Solvent removal device

Abstract

A solvent removal apparatus, the apparatus comprising: a tank configured to contain an emulsion containing a first raw material of a continuous phase and a second raw material of a dispersed phase; a first fluid supply part configured to directly supply bubbles into the emulsion in the tank; and a second fluid supply part configured to directly supply bubbles into the emulsion in the tank, in which the second fluid supply part and the first fluid supply part are separated from each other such that bubbles passing through the first fluid supply part and the second fluid supply part in the emulsion form a rotational flow.

Description

[0001] This application is a divisional application of a Chinese patent application filed on December 3, 2021, with application number 202180084166.4, and invention name “Solvent removal device and microsphere manufacturing method using the same”. Technical Field

[0002] The present invention relates to a solvent removal device and a method for producing microspheres using the solvent removal device, and more particularly to a solvent removal device for extracting and removing a solvent from an emulsion used in producing microspheres and a method for producing microspheres using the solvent removal device. Background Art

[0003] At present, one of the drug delivery systems that is being actively researched, developed and utilized is the so-called polymer drug delivery system (PDDS), which can utilize biodegradable, biocompatible and non-toxic polymers, such as polylactic acid (PLA) / polyethylene glycol (PGA) polymers to release a certain amount of therapeutic agent according to the circulating dosage in a manner that can be adjusted for both hydrophilic and hydrophobic therapeutic agents over a long period of time.

[0004] Such biodegradable polymers can be manufactured in the form of microspheres by various known techniques. When manufacturing these biodegradable polymer microspheres, as the most commonly used method, a known method is used to dissolve the biodegradable polymer or the biodegradable polymer and the substance (drug or other active agent) to be enclosed in a solvent, and disperse or emulsify it in an aqueous solution containing a surfactant. Then, the solvent is removed from the microspheres and dried to obtain a microsphere product. In the process of manufacturing microspheres according to known techniques, toxic solvents such as dichloromethane or chloroform are mainly used when dissolving the biodegradable polymer and the active agent. Therefore, in order to prevent these solvents from remaining in the microsphere product as the final product, it is necessary to invest sufficient time and energy to remove the solvent, thereby increasing the time to obtain the microsphere product, which becomes a factor hindering mass production. Therefore, efforts have been made to mass-produce high-quality microspheres at a low cost.

[0005] In particular, various solvent removal device-related technologies for solvent removal have been developed, but most of them are devices that use an impeller or stirrer coupled to a transmission shaft rotated by a motor to extract and remove the solvent by stirring the emulsion using physical rotational motion. (Patent Document 1) Korean Patent Publication No. 10 2019-0084276 Summary of the invention

[0006] Technical issues

[0007] Therefore, the technical subject of the present invention focuses on these aspects, and an object of the present invention is to provide a solvent removal device which can effectively extract and remove the solvent from the dispersed phase of the emulsion used for producing microspheres and has a simple structure.

[0008] Another object of the present invention is to provide a method for producing microspheres using the above-mentioned solvent removal device.

[0009] Solution to the problem

[0010] A solvent removal device according to one embodiment of the present invention for achieving the above-mentioned purpose includes: a tank body containing an emulsion containing a first raw material of a continuous phase and a second raw material of a dispersed phase; a fluid supply section for supplying fluid to the interior of the tank body to make the emulsion flow; and an exhaust section for discharging gas inside the tank body to the outside of the tank body.

[0011] In one embodiment of the present invention, the fluid supply unit can supply air bubbles to the emulsion contained in the tank.

[0012] In one embodiment of the present invention, the fluid supply unit may include a first fluid supply unit and a second fluid supply unit. The first fluid supply unit and the second fluid supply unit are separately arranged inside the tank body, so that the emulsion can form a rotating flow due to the fluid supplied by the first fluid supply unit and the second fluid supply unit.

