Emulsion homogenization apparatus and method for preparing sustained release microspheres with improved drug encapsulation efficiency

Abstract

An emulsion homogenizing apparatus according to an embodiment of the present invention comprises: a stirring container; a stirring unit provided with a stirring shaft and stirring blades, and installed inside the stirring container so as to be rotatable; and a drug solution injection member having a discharge port through which a main component aqueous solution containing a drug is discharged in the form of droplets, the discharge port being installed in the stirring container between the bottom surface of the stirring container and the stirring blade so as to face the stirring blade.

Description

Technical Field

[0001] The present invention relates to an emulsion homogenization device and a method for preparing sustained-release microspheres with an improved drug encapsulation rate. More specifically, the present invention relates to an emulsion homogenization device and a method for preparing sustained-release microspheres with an improved drug encapsulation rate, which can increase the drug encapsulation rate in microspheres by homogenizing a W1 / O emulsion. Background Art

[0002] Sustained-release injection preparations refer to injection preparations formulated such that a drug can be continuously and uniformly released while maintaining its biological activity in the body upon subcutaneous or intramuscular injection.

[0003] Conventional preparation methods for sustained-release injection preparations include a coacervation method, a melt injection method, a spray drying method, and a solvent evaporation method. Among these methods, the most commonly used is the solvent evaporation method, which is divided into a double emulsion evaporation method (W / O / W emulsion) and a single emulsion evaporation method (O / W emulsion).

[0004] Figure 1 A schematic diagram showing a stirring device according to the prior art is shown.

[0005] See Figure 1 , in a conventional microsphere manufacturing process, when forming a W1 / O emulsion, an aqueous solution W1 containing the main components of a drug and a polymer oil solution O are stirred and homogenized in a stirring container 10 by a stirring device 20. Herein, the aqueous solution W1 of the main components is an aqueous phase, and the polymer oil solution O is an oil phase.

[0006] Conventionally, after putting the polymer oil solution O into the stirring container 10, the aqueous solution W1 of the main components is added to the stirring container 10.

[0007] However, due to the specific gravity difference between dichloromethane (MC), which is a solvent of the polymer oil solution O, and water, which is a solvent of the aqueous solution of the main components, layer separation occurs, and the aqueous solution W1 of the main components is located on the upper surface of the polymer oil solution O.

[0008] After that, the stirring device 20 rotates to stir the aqueous solution W1 of the main components and the polymer oil solution O, thereby homogenizing the mixture of the aqueous solution W1 of the main components and the polymer oil solution O.

[0009] During homogenization using the stirring device 20, when the volume of the mixture of the polymer oil phase solution O (oil phase) and the aqueous solution W1 of the main components (aqueous phase) is small, the mixing method has no significant effect on the encapsulation efficiency. However, as the volume of the mixture increases, due to the high viscosity of the polymer oil phase solution O, the mixing uniformity of the aqueous solution W1 of the main components decreases.

[0010] In order to uniformly mix the high-viscosity polymer oil solution O with the main component aqueous solution W1, it is necessary to increase the rotation speed (rpm) and stirring time of the stirring device 20. At this time, due to the generation of heat, the solvent dichloromethane (MC) (boiling point: 39°C to 40°C) of the polymer oil solution O boils and volatilizes, so the concentration of the polymer oil solution O changes.

[0011] As described above, when the volume of the mixture increases, the mixture is not stirred evenly, and when the mixture is not stirred evenly, the emulsification of the mixture becomes difficult, so the drug encapsulation efficiency decreases. Summary of the Invention

[0012]

Technical Problem

[0013] An object of the present invention is to provide an emulsion homogenization device, in which while pre-stirring an oily polymer aqueous solution O in a stirring container, the main component aqueous solution W1 is injected in the form of droplets below the stirring blade.

[0014] Furthermore, another object of the present invention is to provide an emulsion homogenization device that can homogenize the W1 / O emulsion by stirring the main component aqueous solution W1 injected in the form of droplets together with the polymer oil solution O while being dispersed by the vortex of the polymer oil solution O.

[0015] Furthermore, another object of the present invention is to provide an emulsion homogenization device that can improve the drug encapsulation rate in microspheres by homogenizing the W1 / O emulsion and a method for manufacturing sustained-release microspheres with an improved drug encapsulation rate.

