Emulsion homogenizer and method for producing sustained-release microspheres with improved drug encapsulation rate

Abstract

An emulsion homogenizing apparatus according to one embodiment of the present invention includes a stirring vessel, a stirring unit having a stirring shaft and stirring blades and rotatably installed in the stirring vessel, and a drug solution injection unit having a discharge port for discharging a drug-containing main component aqueous phase solution in the form of droplets and installed in the stirring vessel between the bottom of the stirring vessel and the stirring blades so that the discharge port faces the stirring blades.

Description

[Technical Field]

[0001] The present invention relates to an emulsion homogenizer and a method for producing sustained-release microspheres with an improved drug encapsulation rate, and more particularly to an emulsion homogenizer that can increase the drug encapsulation rate in microspheres by homogenizing a W1 / O emulsion, and a method for producing sustained-release microspheres with an improved drug encapsulation rate. [Background technology]

[0002] A sustained-release injectable dosage form is an injectable dosage form that is formulated so that the drug can be released continuously and uniformly in the body while maintaining its biological activity when injected subcutaneously or intramuscularly.

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

[0004] FIG. 1 is a schematic diagram of a prior art stirring device.

[0005] Referring to Figure 1, in the conventional microsphere manufacturing process, when forming a W1 / O emulsion, a main component aqueous phase solution (W1) containing a drug and a polymer oil phase solution (O) are homogenized by stirring them in a stirring vessel (10) using a stirring device (20). Here, the main component aqueous phase solution (W1) is the water phase, and the polymer oil phase solution (O) is the oil phase.

[0006] Conventionally, the polymer oil phase solution (O) is placed in the stirring vessel (10), and then the main component aqueous phase solution (W1) is placed in the stirring vessel (10).

[0007] However, due to the difference in specific gravity between methylene chloride (MC), the solvent of the polymer oil phase solution (O), and water, the solvent of the main component aqueous phase solution, layer separation occurs, and the main component aqueous phase solution (W1) comes to be located on the upper surface of the polymer oil phase solution (O).

[0008] Thereafter, the stirring device (20) rotates to stir the main component aqueous phase solution (W1) and the polymer oil phase solution (O), thereby homogenizing the mixture of the main component aqueous phase solution (W1) and the polymer oil phase solution (O).

[0009] When homogenizing using the stirrer (20), if the volume of the mixture between the polymer oil phase solution (O) and the main component water phase solution (W1) is small, the difference in encapsulation efficiency between the mixing methods is not significant. However, as the volume of the mixture increases, the high viscosity of the polymer oil phase solution (O) reduces the mixing homogeneity of the main component water phase solution (W1).

[0010] In order to homogeneously mix the highly viscous polymer oil phase solution (O) and the main component aqueous phase solution (W1), it is necessary to increase the rotation speed (RPM) of the stirrer (20) and the stirring time. In this case, heat is generated, and the methylene chloride (bp: 39°C to 40°C), which is the solvent for the polymer oil phase solution (O), boils and evaporates, resulting in a problem of a change in the concentration of the polymer oil phase solution (O).

[0011] As a result, if the volume of the mixture increases, it will not be stirred uniformly, and if the mixture is not stirred uniformly, it will not be easy to emulsify the mixture, resulting in a problem of reduced drug encapsulation efficiency. Summary of the Invention [Problem to be solved by the invention]

[0012] The present invention aims to provide an emulsion homogenizer in which a main component aqueous phase solution (W1) is injected in the form of droplets below the stirring blades while a polymer oil phase solution (O) of an oil phase is being pre-stirred in a stirring vessel.

[0013] Another object of the present invention is to provide an emulsion homogenizer capable of homogenizing a W1 / O emulsion by dispersing a main component aqueous phase solution (W1) injected in the form of droplets by the vortex flow of the polymer oil phase solution (O) and stirring it with the polymer oil phase solution (O).

[0014] Another object of the present invention is to provide an emulsion homogenizer capable of increasing the drug encapsulation rate in microspheres by homogenizing a W1 / O emulsion, and a method for producing sustained-release microspheres with an improved drug encapsulation rate. [Means for solving the problem]

[0015] To achieve the above object, an emulsion homogenizing apparatus according to one embodiment of the present invention includes a stirring unit including a stirring vessel, a stirring shaft, and a stirring blade attached to the stirring shaft, the stirring blade being rotatably installed within the stirring vessel, and a drug solution injector having a discharge port through which a main component aqueous phase solution containing a drug is discharged in the form of droplets.