[0013] In one embodiment of the present invention, the first fluid supply part and the second fluid supply part can supply fluid in different directions from each other. The tank body includes a bottom formed on a plane formed by a first direction and a second direction perpendicular to the first direction, and can have a side wall extending in a third direction perpendicular to the first direction and the second direction. The first fluid supply part and the second fluid supply part can be separated from each other in the first direction, separated from each other in the second direction, and separated from each other in the third direction.

[0014] In one embodiment of the present invention, the exhaust portion may decompress the interior of the tank by sucking the gas inside the tank.

[0015] In one embodiment of the present invention, the solvent removal device may further include a liquid supply unit for supplying liquid into the interior of the tank, and the liquid may contain a main component of the continuous phase.

[0016] In one embodiment of the present invention, the solvent removal device may further include a liquid discharge unit configured to discharge a portion of the continuous phase of the emulsion in the tank to the outside of the tank.

[0017] In one embodiment of the present invention, the liquid discharge portion may include a tube portion extending into the interior of the tank body and an expansion portion connected to the end of the tube portion. The expansion portion is located at a first height from the bottom of the tank body and contacts the water level of the emulsion, thereby maintaining an appropriate volume of the emulsion in the tank body.

[0018] In one embodiment of the present invention, a filter is formed in the expanded tube portion, so that only the continuous phase of the emulsion can pass through the filter, while the dispersed phase of the emulsion or the microspheres solidified from the dispersed phase cannot pass through.

[0019] In one embodiment of the present invention, the first raw material may include purified water and a surfactant, and the second raw material may include an organic solvent, a biodegradable polymer and a drug.

[0020] In one embodiment of the present invention, the solvent removal device may further include a heating unit for heating the emulsion in the tank.

[0021] A method for producing microspheres according to an embodiment of the present invention for achieving the above-mentioned purpose utilizes a solvent removal device. The solvent removal device includes a tank, a fluid supply portion for supplying fluid to the interior of the tank, and an exhaust portion for exhausting gas inside the tank to the exterior of the tank. The method for producing microspheres includes: a step of preparing a first raw material and a second raw material including a biodegradable polymer, a drug, and a solvent; a step of forming an emulsion containing a continuous phase of the first raw material and a dispersed phase of the second raw material using the first raw material and the second raw material; and a step of extracting and removing the solvent from the dispersed phase of the emulsion using the solvent removal device to form microspheres.

[0022] In one embodiment of the present invention, the fluid supply unit can supply air bubbles to the emulsion contained in the tank body so that the emulsion forms a swirling flow.

[0023] In one embodiment of the present invention, the solvent removal device further includes a liquid supply unit for supplying liquid into the tank body, and a liquid discharge unit for discharging a portion of the continuous phase of the emulsion in the tank body to the outside of the tank body.

[0024] In the step of forming microspheres, the liquid containing the main component of the continuous phase is supplied to the interior of the tank, and a portion of the continuous phase of the emulsion inside the tank is discharged to the outside of the tank, thereby maintaining the water level of the emulsion at a preset appropriate water level.

[0025] In one embodiment of the present invention, the first raw material may include purified water and a surfactant, and the solvent of the second raw material may be an organic solvent.

[0026] Effects of the Invention

[0027] According to an embodiment of the present invention, the solvent removal device includes a fluid supply part for supplying fluid to the inside of the tank body to make the emulsion flow, and an exhaust part for exhausting the gas inside the tank body to the outside of the tank body, so that the extraction and evaporation of the solvent can be easily implemented without the need for an impeller or stirrer structure combined with a transmission shaft rotated by a motor. Therefore, the solvent removal device has a simpler structure than the previous structure, and can have a favorable effect in washing the inside of the tank body, sealing for sterilization, etc.

[0028] In addition, the solvent removal device further includes a liquid supply unit for supplying liquid to the inside of the tank body and a liquid discharge unit for discharging a portion of the continuous phase of the emulsion in the inside of the tank body to the outside of the tank body, thereby enabling efficient and continuous extraction and evaporation of the solvent. Thus, the separate filtering and washing steps that follow the solvent removal step can be omitted or minimized, thereby providing an efficient method for producing microspheres.