[0016]

Technical Solution

[0017] In order to achieve the above object, an emulsion homogenization device according to an embodiment of the present invention includes: a stirring container; a stirring unit including a stirring shaft and stirring blades installed on the stirring shaft, the stirring blades being rotatably provided in the stirring container; and a liquid medicine injection member having a discharge port through which the main component aqueous solution containing the drug is discharged in the form of droplets.

[0018] Furthermore, the discharge port is located between the bottom surface of the stirring container and the stirring blade and is arranged to face the stirring blade.

[0019] The liquid medicine injection member can be arranged to discharge the main component aqueous solution in the form of droplets toward the stirring blade.

[0020] Furthermore, the liquid medicine injection member can have a discharge port spaced apart from the stirring blade.

[0021] Furthermore, the emulsion homogenization device can further include a control unit for controlling the stirring unit and the liquid medicine supply member.

[0022] In addition, the control unit can be configured to, before supplying the aqueous solution of the main component through the liquid medicine injection member, when the polymer oil phase solution is accommodated in the stirring container, perform stirring of the polymer oil phase solution by rotating the stirring blade at a first speed.

[0023] In addition, the control unit can be configured to supply the aqueous solution of the main component into the stirring container through the liquid medicine supply member and increase the rotation speed of the stirring blade to a second speed greater than the first speed while stirring the polymer oil phase solution.

[0024] In addition, the liquid medicine injection member can include an injection tube.

[0025] In addition, the injection tube can be arranged in the stirring container in a state of being bent at least twice.

[0026] In addition, a main body through-hole can be provided at the bottom surface of the stirring container at a position facing the stirring blade, and the liquid medicine injection member can be inserted into the stirring container through the main body through-hole, and the discharge port can be installed facing the stirring blade.

[0027] In addition, the stirring unit can have a stirring through-hole passing through the stirring shaft and the stirring blade, the liquid medicine injection member can be arranged in the stirring unit along the stirring through-hole, and the discharge port can be arranged to pass through the stirring through-hole and be exposed below the stirring blade.

[0028] In addition, according to an embodiment of the present invention, a method for preparing sustained-release microspheres with an improved drug encapsulation rate includes: S1) a step of using the emulsion homogenization device described in claim 1 to stir the polymer oil phase solution O as the oil phase; S2) a step of injecting the aqueous solution W1 of the main component in the form of droplets into the polymer oil phase solution O being stirred; S3) a step of forming a W1 / O emulsion through a first homogenization process of the aqueous solution W1 of the main component and the polymer oil phase solution; S4) a step of injecting the W1 / O emulsion in the form of droplets into the aqueous polymer solution W2 while stirring the aqueous polymer solution W2; S5) a step of forming a W1 / O / W2 emulsion through a second homogenization process of the aqueous polymer solution W2 and the W1 / O emulsion; and S6) a step of forming microspheres through an underwater drying process of the W1 / O / W2 emulsion.

[0029] In step S2, the droplets of the aqueous solution W1 of the main component can be injected below the stirring unit of the emulsion homogenization device and mixed with the polymer oil phase solution O while being dispersed by the vortex of the polymer oil phase solution O.

[0030] In step S2, the polymer oil phase solution O can be stirred at a speed 1.5 times faster than the speed in step S1.

[0031] In step S4, while the aqueous polymer solution W2 flows into the stirring container, the W1 / O emulsion can be injected within a predetermined time at a speed that is 1 / 100 or less than the injection speed of the aqueous polymer solution W2.

[0032] The polymer oil phase solution O can be a solution obtained by dissolving a polymer material such as polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) in dichloromethane (MC).

[0033] In addition, the aqueous polymer solution W2 can be a solution obtained by dissolving a polymer substance such as polyvinyl alcohol (PVA) in water for injection (WFI).

[0034] In addition, the main component aqueous solution W1 can be a solution obtained by dissolving a drug in WFI.

[0035] In this article, the drug can be leuprorelin acetate, and the chemical formula of leuprorelin acetate can be (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide; [(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate.

[0036]

Beneficial effects

[0037] As described above, the emulsion homogenization device according to at least one embodiment of the present invention has the following effects.

[0038] While the polymer oil phase solution O is being pre-stirred, the main component aqueous solution can be injected in the form of droplets below the stirring blade in the stirring container. At this time, the injected droplets of the main component aqueous solution can be dispersed by the vortex of the polymer oil phase solution O being stirred and stirred together with the polymer oil phase solution O. Therefore, the main component aqueous solution W1 and the polymer oil phase solution O can be stirred evenly, so that the W1 / O emulsion can be homogenized.