[0016] The discharge port is located between the bottom surface of the stirring vessel and the stirring blade, and is arranged so as to face the stirring blade. The chemical solution injector can be provided so as to eject the aqueous solution of the main component in the form of droplets toward the stirring blade.

[0017] The chemical solution injector may be provided so that the discharge port is positioned away from the stirring blade.

[0018] The emulsion homogenizer may further include a control unit that controls the stirring unit and the chemical supply unit.

[0019] The control unit may be configured to rotate the stirring blades at a first speed to stir the polymer oil phase solution when the polymer oil phase solution is contained in the stirring vessel before the main component aqueous phase solution is supplied through the chemical solution supply unit.

[0020] The control unit may be configured to supply the main component aqueous phase solution into the stirring vessel through the chemical supply unit while stirring the polymer oil phase solution, and to increase the rotation speed of the stirring blades to a second speed higher than the first speed.

[0021] The chemical solution injector may include an injection tube.

[0022] The injection pipe may be bent at least two times within the stirring vessel.

[0023] In addition, a main body through-hole is provided on the bottom surface of the stirring vessel at a position opposite the stirring blade, and the chemical solution injection part can be inserted into the stirring vessel by passing through the main body through-hole, and installed so that the discharge outlet faces the stirring blade.

[0024] In addition, the stirring unit has a stirring through-hole that penetrates the stirring shaft and the stirring blade, and the chemical solution injection unit is arranged within the stirring unit along the stirring through-hole, and the discharge outlet can be arranged so as to pass through the stirring through-hole and be exposed at the bottom of the stirring blade.

[0025] In addition, a method for producing sustained-release microspheres with improved drug loading rate according to one embodiment of the present invention includes the steps of: S1) stirring a polymer oil phase solution (O) using the emulsion homogenizer of claim 1; S2) injecting a main component aqueous phase solution (W1) in the form of droplets into the polymer oil phase solution (O) during stirring; S3) forming a W1 / O emulsion by a first homogenization process of the main component aqueous phase solution (W1) and the polymer oil phase solution (O); S4) injecting the W1 / O emulsion in the form of droplets into the polymer aqueous phase solution (W2) while stirring the polymer aqueous phase solution (W2); S5) forming a W1 / O / W2 emulsion by a second homogenization process of the polymer aqueous phase solution (W2) and the W1 / O emulsion; and S6) drying the W1 / O / W2 emulsion in water to form microspheres.

[0026] In step S2, droplets of the main component aqueous phase solution (W1) are injected into the lower part of the stirring section of the emulsion homogenizer, and can be mixed into the polymer oil phase solution (O) while being dispersed by the vortex of the polymer oil phase solution (O).

[0027] In the S2 stage, the polymer oil phase solution (O) can be stirred at a speed 1.5 times faster than in the S1 stage.

[0028] In step S4, the W1 / O emulsion can be injected for a predetermined time at a rate within 1 / 100 of the injection rate of the polymer aqueous phase solution (W2) while the polymer aqueous phase solution (W2) is flowing into the stirring vessel.

[0029] The polymer oil phase solution (O) may be a solution in which a polymer substance, polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA), is dissolved in methylene chloride (MC).

[0030] The polymer aqueous phase solution (W2) may also be a solution in which a polymer substance, polyvinyl alcohol (PVA), is dissolved in water for injection.

[0031] The main aqueous solution (W1) may also be a solution in which a drug is dissolved in water for injection (WFI).

[0032] Here, the drug is leuprolide acetate, and the chemical formula of leuprolide acetate is (2S)-N-[(2S)-1-[[(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-oxopropane-2-yl [(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. [Effects of the Invention]

[0033] As described above, an emulsion homogenizer in accordance with at least one embodiment of the present invention has the following advantages:

[0034] While the polymer oil phase solution (O) is being pre-mixed, the main component aqueous phase solution can be injected in droplets into the stirring vessel under the stirring blade. The droplets of the injected main component aqueous phase solution are dispersed by the vortex of the polymer oil phase solution (O) during mixing, and are mixed with the polymer oil phase solution (O). As a result, the main component aqueous phase solution (W1) and the polymer oil phase solution (O) are mixed homogenously, resulting in a homogenized W1 / O emulsion.