[0029] However, the effects of the present invention are not limited to the above effects, and various extensions can be made without departing from the spirit and scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 FIG. 1 is a schematic diagram of a solvent removal device according to an embodiment of the present invention.

[0031] Figure 2 It is a top cross-sectional view of a solvent removal apparatus according to an embodiment of the present invention.

[0032] Figure 3 FIG. 1 is a diagram showing the steps of a method for producing microspheres using a solvent removal apparatus according to an embodiment of the present invention. DETAILED DESCRIPTION

[0033] Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to the accompanying drawings.

[0034] The present invention may have many variations and various forms, so specific embodiments are illustrated in the drawings and described in detail herein. However, this is not intended to limit the present invention to a specific disclosed form, and should be understood to include all variations, equivalents, and even substitutes included in the concept and technical scope of the present invention.

[0035] Figure 1 FIG. 1 is a schematic diagram of a solvent removal device according to an embodiment of the present invention.

[0036] Reference Figure 1 The solvent removal device may include a tank body 100 , a liquid supply part 200 , a liquid discharge part 300 , a fluid supply part 400 , an exhaust part 500 , and a heating part 600 .

[0037] The tank 100 may contain an emulsion containing a first raw material of a continuous phase and a second raw material of a dispersed phase. The tank 100 may include a wall 110 forming a space for containing the emulsion EM therein. The tank 100 may include a bottom formed on a plane formed by a first direction D1 and a second direction D2 perpendicular to the first direction D1, and may include a side wall portion extending in a third direction D3 perpendicular to the first direction D1 and the second direction D2.

[0038] The first raw material may include pure water and a surfactant. For example, the first raw material may be an aqueous solution in which polyvinyl alcohol (PVA) is dissolved in pure water as a surfactant.

[0039] The type of the above-mentioned surfactant is not particularly limited, and any surfactant can be used as long as it can help the biodegradable polymer solution form a stable droplet dispersion phase in the aqueous solution phase as the continuous phase. The above-mentioned surfactant can preferably be selected from the group consisting of methyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives and mixtures thereof.

[0040] The second raw material may include an organic solvent, a biodegradable polymer dissolved in the organic solvent, and a drug as an oil-phase solution. The organic solvent is a solvent for dissolving the biodegradable polymer, and may have a property of not being miscible with water. The type of the organic solvent for dissolving the biodegradable polymer is not particularly limited, and preferably, one or more may be selected from the group consisting of dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, acetic acid, methanol, ethanol, propanol, benzyl alcohol, and a mixed solvent thereof.

[0041] The type of the biodegradable polymer is not particularly limited, and preferably polyester can be used, and in particular, can be selected from the group consisting of polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polycaprolactone and mixtures thereof.

[0042] The types of the above-mentioned drugs are not particularly limited, and for example, they can be selected from dementia therapeutic agents; Parkinson's disease therapeutic agents; anticancer agents; antipsychotic drugs such as antianxiety agents, antidepressants, sedatives and psychotherapeutics; cardiovascular therapeutic agents such as hyperlipidemia therapeutic agents, hypertension therapeutic agents, hypotension therapeutic agents, antithrombotic agents, vasodilators and arrhythmia therapeutic agents; epilepsy therapeutic agents; gastrointestinal therapeutic agents such as antiulcer agents; rheumatoid therapeutic agents; antispasmodics; tuberculosis therapeutic agents; muscle relaxants; osteoporosis therapeutic agents; erectile dysfunction Therapeutic agents; hemostatic agents; hormonal agents such as sex hormones; diabetes therapeutic agents; antibiotics; antifungal agents; antiviral agents; antipyretic, analgesic and anti-inflammatory agents; autonomic nerve modulators; corticosteroids; diuretics; antidiuretics; analgesics; anesthetics; antihistamines; antiprotozoal agents; antianemic agents; antiasthmatic agents; antispasmodics; antidote; antimigraine agents; antiemetics; antiparkinson's agents; antiepileptic agents; antiplatelet agents; antitussive and expectorant agents; bronchodilators; cardiotonic agents; immunomodulators; protein drugs; gene drugs; and mixtures thereof.