[0039] In addition, the method for preparing sustained-release microspheres with an improved drug encapsulation rate using an emulsion homogenization device can increase the drug encapsulation rate by approximately two times compared to the conventional method of homogenizing a W1 / O emulsion. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 FIG. shows a schematic diagram of a stirring device according to the prior art.

[0041] Figure 2 FIG. shows an operating state diagram of an emulsion homogenization device according to an embodiment of the present invention.

[0042] Figures 3 to 5 FIG. is a schematic structural diagram of an emulsion homogenization device according to various embodiments.

[0043] Figure 6 FIG. shows a flowchart of a method for preparing sustained-release microspheres with an improved drug encapsulation rate according to an embodiment of the present invention. DETAILED DESCRIPTION

[0044] Hereinafter, an emulsion homogenization device and a method for preparing sustained-release microspheres with an improved drug encapsulation rate according to preferred embodiments of the present invention will be described with reference to the accompanying drawings.

[0045] Figure 2 FIG. shows an operating state diagram of an emulsion homogenization device according to an embodiment of the present invention, and Figures 3 to 5 is a schematic structural diagram of an emulsion homogenization device according to various embodiments.

[0046] Referring to Figure 2 and Figure 3 , an emulsion homogenization device 100 according to an embodiment of the present invention includes a stirring container 110, a stirring unit 120, and a liquid medicine injection member 130.

[0047] The stirring unit 120 includes a stirring shaft 121 and stirring blades 122 mounted on the stirring shaft 121. In addition, the stirring unit 120 is arranged such that the stirring blades 122 can rotate within the stirring container 110. The stirring unit 120 may include a driving unit 123 (e.g., a motor, etc.) for rotating the stirring shaft 121.

[0048] As described by Figure 1 , the stirring container 110 and the stirring unit 120 are well-known components, and their detailed descriptions will be omitted in this embodiment.

[0049] The liquid medicine injection component 130 is arranged to supply the aqueous solution W1 of the main component into the stirring container 110. Herein, the aqueous solution W1 of the main component is a solution in which a drug is dissolved in water for injection (WFI), and various types of drugs can be used according to the type of injection prepared.

[0050] The liquid medicine injection component 130 has a discharge port 131, and the aqueous solution of the main component containing the drug is discharged through the discharge port 131 in the form of droplets. In addition, the discharge port 131 is located between the bottom surface 112 of the stirring container 110 and the stirring blade 120, and the discharge port 131 is arranged to face the stirring blade 120.

[0051] The liquid medicine injection component 130 can be arranged to discharge the aqueous solution of the main component towards the stirring blade 120 in the form of droplets. In addition, the liquid medicine injection component 130 can be arranged such that the discharge port 131 is spaced apart from the stirring blade 120 by a predetermined distance.

[0052] In addition, the liquid medicine injection component 130 may include an injection tube 133. In this embodiment, the liquid medicine injection component 130 may include an injection tube 133 with a diameter in single - digit mm units (for example, 3 mm to 5 mm). The discharge port 131 of the liquid medicine injection component 130 can discharge the aqueous solution of the main component in the form of droplets. The liquid medicine injection component 130 can be installed in the stirring container 110 such that the discharge port 131 faces the stirring blade 122 between the bottom surface 112 of the stirring container 110 and the stirring blade 122. For example, when the organic solvent constituting the polymer oil - phase solution O is dichloromethane (MC) with extremely low solubility in water, when the aqueous solution W1 of the main component flows out from inside the polymer oil - phase solution O through the injection tube 133, due to the different polarities between the aqueous solution W1 and the oil - phase solution O, they cannot be mixed, so the aqueous solution of the main component can flow out in the form of droplets.

[0053] For example, referring to Figure 3 , the liquid medicine injection component 130 may include an injection tube 133, and the injection tube 133 may be arranged in the stirring container 110 in a state of being bent at least twice. For example, the injection tube 133 may be arranged in a hook shape in the stirring container 110.

[0054] At this time, the liquid medicine injection component 130 is arranged such that the discharge port 131 is on the top of the bottom surface 112 of the stirring container 110 (in the direction towards the stirring unit), specifically, below the stirring blade 122, and the discharge port 131 is arranged to be spaced apart from the stirring blade 122.

