheres according to claim 1, wherein the emulsion forming unit includes a first flow path through which the first raw material flows, a second flow path through which the second raw material flows, and a third flow path through which the emulsion containing the continuous phase and the dispersed phase flows.

3. 3. The system for producing microspheres according to claim 2, wherein the emulsion forming section includes a plurality of microchips, each of the microchips including the first flow path, the second flow path and the third flow path.

4. 2. The system of claim 1, wherein the emulsion forming unit sequentially supplies the continuously produced emulsion to the first solvent extraction removal unit and the second solvent extraction removal unit.

5. 2. The system for producing microspheres according to claim 1, further comprising a washing unit for washing the microspheres formed in the first solvent extraction unit or the second solvent extraction unit with a washing solution.

6. 6. The system for producing microspheres according to claim 5, wherein the cleaning unit includes a first cleaning unit for cleaning the microspheres formed in the first solvent extraction removal unit, and a second cleaning unit for cleaning the microspheres formed in the second solvent extraction removal unit, the first cleaning unit and the second cleaning unit being spaced apart from each other.

7. 2. The system of claim 1, further comprising a drying unit for drying the microspheres formed in the first solvent extraction unit or the second solvent extraction unit to obtain a microsphere powder.

8. The first raw material includes water and a surfactant; 2. The system for producing microspheres according to claim 1, wherein the solvent for the second raw material is at least one selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, or a mixture thereof.

9. 2. The system for producing microspheres according to claim 1, wherein each of the first and second solvent extraction and removal units creates a fluid flow in the emulsion to extract the solvent of the second raw material, and removes the extracted solvent by evaporation.

10. 2. The system for producing microspheres according to claim 1, wherein each of the first and second solvent extraction removal units heats the emulsion to a temperature equal to or higher than the boiling point of the solvent to vaporize and remove the solvent.

11. providing a first material and providing a second material comprising a biodegradable polymer, a drug, and a solvent; providing the first raw material and the second raw material to an emulsion forming section, the emulsion forming section continuously forming an emulsion including the first raw material in a continuous phase and the second raw material in a dispersed phase; supplying the emulsion produced from the emulsion forming unit to a first solvent extraction and removal unit, extracting and removing the solvent from the dispersed phase in the first solvent extraction and removal unit to form microspheres; supplying the emulsion produced in the emulsion forming unit to a second solvent extraction and removal unit spaced apart from the first solvent extraction unit, and extracting and removing the solvent from the dispersed phase in the second solvent extraction and removal unit to form microspheres.

12. The method of claim 11, wherein the emulsion is sequentially supplied to the second solvent extraction unit after the first solvent extraction unit has been completed.

13. 13. The method of claim 12, further comprising washing and drying the microspheres formed in the first solvent extraction unit, or drying the microspheres to obtain a dried microsphere powder.

14. After recovering the microspheres formed in the first solvent extraction removal section, 14. The method of claim 13, further comprising the step of: supplying the emulsion newly formed in the emulsion forming unit to the first solvent extraction and removal unit; and extracting and removing the solvent from the second raw material of the dispersed phase of the newly formed emulsion in the first solvent extraction and removal unit to form microspheres.

15. 12. The method for producing microspheres according to claim 11, wherein the emulsion forming unit includes a microchip including a first flow path through which the first raw material flows, a second flow path through which the second raw material flows, and a third flow path through which the emulsion containing the continuous phase and the dispersed phase flows.

16. washing the microspheres formed in the first solvent extraction removal unit in a first washing unit; 14. The method of claim 13, further comprising: washing the microspheres formed in the second solvent extraction removal unit in a second washing unit spaced apart from the first washing unit.

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