[0043] Among the types of the above-mentioned drugs, although not particularly limited, it is 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, pamacoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, goserelin, leuprolide, triptorelin, buserelin, nafarelin, deserorelin, octreotide, pasireotide, lanreotide, vapreotide, exenatide, liraglutide, lixisenatide, semaglutide, and salts thereof and mixtures thereof.

[0044] The emulsion EM can be formed using the first raw material and the second raw material by various known methods, such as a method of mixing and stirring the first raw material and the second raw material, or a microfluidic method of forming microsphere droplets by flowing in a microchannel.

[0045] In addition, in the embodiments of the present invention, the dispersed phase of the emulsion EM is described as comprising an oil phase solution and the continuous phase is comprising an aqueous phase solution, but the present invention is not limited thereto. The dispersed phase of the emulsion may also be comprising an aqueous phase solution and the continuous phase may be comprising an oil phase solution, in which case the drug contained in the microspheres may comprise a hydrophilic therapeutic agent.

[0046] The liquid supply unit 200 may supply the liquid to the inside of the tank body 100. The liquid supply unit 200 may supply the liquid to the inside of the tank body 100 through a liquid supply pipe 210 penetrating the wall body 110 of the tank body 100. The liquid may contain a substance that is the same as or similar to the continuous phase of the emulsion EM. For example, when the first raw material as the continuous phase of the emulsion EM contains pure water and a surfactant, the liquid may contain pure water.

[0047] The liquid supply pipe 210 may extend from the upper portion of the tank body 100 to the space side containing the emulsion EM. The portion of the liquid supply pipe 210 penetrating the wall body 110 of the tank body 100 is formed at the upper portion of the tank body 100, so the possibility of leakage of the emulsion EM from the portion penetrating the wall body 110 is small.

[0048] The liquid discharge unit 300 can discharge a portion of the continuous phase of the emulsion EM in the tank body 100 to the outside of the tank body 100. Thus, a portion of the continuous phase containing the organic solvent extracted from the dispersed phase of the emulsion EM is removed, and a new aqueous solution (supplied by the liquid supply unit 200) that can replace the removed continuous phase is supplied, so that the organic solvent present in the dispersed phase can be fully extracted into the continuous phase and evaporated.

[0049] The solvent removal device may further include a discharged liquid storage unit 310 and a liquid discharge pipe 320. The liquid discharge pipe 320 may include a pipe unit 322, a pipe expansion unit 324, and a filter 340 formed on the pipe expansion unit 324. The discharged liquid storage unit 310 may be connected to the liquid discharge unit 300 to store a portion of the discharged continuous phase. One end of the pipe unit 322 may be connected to the liquid discharge unit 300, and the other end may be connected to the pipe expansion unit 324. The pipe unit 322 may extend from the upper portion of the tank body 100 to the space side containing the emulsion EM, so that the pipe expansion unit 324 may be formed at a first height h1 from the bottom of the tank body 100.

[0050] The emulsion EM is discharged to the outside of the tank body 100 through the filter 340 formed at the end of the expansion tube 324, so if the first height h1 is appropriately adjusted, the water level of the emulsion EM can be maintained at an appropriate position. That is, the expansion tube 324 is located at the first height h1 from the bottom of the tank body 100, and by contacting the water level surface of the emulsion EM, the appropriate volume of the emulsion EM inside the tank body 100 can be maintained.

[0051] The filter 340 is formed in the expansion tube portion 324, so that only the continuous phase of the emulsion can pass through the filter, while the dispersed phase of the emulsion or the microspheres obtained by solidifying the dispersed phase cannot pass through. For example, the filter 340 can have pores less than 2 / 3 of the average size of the dispersed phase of the emulsion EM, for example, the pore size of the filter 340 can be about 10 um (micrometer). The filter 340 can use a variety of known filters such as a microporous filter and a microporous membrane.