[0055] The discharge direction of the liquid medicine injection part 130 is arranged to face upward from the bottom surface 112 of the stirring container 110. The discharge direction of the liquid medicine injection part 130 indicates the direction of the pressure received by the discharged liquid medicine. The discharge port 131 can be set such that its center is within the rotation radius of the stirring blade 122, and can be set, for example, coaxially with the stirring shaft 121 at C (see Figure 3 ).

[0056] As another example, referring to Figure 4 , in the emulsion homogenization device 100a, the liquid medicine injection part 130a can be inserted into the stirring container 110a through a main body through-hole 111a provided on the bottom surface 112a of the stirring container 110a, so that the discharge port 131a is set at a position spaced apart from the bottom of the stirring blade and facing the stirring blade.

[0057] In other words, the main body through-hole 111a can be provided at a position on the bottom surface 112a of the stirring container 110a facing the stirring blade. The liquid medicine injection part 130a can be inserted into the stirring container 110a through the main body through-hole 111a, and the discharge port 131a can be installed to face the stirring blade.

[0058] In addition, the main body through-hole 111a can be set to a size that allows the liquid medicine injection part 130a to pass through. After the liquid medicine injection part 130 is installed in the stirring container 110, the gap between the liquid medicine injection part 130a and the main body through-hole 111a can be sealed to prevent the leakage of the contents contained in the stirring container 110.

[0059] As another example, referring to Figure 5 , in the emulsion homogenization device 100b, the stirring unit 120b can have a stirring through-hole 124b passing through the stirring shaft 121 and the stirring blade 122b.

[0060] In addition, the liquid medicine injection part 130b can be provided in the stirring unit 120b along the stirring through-hole 124b, and the discharge port 131b can be set to pass through the stirring through-hole 124b and be exposed below the stirring blade 122b. In other words, the liquid medicine injection part 130b can be provided as an integral part with the stirring unit 120b. In this embodiment, the stirring unit 120b can include a stirring through-hole 124b passing through the stirring shaft 121b and the stirring blade 122b. The liquid medicine injection part 130b can be installed in the stirring unit 120b along the stirring through-hole 124b such that the discharge port 131b is exposed below the stirring blade 122b.

[0061] In addition, referring to Figure 2 , the emulsion homogenization device 100 can further include a control unit 140 for controlling the stirring unit 120 and the liquid medicine injection part 130.

[0062] In addition, the control unit 140 can be set to perform stirring of the polymer oil phase solution O by rotating the stirring blade 122 at a first speed when the polymer oil phase solution O is accommodated in the stirring container 110 before the aqueous solution of the main component is supplied through the liquid medicine injection member 130.

[0063] In addition, the control unit 140 can also be set to supply the aqueous solution W1 of the main component into the stirring container 110 through the liquid medicine injection member 130 and increase the rotation speed of the stirring blade 122 to a second speed greater than the first speed while stirring the polymer oil phase solution O. For example, the second speed can be 1.5 times faster than the first speed.

[0064] In the emulsion homogenization apparatuses 100, 100a, 100b having the above structure, the polymer oil phase solution O as the oil phase can be pre-stirred in the stirring containers 110, 110a, 110b, and at the same time, the aqueous solution W1 of the main component can be injected in the form of droplets below the stirring blade in the stirring container. At this time, the aqueous solution W1 of the main component is dispersed and mixed with the polymer oil phase solution O by the vortex flow of the polymer oil phase solution O caused by the rotation of the stirring unit, so that the W1 / O emulsion can be homogenized.

[0065] Hereinafter, the effects of the present invention will be described by experimental examples of a method for manufacturing sustained-release microspheres of a W1 / O emulsion using a conventional stirring apparatus 10 and the emulsion homogenization apparatus 100 of the present invention.

[0066]

Table 1

[0067] Drug encapsulation efficiency (%) Average particle size (um) Experiment 1 42.8 35.1 Experiment 2 91.7 20.3 Experiment 3 85.9 17.8 Experiment 4 98.0 20.9 Experiment 5 95.5 20.4

[0068] Table 1 compares the drug encapsulation rate and the average particle size of the microparticles in the case of preparing a W1 / O emulsion using a conventional stirring apparatus 10 (Experiment 1) and in the case of preparing a W1 / O emulsion using the emulsion homogenization apparatus 100 of the present invention (Experiments 2 to 5). Experiments 1 to 5 were all carried out under the same conditions.