[0035] Furthermore, the method for producing sustained-release microspheres with improved drug encapsulation rate using an emulsion homogenizer can improve the drug encapsulation rate by approximately two times compared to conventional methods by homogenizing the W1 / O emulsion. [Brief explanation of the drawings]

[0036] [Figure 1] 1 is a schematic diagram of a stirring device according to the prior art; [Figure 2] 1 is a diagram illustrating an operation state of an emulsion homogenizer according to an embodiment of the present invention. FIG. [Figure 3] 1A-1D are schematic diagrams of emulsion homogenizers according to various embodiments. [Figure 4] 1A-1D are schematic diagrams of emulsion homogenizers according to various embodiments. [Figure 5] 1A-1D are schematic diagrams of emulsion homogenizers according to various embodiments. [Figure 6] 1 is a flowchart illustrating a method for manufacturing sustained-release microspheres with improved drug encapsulation efficiency according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0037] Hereinafter, an emulsion homogenizing apparatus and a method for producing sustained-release microspheres with improved drug encapsulation rate according to a preferred embodiment of the present invention will be described with reference to the accompanying drawings.

[0038] FIG. 2 is a diagram illustrating the operation state of an emulsion homogenizer according to one embodiment of the present invention, and FIGS. 3 to 5 are schematic diagrams illustrating the configurations of emulsion homogenizers according to various embodiments.

[0039] Referring to FIGS. 2 and 3, an emulsion homogenizer (100) according to one embodiment of the present invention includes a stirring vessel (110), a stirring unit (120), and a chemical injection unit (130). The agitator (120) includes an agitator shaft (121) and an agitator blade (122) attached to the agitator shaft (121). The agitator (120) includes the agitator blade (122) rotatably mounted within the agitator vessel (110). The agitator (120) may include a drive unit (123, such as a motor, for example) for rotating the agitator shaft (121).

[0040] The stirring vessel 110 and the stirring unit 120 are well-known components as described with reference to FIG. 1, and detailed description thereof will be omitted in this embodiment.

[0041] The drug solution injector 130 is provided to supply a main component aqueous solution W1 into the agitator 110. The main component aqueous solution W1 is a solution in which a drug is dissolved in water for injection, and various types of drugs can be used depending on the type of injection to be prepared.

[0042] The drug solution injector (130) has a discharge port (131) through which a drug-containing aqueous solution containing a main component is discharged in the form of droplets. The discharge port (131) is located between the bottom surface (112) of the stirring vessel (110) and the stirring blade (120), and the discharge port (131) is arranged to face the stirring blade (120). The chemical solution injector (130) may be installed to discharge the aqueous solution of the main component in the form of droplets toward the agitating blade (120). The chemical solution injector (130) may be installed such that the discharge port (131) is positioned at a predetermined distance from the agitating blade (120).

[0043] The chemical solution injector (130) may include an injection pipe (133). In this embodiment, the chemical solution injector (130) may include an injection pipe (133) having a diameter in the single-digit millimeter range (e.g., 3 mm to 5 mm). The discharge port (131) of the chemical solution injector (130) discharges the main component aqueous phase solution in the form of droplets. The chemical solution injector (130) may be installed in the agitator vessel (110) between the bottom surface (112) of the agitator vessel (110) and the agitator blade (122) such that the discharge port (131) faces the agitator blade (122). For example, the organic solvent constituting the polymer oil phase solution (O) is methylene chloride (MC), which has very low solubility in water. When the main component aqueous phase solution (W1) is allowed to flow out of the polymer oil phase solution (O) through the injection tube (133), the aqueous phase solution (W1) cannot mix with the oil phase solution (O) due to the difference in polarity between the solutions, and can be ejected in the form of droplets.

[0044] 3, the chemical solution injector 130 may include an injection pipe 133, which may be bent at least twice within the agitator vessel 110. For example, the injection pipe 133 may be arranged in the agitator vessel 110 in a hook-like shape.

[0045] In this case, the chemical solution injection section (130) is provided so that the discharge port (131) is directed upward (toward the stirring section) from the bottom surface (112) of the stirring vessel (110), specifically, located below the stirring blade (122), and the discharge port (131) is positioned so as to be spaced apart from the stirring blade (122).