[0052] On the other hand, as the emulsion EM is stirred, a large amount of foam will be generated on the water level of the emulsion EM. In particular, when the emulsion EM contains a surfactant as a constituent component, the degree of foam generation may increase. The foam generated on the water level of the emulsion EM makes it difficult to confirm the current water level of the emulsion EM, and in particular, when a sensor device such as an optical sensor is used to confirm the water level of the emulsion EM, the measurement accuracy will inevitably decrease. However, according to the present embodiment, only by setting the expansion tube portion 324 to be located at the first height h1 from the bottom of the tank body 100, the appropriate water level of the emulsion EM can be easily maintained without a separate sensor device.

[0053] The fluid supply unit 400 can supply fluid to the emulsion EM contained in the tank 100. The supply of the fluid can make the emulsion EM flow, accelerating the extraction and evaporation of the solvent from the dispersed phase to the continuous phase of the emulsion EM. The fluid is a gas and can be supplied to the emulsion EM in the form of bubbles.

[0054] The fluid supply part 400 may supply the fluid stored in the supply fluid storage part 410 to the emulsion EM through a fluid supply mechanism formed inside the tank body 100. The supply fluid storage part 410 may store a gas, such as nitrogen or air.

[0055] The fluid supply mechanism may include a first fluid supply part Ain1 and a second fluid supply part Ain2. The first fluid supply part Ain1 and the second fluid supply part Ain2 may be connected to the fluid supply part 400 via a first fluid supply pipe 420a and a second fluid supply pipe 420b, respectively.

[0056] The first fluid supply part Ain1 and the second fluid supply part Ain2 are arranged separately from each other inside the tank body, so that a swirling flow can be formed in the emulsion EM by the fluid supplied by the first fluid supply part Ain1 and the second fluid supply part Ain2 (see Figure 2(a) and (b)).

[0057] The fluid, i.e., the bubbles, supplied to the emulsion EM by the fluid supply unit 400 play a role in stirring the emulsion EM. As a result, the dispersed phase in the emulsion EM can be prevented from sinking or adhering to each other, thereby accelerating the extraction and evaporation of the solvent. Furthermore, the bubbles in the emulsion EM can be brought into contact to maximize the extraction of the solvent from the dispersed phase. For example, this embodiment can achieve an effect similar to the effect of adding a purge of nitrogen to an emulsion stirred by a common stirrer.

[0058] In fact, it has been confirmed through experiments that the use of bubbles is more effective than the use of a physical stirrer to extract and evaporate the solvent.

[0059] For an emulsion containing an organic solvent in the dispersed phase, if it is kept or stirred for a certain period of time at a temperature below the boiling point, the organic solvent can be extracted from the biodegradable polymer solution in the form of droplets as the dispersed phase to the continuous phase. A portion of the organic solvent extracted to the continuous phase can 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 can solidify to form microspheres. At this time, the extraction and evaporation can be accelerated by causing the emulsion to flow or heating it. For example, the emulsion can be made to form a fluid flow, thereby extracting the solvent of the second raw material, and the extracted solvent can be evaporated and removed.

[0060] The exhaust part 500 can suck the gas inside the tank body 100 and reduce the pressure inside the tank body 100. As a result, the boiling point of the organic solvent is reduced, and the organic solvent extracted into the continuous phase can be vaporized even at low temperatures. In addition, the organic solvent gas extracted and evaporated from the dispersed phase of the emulsion EM can be discharged to the outside of the tank body 100 through the exhaust part 500. As a result, the partial pressure of the organic solvent in the tank body 100 is reduced, and continuous solvent extraction and evaporation can be achieved.

[0061] The exhaust unit 500 may inhale gas inside the can body 100 through an exhaust pipe 510 inserted through an upper portion of the can body 100 .