[0069] Experiment 1 was an experiment in which the aqueous solution W1 of the main component was injected into the polymer oil phase solution O (see Figure 1 ) to homogenize the polymer oil phase solution O and the aqueous solution W1 of the main component. As a result of Experiment 1, the average particle size of the microparticles was 35.1 μm, and the drug encapsulation rate was 42.8%.

[0070] Experiments 2 to 5 in Table 2 were experiments conducted using the emulsion homogenization device 100 according to an embodiment of the present invention. Experiments 2 to 5 were experiments in which the aqueous solution W1 of the main component was injected in the form of droplets below the polymer oil phase solution O being stirred through the liquid medicine injection member 130 to homogenize the polymer oil phase solution O and the aqueous solution W1 of the main component.

[0071] As a result of Experiment 2, the average particle size of the microspheres was 20.3 μm, and the drug encapsulation rate was 91.7%. As a result of Experiment 3, the average particle size of the microspheres was 17.8 μm, and the drug encapsulation rate was 85.9%. As a result of Experiment 4, the average particle size of the microspheres was 20.9 μm, and the drug encapsulation rate was 98.0%. As a result of Experiment 5, the average particle size of the microspheres was 20.4 μm, and the drug encapsulation rate was 95.5%.

[0072] As a result of Experiments 2 to 5, the average particle size range of the microparticles was 17.8 μm to 20.9 μm, and the drug encapsulation rate range was 85.9% to 98%. Compared with the results of Experiment 1, it can be seen that the drug encapsulation rate (average 92.78%) in the case of using the liquid medicine injection member 130 (Experiments 2 to 5) was increased by 2.16 times compared with the drug encapsulation rate (42.8%) in the case of not using the liquid medicine injection member 130 (Experiment 1), and the average particle size was reduced to about half of the size in the case of not using the liquid medicine injection member 130 (Experiment 1).

[0073] Figure 6 A flowchart showing a method for preparing sustained-release microspheres with an improved drug encapsulation rate according to an embodiment of the present invention is shown.

[0074] Hereinafter, with reference to Figure 6 a method for preparing sustained-release microspheres with an improved drug encapsulation rate according to a preferred embodiment of the present invention will be described.

[0075] Compared with the conventional method of mixing and stirring the polymer oil phase solution O and the aqueous solution W1 of the main component to prepare a W1 / O emulsion, in the method for preparing sustained-release microspheres with an improved drug encapsulation rate according to an embodiment of the present invention, the polymer oil phase solution O is first stirred, and then the aqueous solution W1 of the main component is injected into the polymer oil phase solution O being stirred.

[0076] The aqueous solution W1 of the main component is discharged from the bottom of the stirring container 110 in the form of droplets through the liquid medicine injection member 130 to the stirring blade 122. The droplets of the aqueous solution W1 of the main component are dispersed along the vortex of the polymer oil phase solution O under the action of the rotational force of the stirring blade 122 and mixed with the polymer oil phase solution O. Through the first homogenization process, the resulting mixed liquid of the aqueous solution W1 of the main component and the polymer oil phase solution O is homogenized while being stirred by the stirring unit 120, thereby forming a W1 / O emulsion.

[0077] The preparation process of the W1 / O emulsion will be described below in combination with experimental examples.

[0078] First, the components and dosages of the polymer oil phase solution O and the aqueous solution W1 of the main component used for preparing the W1 / O emulsion are described.

[0079]

Table 2

[0080] Solution Injection volume (g) Polymer oil phase solution O 1397.28g Aqueous solution of main component W1 158.72g

[0081] Table 2 shows the dosages of the polymer oil phase solution O and the aqueous solution W1 of the main component used for preparing the W1 / O emulsion in the first homogenization process.

[0082] When 1397.28 g of the polymer oil phase solution O is injected, 158.72 g of the aqueous solution W1 of the main component is injected. The polymer oil phase solution O is injected in step S1, and the aqueous solution W1 of the main component is injected in the form of droplets from the bottom of the stirring container 110 to the stirring blade 122 in step S2.

[0083] The polymer oil phase solution O is a solution in which the polymer materials polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) are dissolved in dichloromethane (MC).