[0046] The discharge direction of the chemical liquid injector (130) is set so as to face upward from the bottom surface (112) of the agitator vessel (110). The discharge direction of the chemical liquid injector (130) means the direction of the pressure that discharges the chemical liquid. The discharge port (131) can be arranged so that its center is located within the rotation radius of the agitator blade (122), and can be arranged, for example, so as to be coaxial (C) with the agitator shaft (121) (see FIG. 3).

[0047] As another example, referring to FIG. 4, in the emulsion homogenizer (100a), the chemical solution injector (130a) can be inserted into the agitator (110a) by penetrating the main body through-hole (111a) formed in the bottom surface (112a) of the agitator (110a), and the discharge outlet (131a) can be disposed at a position spaced apart from the lower part of the agitator and facing the agitator.

[0048] That is, a body through-hole (111a) is provided on the bottom surface (112a) of the stirring vessel (110a) at a position opposite the stirring blade, and the chemical solution injection section (130a) can be inserted into the stirring vessel (110a) through the body through-hole (111a) and installed so that the discharge outlet (131a) faces the stirring blade.

[0049] In addition, the body through-hole 111a may be formed to a size that allows the chemical solution injector 130a to pass through. After the chemical solution injector 130 is installed in the agitator 110, the gap between the chemical solution injector 130a and the body through-hole 111a may be sealed, thereby preventing leakage of the contents contained in the agitator 110.

[0050] As another example, referring to FIG. 5, in an emulsion homogenizer (100b), the stirring unit (120b) may have a stirring through-hole (124b) penetrating the stirring shaft (121b) and the stirring blade (122b).

[0051] The chemical solution injector 130b may be disposed within the agitator 120b along the agitation through-hole 124b, with the discharge port 131b passing through the agitation through-hole 124b and exposed to the bottom of the agitator blade 122b. That is, the chemical solution injector 130b may be integral with the agitator 120b. In this embodiment, the agitator 120b may include an agitation through-hole 124b passing through the agitator shaft 121b and the agitator blade 122b. The chemical solution injector 130b may be disposed within the agitator 120b along the agitation through-hole 124b, with the discharge port 131b exposed to the bottom of the agitator blade 122b.

[0052] Referring to FIG. 2, the emulsion homogenizer (100) may further include a control unit (140) for controlling the stirring unit (120) and the chemical solution injecting unit (130).

[0053] The control unit (140) may be configured to rotate the stirring blades (122) at a first speed to stir the polymer oil phase solution (O) when the polymer oil phase solution (O) is contained in the stirring vessel (110) before the main component aqueous phase solution is supplied through the chemical solution injector (130).

[0054] The control unit (140) may be configured to supply the main component aqueous phase solution (W1) into the stirring vessel (110) through the chemical injector (130) while stirring the polymer oil phase solution (O), and to increase the rotation speed of the stirring blades (122) to a second speed that is greater than the first speed. For example, the second speed may be 1.5 times the first speed.

[0055] In the emulsion homogenizer (100, 100a, 100b) having the above-described structure, while the oil phase polymer oil phase solution (O) is being pre-stirred in the stirring vessel (110, 110a, 110b), the main component aqueous phase solution (W1) can be injected in the form of droplets into the stirring vessel below the stirring blade. At this time, the rotation of the stirring vessel creates a vortex in the polymer oil phase solution (O), dispersing the main component aqueous phase solution (W1) and mixing it with the polymer oil phase solution (O), thereby homogenizing the W1 / O emulsion.

[0056] The effects of the present invention will be explained below through experimental examples of a method for producing sustained-release microspheres in which a W1 / O emulsion is produced using a conventional stirring device (10) and the emulsion homogenizer (100) of the present invention.

[0057] [Table 1]

[0058] Table 1 compares the drug encapsulation rate and average particle size of the microparticles when a W1 / O emulsion was produced using a conventional stirring device (10) (Experiment 1) and when a W1 / O emulsion was produced using the emulsion homogenizer (100) of the present invention (Experiments 2 to 5). Experiments 1 to 5 were conducted under the same conditions.