[0062] The heating unit 600 may heat the emulsion EM in the tank 100. The heating unit 600 may have various known structures capable of heating the inside of the tank 100. The emulsion EM is heated to a boiling point of the organic solvent or higher, for example, 40 degrees, by the heating unit 600, so that the solvent can be vaporized and removed.

[0063] Although not shown, the solvent removal apparatus may further include a control unit for controlling each component in the solvent removal apparatus, so that the supply and discharge of fluid, the supply and discharge of liquid, the exhaust, etc. can be controlled to a desired degree.

[0064] According to this embodiment, the solvent removal device includes a fluid supply part for supplying fluid to the inside of the tank body to make the emulsion flow, and an exhaust part for exhausting the gas inside the tank body to the outside of the tank body, so that the extraction and evaporation of the solvent can be easily implemented without the need for an impeller or stirrer structure combined with a transmission shaft rotated by a motor. Therefore, the solvent removal device has a simpler structure than the previous structure, and can have a favorable effect in washing the inside of the tank body, sealing for sterilization, etc.

[0065] In addition, the solvent removal device further includes a liquid supply unit for supplying liquid to the inside of the tank body and a liquid discharge unit for discharging a portion of the continuous phase of the emulsion in the inside of the tank body to the outside of the tank body, thereby enabling efficient and continuous extraction and evaporation of the solvent. Thus, the separate filtering and washing steps that follow the solvent removal step can be omitted or minimized, thereby providing an efficient method for producing microspheres.

[0066] On the other hand, the method for recovering the microspheres from the continuous phase containing the microspheres and washing them is not particularly limited, and the microspheres may be recovered by filtration or centrifugal separation and then washed with water.

[0067] After the filtering and washing steps, the obtained microspheres can be dried by a common drying method to finally obtain dry microsphere powder. The method for drying the microspheres is not limited, and freeze drying, vacuum drying or reduced pressure drying can be used.

[0068] After the drying process of the microspheres, the target monodisperse biodegradable polymer-based microsphere powder is finally obtained. Then, the obtained microsphere powder is suspended in a suspension and filled into a suitable container, such as a disposable syringe, to obtain the final product.

[0069] Figure 2 It is a top cross-sectional view of a solvent removal apparatus according to an embodiment of the present invention.

[0070] Reference Figure 1 and 2 The solvent removal device may include a tank body 100 , a liquid supply part 200 , a liquid discharge part 300 , a fluid supply part 400 , an exhaust part 500 , and a heating part 600 .

[0071] The tank 100 may contain an emulsion containing a first raw material of a continuous phase and a second raw material of a dispersed phase. The tank 100 may include a wall 110 forming a space for containing the emulsion EM therein. The tank 100 may include a bottom formed on a plane formed by a first direction D1 and a second direction D2 perpendicular to the first direction D1, and may include a side wall portion extending in a third direction D3 perpendicular to the first direction D1 and the second direction D2.

[0072] The fluid supply part 400 may supply the fluid stored in the supply fluid storage part 410 to the emulsion EM through a fluid supply mechanism formed inside the tank body 100. The fluid supply mechanism may include a first fluid supply part Ain1 and a second fluid supply part Ain2.

[0073] Figure 2 (a) shows a case where the top cross-sectional view of the tank body 100 has a quadrilateral shape. Figure 2 (b) shows a case where the top cross-sectional view of the can body 100 has a circular shape, but the can body 100 may have various shapes.

[0074] The first fluid supply part Ain1 and the second fluid supply part Ain2 may be formed to supply fluid in different directions, that is, the first fluid supply part Ain1 may supply fluid in the second direction D2, and the second fluid supply part Ain2 may supply fluid in the opposite direction of the second direction D2.

[0075] The first fluid supply part Ain1 and the second fluid supply part Ain2 can be separated from each other in the first direction D1, separated from each other in the second direction D2, and separated from each other in the third direction D3. Thus, in the tank body 100, the emulsion EM can form a three-dimensional rotating flow, and the best effect can be obtained with a small amount of fluid supply parts (gas supply pipes for supplying bubbles). On the other hand, in the present embodiment, the fluid supply mechanism includes two fluid supply parts, but is not limited to this. The gas supply pipe for supplying bubbles in the fluid supply part can also be provided with only one, or more than three can be formed at different positions.