[0084] In addition, the aqueous solution W1 of the main component is a solution in which the drug is dissolved in WFI. The drug dissolved in WFI can vary depending on the type of injection to be prepared.

[0085] For example, when preparing a sustained-release injection of leuprorelin for the treatment of endometriosis, uterine fibroids, prostate cancer, premenopausal breast cancer, and central precocious puberty, the drug contained in the aqueous solution W1 of the main component can be leuprorelin acetate.

[0086] The chemical formula of leuprorelin acetate is (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethyleneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide; [(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate.

[0087]

Table 3

[0088]

[0089] Table 3 shows the stirring speed and stirring time for each step in the preparation of the W1 / O emulsion.

[0090] Referring to Table 3 and Figure 6 , in step S1, the stirring unit 120 rotates at 4000 rpm for one minute to stir the polymer oil phase solution O. Thereafter, the aqueous solution W1 of the main component is injected in the form of droplets into the polymer oil phase solution O being stirred (S2). In step S2, the stirring unit 120 rotates at 6000 rpm for three minutes.

[0091] Even after the complete injection of the aqueous solution W1 of the main component, the stirring unit 120 further rotates at 6000 rpm for two minutes to homogenize the aqueous solution W1 of the main component and the polymer oil phase solution O. After steps S2 and S3, the aqueous solution W1 of the main component and the polymer oil phase solution O are homogenized to form the W1 / O emulsion.

[0092] When the W1 / O emulsion is prepared by the above process, the W1 / O / W2 emulsion preparation process is then carried out. Step S4 is carried out in a separate stirring device (not shown), rather than in the emulsion homogenization device 100 used in steps S1 to S3.

[0093] In step S4, while stirring the aqueous polymer solution W2, the W1 / O emulsion is injected into the aqueous polymer solution W2 in the form of droplets. Herein, the aqueous polymer solution W2 is a solution obtained by dissolving the polymer material polyvinyl alcohol (PVA) in WFI. The aqueous polymer solution W2 is the aqueous phase.

[0094] In step S4, while injecting the aqueous polymer solution W2 and making it flow, the stirring unit of a separate stirring device (not shown) rotates at 7200 rpm for stirring. The aqueous polymer solution W2 is injected into the stirring container at an injection rate of 1.5 L / min. In addition, the W1 / O emulsion is injected at an injection rate of 14.6 mL / min for 80 minutes. At this time, while the aqueous polymer solution W2 flows into the stirring container of the stirring device (not shown), the W1 / O emulsion is injected into the aqueous polymer solution W2 in the form of droplets.

[0095] In step S5, the W1 / O / W2 emulsion is formed by a second homogenization process of the aqueous polymer solution W2 and the W1 / O emulsion. The stirring speed in step S5 is 7200 rpm, which is the same as the stirring speed in step S4.

[0096] After the W1 / O / W2 emulsion is prepared through steps S4 and S5, a microsphere preparation step is carried out.

[0097] In step S6, the W1 / O / W2 emulsion forms microspheres as the organic solvent volatilizes through an underwater drying process. The W1 / O / W2 emulsion is centrifuged, the supernatant of the W1 / O / W2 emulsion is discarded, and the microspheres are washed with distilled water and then freeze-dried.

[0098] Step S6 is a well-known technique for preparing microspheres, and the underwater drying process, washing process, freeze-drying process, and microsphere pulverization process will not be elaborated herein.

[0099] The method for preparing sustained-release microspheres with an improved drug encapsulation rate according to an embodiment of the present invention can increase the drug encapsulation rate to about twice that of the conventional method through the homogenization of the W1 / O emulsion and the W1 / O / W2 emulsion even when mass-producing microspheres, thereby mass-producing sustained-release microspheres showing a stable effect.

[0100] The above preferred embodiments of the present invention are disclosed for illustrative purposes, and those skilled in the art with common general knowledge of the present invention will be able to make various modifications, changes, and additions within the spirit and scope of the present invention, and such modifications, changes, and additions should be considered to fall within the scope of the appended claims.

[0101]

Industrial Applicability

[0102] An emulsion homogenization device according to at least one embodiment of the present invention, while pre-stirring a polymer oil phase solution O, is capable of injecting an aqueous solution of the main component in the form of droplets below the stirring blades in a stirring container, thereby uniformly stirring the aqueous solution W1 of the main component and the polymer oil phase solution O, so as to homogenize the W1 / O emulsion.