[0059] In the first experiment, the main component aqueous phase solution (W1) was injected onto the polymer oil phase solution (O) (see Figure 1) to homogenize the polymer oil phase solution (O) and the main component aqueous phase solution (W1). The results of the first experiment showed that the average particle size of the microspheres was 35.1 μm and the drug encapsulation efficiency was 42.8%.

[0060] Experiments 2 to 5 in Table 1 were conducted using an emulsion homogenizer 100 according to one embodiment of the present invention. Experiments 2 to 5 were conducted by injecting droplets of the main component aqueous phase solution W1 through the chemical injection section 130 into the bottom of the polymer oil phase solution O during stirring, thereby homogenizing the polymer oil phase solution O and the main component aqueous phase solution W1.

[0061] The results of the second experiment showed that the average particle size of the microspheres was 20.3 um and the drug encapsulation efficiency was 91.7%. The results of the third experiment showed that the average particle size of the microspheres was 17.8 um and the drug encapsulation efficiency was 85.9%. The results of the fourth experiment showed that the average particle size of the microspheres was 20.9 um and the drug encapsulation efficiency was 98.0%. The results of the fifth experiment showed that the average particle size of the microspheres was 20.4 um and the drug encapsulation efficiency was 95.5%.

[0062] The results of the second to fifth experiments showed that the average particle size of the microspheres was in the range of 17.8 μm to 20.9 μm, and the drug encapsulation rate was in the range of 85.9% to 98%. Compared with the results of the first experiment, the drug encapsulation rate (average 92.78%) when the drug solution injection section (130) was used (experiments 2 to 5) was 2.16 times higher than the drug encapsulation rate (42.8%) when the drug solution injection section (130) was not used (experiment 1), and the average particle size was reduced to approximately half the size.

[0063] FIG. 6 is a flow chart illustrating a method for producing sustained-release microspheres with improved drug loading rate according to one embodiment of the present invention.

[0064] Hereinafter, a method for producing sustained-release microspheres with improved drug loading rate according to a preferred embodiment of the present invention will be described with reference to FIG.

[0065] Compared to the conventional method of preparing a W1 / O emulsion by mixing a polymer oil phase solution (O) and a main component aqueous phase solution (W1) and stirring the mixture, in the method of preparing sustained-release microspheres with an improved drug encapsulation rate according to one embodiment of the present invention, the polymer oil phase solution (O) is stirred first, and then the main component aqueous phase solution (W1) is poured into the polymer oil phase solution (O) while stirring.

[0066] The main component aqueous phase solution (W1) is discharged in the form of droplets from the bottom of the stirring vessel (110) toward the stirring blade (122) by the chemical solution injector (130). The droplets of the main component aqueous phase solution (W1) are dispersed and mixed into the polymer oil phase solution (O) by the vortex of the polymer oil phase solution (O) caused by the rotational force of the stirring blade (122). In the first homogenization step, the mixture of the main component aqueous phase solution (W1) and the polymer oil phase solution (O) is homogenized while being stirred by the stirring unit (120) to form a W1 / O emulsion.

[0067] The process for producing a W1 / O emulsion is explained below using an experimental example.

[0068] First, the components and volumes of the polymer oil phase solution (O) and the main component aqueous phase solution (W1) used to prepare the W1 / O emulsion will be described.

[0069] [Table 2]

[0070] Table 2 shows the volumes of polymeric oil phase solution (O) and main component water phase solution (W1) used to prepare the W1 / O emulsion in the first homogenization step.

[0071] When 1397.28 g of the polymer oil phase solution (O) is injected, 158.72 g of the main component aqueous phase solution (W1) is injected. The polymer oil phase solution (O) is injected in the S1 stage, and the main component aqueous phase solution (W1) is injected in the form of droplets from the bottom of the stirring vessel (110) toward the stirring blade (122) in the S2 stage.

[0072] The polymer oil phase solution (O) is a solution in which the polymeric substance polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA) is dissolved in methylene chloride (MC).

[0073] The main aqueous solution (W1) is a solution in which a drug is dissolved in water for injection (WFI). The drug dissolved in water for injection can be varied depending on the type of injection to be prepared.

[0074] For example, when producing a leuprorelin depot injection used to treat endometriosis, uterine fibroids, prostate cancer, premenopausal breast cancer, and central precocious puberty, the drug contained in the main component aqueous phase solution (W1) can be leuprolide acetate.