[0076] Figure 3 FIG. 1 is a diagram showing the steps of a method for producing microspheres using a solvent removal apparatus according to an embodiment of the present invention.

[0077] Reference Figure 3The microsphere manufacturing method is implemented by using a solvent removal device. The solvent removal device includes a tank, a fluid supply unit for supplying fluid to the inside of the tank, and an exhaust unit for exhausting gas inside the tank to the outside of the tank.

[0078] The microsphere manufacturing method includes: preparing a first raw material and preparing a second raw material containing a biodegradable polymer, a drug and a solvent (S100); using the first raw material and the second raw material to form an emulsion containing the first raw material as a continuous phase and the second raw material as a dispersed phase (S200); and using the solvent removal device to extract and remove the solvent from the dispersed phase of the emulsion to form microspheres (S300).

[0079] In the step (S100) of preparing the first raw material and preparing the second raw material including the biodegradable polymer, the drug and the solvent, the first raw material and the second raw material may be prepared. The first raw material may include purified water and a surfactant. The second raw material may include an organic solvent, a biodegradable polymer dissolved in the organic solvent and the drug as an oil-phase solution.

[0080] In the step (S200) of forming an emulsion containing the first raw material as a continuous phase and the second raw material as a dispersed phase using the first raw material and the second raw material, the emulsion can be formed using the first raw material and the second raw material by various known methods. For example, a method of mixing and stirring the first raw material and the second raw material, a microfluidic method of forming microsphere droplets through the flow of a microchannel, etc. can be used. The emulsion contains the first raw material as a continuous phase and the second raw material as a dispersed phase.

[0081] In the step (S300) of extracting and removing the solvent from the dispersed phase of the emulsion by the solvent removal device to form microspheres, a fluid can be supplied to the emulsion contained in the tank to make the emulsion flow. The fluid is a gas and can be supplied to the emulsion in the form of bubbles. Thus, the extraction of the solvent from the dispersed phase of the emulsion to the continuous phase and the evaporation of the extracted solvent can be accelerated. The gas can be nitrogen or air.

[0082] On the other hand, the solvent removal device may further include a liquid supply unit for supplying liquid to the inside of the tank body and a liquid discharge unit for discharging a portion of the continuous phase of the emulsion in the tank body to the outside of the tank body. By removing a portion of the continuous phase containing the organic solvent extracted from the dispersed phase of the emulsion and supplying a new aqueous solution that can replace the removed continuous phase (supplied by the liquid supply unit), the solvent present in the dispersed phase can be fully extracted into the continuous phase and evaporated.

[0083] In addition, the solvent removal device may further include a heating unit for heating the emulsion in the tank. The emulsion may be heated to a boiling point or higher of the solvent to vaporize and remove the solvent.

[0084] Thus, the dispersed phase in the form of droplets can be solidified to form microspheres.

[0085] The microsphere manufacturing method may further include the step of washing and drying the formed microspheres, or drying to obtain a dry microsphere powder (S400). The solidified microspheres may be recovered by filtering or centrifugal separation, and then washed with water. After filtering and washing, the obtained microspheres may be dried by a conventional drying method to finally obtain a dried microsphere powder. The method of drying the microspheres is not limited, and freeze drying, vacuum drying or reduced pressure drying may be used.

[0086] After the drying process of the microspheres, the target monodisperse biodegradable polymer-based microsphere powder is finally obtained. Then, the obtained microsphere powder is suspended in a suspension and filled into a suitable container, such as a disposable syringe, to obtain the final product.

[0087] According to an embodiment of the present invention, the solvent removal device includes a fluid supply part for supplying fluid to the inside of the tank body to make the emulsion flow, and an exhaust part for exhausting the gas inside the tank body to the outside of the tank body, so that the extraction and evaporation of the solvent can be easily implemented without an impeller or stirrer structure combined with a transmission shaft rotated by a motor. Therefore, the solvent removal device has a simpler structure than the previous structure, and can have a favorable effect in washing the inside of the tank body, sealing for sterilization, etc.