Claims

1. An emulsion homogenization device, comprising: A stirring container; A stirring unit, the stirring unit includes a stirring shaft and stirring blades installed on the stirring shaft, and the stirring blades are rotatably arranged in the stirring container; And A liquid medicine injection component, the liquid medicine injection component has a discharge port, and an aqueous solution of the main component of the medicine is discharged in the form of droplets through the discharge port, Wherein, the discharge port is located between the bottom surface of the stirring container and the stirring blades and is arranged to face the stirring blades.

2. The device according to claim 1, wherein, The liquid medicine injection component is arranged to discharge the aqueous solution of the main component in the form of droplets towards the stirring blades.

3. The apparatus according to claim 2, wherein The liquid medicine injection component has a discharge port spaced apart from the stirring blades.

4. The device according to claim 1, wherein, The device further includes a control unit for controlling the stirring unit and the liquid medicine supply component, Wherein, the control unit is arranged to, before supplying the aqueous solution of the main component through the liquid medicine injection component, when the polymer oil phase solution is contained in the stirring container, perform stirring of the polymer oil phase solution by rotating the stirring blades at a first speed.

5. The device according to claim 4, wherein The control unit supplies the aqueous solution of the main component into the stirring container through the liquid medicine supply unit, and increases the rotation speed of the stirring blades to a second speed greater than the first speed while stirring the polymer oil phase solution.

6. The device according to claim 1, wherein, The liquid medicine injection component includes an injection pipe.

7. The apparatus according to claim 5, wherein The injection pipe is bent at least twice in the stirring container.

8. The device according to claim 1, wherein The bottom surface of the stirring container is provided with a main body through hole at a position facing the stirring blades, and the liquid medicine injection component is inserted into the stirring container through the main body through hole, and the discharge port is installed to face the stirring blades.

9. The device according to claim 1, wherein, The stirring unit has a stirring through hole passing through the stirring shaft and the stirring blades, the liquid medicine injection component is arranged in the stirring unit along the stirring through hole, and the discharge port is arranged to pass through the stirring through hole and be exposed below the stirring blades.

10. A method for preparing sustained-release microspheres with an improved drug encapsulation rate, the method comprising: S1) The step of using the emulsion homogenization device according to claim 1 to stir a polymer oil phase solution (O) as the oil phase; S2) The step of injecting an aqueous solution of the main component (W1) in the form of droplets into the polymer oil phase solution (O) being stirred; S3) The step of forming a W1 / O emulsion through a first homogenization process of the aqueous solution of the main component (W1) and the polymer oil phase solution (O); S4) The step of injecting the W1 / O emulsion in the form of droplets into the polymer aqueous solution (W2) while stirring the polymer aqueous solution (W2); S5) The step of forming a W1 / O / W2 emulsion through a second homogenization process of the polymer aqueous solution (W2) and the W1 / O emulsion; and S6) The step of forming microspheres through an underwater drying process of the W1 / O / W2 emulsion.

11. The method according to claim 10, wherein, In step S2, the droplets of the aqueous solution of the main component (W1) are injected below the stirring unit of the emulsion homogenization device and mixed with the polymer oil-phase solution (O) while being dispersed by the vortex of the polymer oil-phase solution (O).

12. The method according to claim 10, wherein, In step S2, the polymer oil-phase solution (O) is stirred at a speed 1.5 times faster than that in step S1.

13. The method according to claim 10, wherein, In step S4, while the aqueous polymer solution (W2) flows into the stirring container, the W1 / O emulsion is injected at a rate within a range 1 / 100 slower than the injection rate of the aqueous polymer solution (W2) within a predetermined time.

14. The method according to claim 10, wherein, The polymer oil-phase solution (O) is a solution in which a polymer material, polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA), is dissolved in dichloromethane (MC).

15. The method according to claim 10, wherein The aqueous polymer solution (W2) is a solution in which a polymer substance, polyvinyl alcohol (PVA), is dissolved in water for injection (WFI).

16. The method according to claim 10, wherein, The aqueous solution of the main component (W1) is a solution in which a drug is dissolved in WFI.

17. The method according to claim 16, wherein, The drug is leuprorelin acetate, and the chemical formula of leuprorelin acetate is (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethyleneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide; [(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate.

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