[0075] The chemical formula of leuprorelin acetate is (2S)-N-[(2S)-1-[[(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 [(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.

[0076] [Table 3]

[0077] Table 3 shows the stirring speed and stirring time for each stage in the preparation of the W1 / O emulsion.

[0078] 6, in step S1, the stirring unit (120) rotates at 4000 rpm for 1 minute to stir the polymer oil phase solution (O). Then, in step S2, the main component aqueous phase solution (W1) is injected in the form of droplets into the stirred polymer oil phase solution (O). In step S2, the stirring unit (120) rotates at 6000 rpm for 3 minutes.

[0079] After the injection of the main component aqueous phase solution (W1) is completed, the stirring unit (120) continues to rotate at 6000 rpm for 2 minutes to stir and homogenize the main component aqueous phase solution (W1) and the polymer oil phase solution (O). Through steps S2 and S3, the main component aqueous phase solution (W1) and the polymer oil phase solution (O) are homogenized to form a W1 / O emulsion.

[0080] Once the W1 / O emulsion is prepared through the above process, the W1 / O / W2 emulsion preparation process is carried out. Step S4 is carried out in a separate agitator (not shown) rather than the emulsion homogenizer (100) used in steps S1 to S3.

[0081] In step S4, the W1 / O emulsion is injected into the polymer aqueous phase solution (W2) in the form of droplets while the polymer aqueous phase solution (W2) is being stirred. Here, the polymer aqueous phase solution (W2) is a solution in which the polymeric substance polyvinyl alcohol (PVA) is dissolved in water for injection. The polymer aqueous phase solution (W2) is the water phase.

[0082] In step S4, while the polymer aqueous phase solution (W2) is being poured into the stirring vessel, the stirring unit of a separate stirring device (not shown) rotates at 7200 RPM. The polymer aqueous phase solution (W2) is poured into the stirring vessel at a rate of 1.5 L / min. Then, the W1 / O emulsion is poured into the stirring vessel at a rate of 14.6 mL / min for 80 minutes. At this time, while the polymer aqueous phase solution (W2) is poured into the stirring vessel of the stirring device (not shown), the W1 / O emulsion is poured into the polymer aqueous phase solution (W2) in the form of droplets.

[0083] In stage S5, the polymer aqueous phase solution (W2) and the W1 / O emulsion are homogenized to form a W1 / O / W2 emulsion. The stirring speed in stage S5 is 7200 RPM, the same as that in stage S4.

[0084] After the W1 / O / W2 emulsion is prepared through steps S4 and S5, the microsphere preparation step is carried out.

[0085] In step S6, the W1 / O / W2 emulsion is dried in water to form microspheres as the organic solvent evaporates. The W1 / O / W2 emulsion is centrifuged, the supernatant is discarded, and the microspheres are washed with distilled water and then freeze-dried.

[0086] Step S6 is a known technique for producing microspheres, and the detailed description of the underwater drying step, washing step, freeze-drying step and microsphere pulverization step will be omitted.

[0087] The method for producing sustained-release microspheres with improved drug loading according to one embodiment of the present invention can mass-produce sustained-release microspheres with stable efficacy by increasing the drug loading rate by approximately two times compared to conventional methods through the homogenization of W1 / O emulsion and W1 / O / W2 emulsion.

[0088] The preferred embodiments of the present invention described above have been disclosed for illustrative purposes, and those skilled in the art with ordinary skill in the art may 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 following claims. [Industrial Applicability]

[0089] According to at least one embodiment of the present invention, the emulsion homogenizer can inject the main component aqueous phase solution in the form of droplets into the lower part of the stirring blade in the stirring vessel during the pre-stirring of the polymer oil phase solution (O). As a result, the main component aqueous phase solution (W1) and the polymer oil phase solution (O) are stirred uniformly, and the W1 / O emulsion can be homogenized.

Claims

1. Stirring vessel; a stirring section including a stirring shaft and a stirring blade attached to the stirring shaft, the stirring blade being rotatably provided within the stirring vessel; and a drug solution injector having a discharge port through which a drug-containing aqueous solution containing the drug is discharged in the form of droplets; The emulsion homogenizing device, wherein the discharge port is located between the bottom surface of the stirring vessel and the stirring blade, and is arranged so as to face the stirring blade.