[0088] In addition, the solvent removal device further includes a liquid supply unit for supplying liquid to the inside of the tank body and a liquid discharge unit for discharging a portion of the continuous phase of the emulsion in the inside of the tank body to the outside of the tank body, thereby enabling efficient and continuous extraction and evaporation of the solvent. Thus, the separate filtering and washing steps that follow the solvent removal step can be omitted or minimized, thereby providing an efficient method for producing microspheres.

[0089] On the other hand, the embodiments of the present invention illustrate the case where the dispersed phase of the emulsion includes an oil phase solution and the continuous phase includes an aqueous phase solution, but the present invention is not limited thereto. The dispersed phase of the emulsion may also include an aqueous phase solution and the continuous phase may include an oil phase solution, in which case the drug contained in the microspheres may include a hydrophilic therapeutic agent.

[0090] Although the above description is made with reference to the embodiments, those skilled in the art should be aware that various modifications and changes may be made to the present invention without departing from the concept and scope of the present invention as described in the following claims.

[0091] (Explanation of symbols)

[0092] 100: Tank 110: Wall

[0093] 200: Liquid supply unit 210: Liquid supply pipe

[0094] 300: Liquid discharge unit 310: Discharge liquid storage unit

[0095] 320: Liquid discharge pipe 340: Filter

[0096] 400: Fluid supply unit 410: Supply fluid storage unit

[0097] 420a, 420b: first and second fluid supply pipes

[0098] Ain1, Ain2: first and second fluid supply parts

[0099] 500: Exhaust section 510: Exhaust pipe

[0100] 600: Heating unit

Claims

1. A solvent removal device, comprising: a tank configured to contain an emulsion comprising a first raw material in a continuous phase and a second raw material in a dispersed phase; a first fluid supply unit configured to directly supply air bubbles into the emulsion in the tank; The second fluid supply part is configured to directly supply bubbles to the emulsion in the tank, wherein the second fluid supply part is separated from the first fluid supply part, so that the bubbles in the emulsion passing through the first fluid supply part and the second fluid supply part form a rotating flow.

2. The device according to claim 1, wherein: The can body has a bottom formed on a plane formed by a first direction and a second direction perpendicular to the first direction, and has a side wall portion extending in a third direction perpendicular to the first direction and the second direction. The first fluid supply portion and the second fluid supply portion are separated from each other in the first direction, separated from each other in the second direction, and separated from each other in the third direction.

3. The apparatus according to claim 1, further comprising: an exhaust portion configured to discharge the gas inside the tank to the outside of the tank, The exhaust unit inhales the gas in the tank and reduces the pressure inside the tank.

4. The apparatus according to claim 1, further comprising: a liquid supply unit configured to supply liquid into the tank, Wherein, the liquid contains the main component of the continuous phase.

5. The device according to claim 4, further comprising: The liquid discharge unit is configured to discharge a portion of the continuous phase of the emulsion in the tank body to the outside of the tank body.

6. The device according to claim 5, in, The liquid discharge portion includes a tube portion extending to the tank body and a flared tube portion connected to a distal end of the tube portion, and The expansion tube portion is located at a first height from the bottom of the tank body and is in contact with the water level of the emulsion to maintain an appropriate volume of the emulsion inside the tank body.

7. The device according to claim 6, wherein: A filter is formed in the expanded tube portion so that only the continuous phase of the emulsion passes through the filter, while the dispersed phase of the emulsion or microspheres obtained by solidifying the dispersed phase does not pass through the filter.

8. The device according to claim 1, wherein: The first raw material comprises pure water and a surfactant, and the second raw material comprises an organic solvent, a biodegradable polymer and a drug.

9. The apparatus according to claim 1, further comprising: A heating unit is configured to heat the emulsion in the tank.

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