2. 2. The emulsion homogenizer according to claim 1, wherein the chemical solution injector is configured to discharge the aqueous solution of the main component in the form of droplets toward the stirring blade.

3. 3. The emulsion homogenizer according to claim 2, wherein the chemical liquid injector has a discharge port positioned away from the stirring blade.

4. Further comprising a control unit that controls the stirring unit and the chemical solution supply unit, 2. The emulsion homogenizer according to claim 1, wherein the control unit is configured to rotate the stirring blades at a first speed to stir the polymer oil phase solution when the polymer oil phase solution is contained in the stirring vessel before the main component aqueous phase solution is supplied through the chemical solution supply unit.

5. 5. The emulsion homogenizer according to claim 4, wherein the control unit supplies the main component aqueous phase solution into the stirring vessel through the chemical solution supply unit while stirring the polymer oil phase solution, and increases the rotation speed of the stirring blades to a second speed that is higher than the first speed.

6. 2. The emulsion homogenizer of claim 1, wherein the chemical liquid injector includes an injection pipe.

7. 6. The emulsion homogenizer according to claim 5, wherein the injection pipe is bent at least two times within the stirring vessel.

8. a main body through-hole is provided in a bottom surface of the stirring vessel at a position facing the stirring blade; 2. The emulsion homogenizer according to claim 1, wherein the chemical solution injector is inserted into the stirring vessel through the main body through-hole, and is installed so that the discharge port faces the stirring blade.

9. the stirring unit has a stirring through-hole that penetrates the stirring shaft and the stirring blade, 2. The emulsion homogenizer according to claim 1, wherein the chemical liquid injection section is disposed within the stirring section along the stirring through-hole, and the discharge outlet is disposed so as to pass through the stirring through-hole and be exposed at a lower part of the stirring blade.

10. S1) A step in which the polymer oil phase solution (O) of the oil phase is stirred using the emulsion homogenizer of claim 1; S2) A step in which the main component aqueous phase solution (W1) is injected in the form of droplets into the polymer oil phase solution (O) under stirring; S3) A step of forming a W1 / O emulsion by a first homogenization process of the main component aqueous phase solution (W1) and the polymer oil phase solution (O); S4) A step in which the W1 / O emulsion is injected into the polymer aqueous phase solution (W2) in the form of droplets while stirring the polymer aqueous phase solution (W2); S5) A step of forming a W1 / O / W2 emulsion by a second homogenization process of the polymer aqueous phase solution (W2) and the W1 / O emulsion; and S6) A method for producing sustained-release microspheres with improved drug loading, comprising the step of forming microspheres by an in-water drying process of the W1 / O / W2 emulsion.

11. 11. The method for producing sustained-release microspheres with improved drug encapsulation rate according to claim 10, wherein in step S2, the droplets of the main component aqueous phase solution (W1) are injected into a lower part of the stirring section of the emulsion homogenizer and dispersed by a vortex of the polymer oil phase solution (O) while being mixed into the polymer oil phase solution (O).

12. 11. The method for producing sustained-release microspheres with improved drug loading rate 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. 11. The method for producing sustained-release microspheres with improved drug loading rate according to claim 10, wherein in step S4, the W1 / O emulsion is injected for a predetermined time at a rate within 1 / 100 of the injection rate of the polymer aqueous phase solution (W2) while the polymer aqueous phase solution (W2) is flowing into the stirring vessel.

14. 11. The method for producing sustained-release microspheres with improved drug loading rate according to claim 10, wherein the polymer oil phase solution (O) is a solution in which a polymer substance, polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA), is dissolved in methylene chloride (MC).

15. 11. The method for producing sustained-release microspheres with improved drug loading rate according to claim 10, wherein the polymer aqueous phase solution (W2) is a solution in which a polymeric substance, polyvinyl alcohol (PVA), is dissolved in water for injection.

16. 11. The method for producing sustained-release microspheres with improved drug loading according to claim 10, wherein the main aqueous solution (W1) is a solution in which a drug is dissolved in water for injection (WFI).

17. the drug is leuprolide acetate, The chemical formula of the leuprorelin acetate salt is (2S)-N-[(2S)-1-[[(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-oxopropane-2 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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