Method for producing large amounts of microspheres

Abstract

The present invention relates to a method for producing biodegradable microspheres, whereby a greater amount of microspheres is produced per batch. In the method, a fresh continuous phase is supplied from the moment the supply of an emulsion solution is begun, and at the same time a continuous phase mixed with an organic solvent is discharged, and thus a dispersed solution can be additionally and continuously supplied in an amount exceeding that which can be supplied in a single batch to an emulsion tank in a conventional process, thus having the effect of increasing the production amount per batch. In addition, the residual concentration of the organic solvent mixed in the continuous phase can be constantly maintained at or below an appropriate level, thus having the effect of preventing agglomeration or deformation of microspheres that are in a soft state.

Description

Method for producing microspheres with high yield

[0001] The present invention relates to a method for producing microspheres at high production yields, and more particularly, to a method for producing biodegradable microspheres with increased production yield per microsphere production cycle (per batch).

[0002] Microsphere or microparticle formulations containing biodegradable polymers and active drug ingredients are widely studied as sustained-release or delayed-release formulations in various therapeutic areas. These formulations offer the advantage of controlling drug release rates, extending in vivo duration, and minimizing side effects, and are particularly utilized in long-acting injectables, anticancer drug delivery systems, and vaccine formulations.

[0003] Various processes have been used to manufacture such microspheres, including the emulsion-solvent evaporation technique, which is a microsphere manufacturing technique related to the present invention, as well as phase separation, spray drying, and supercritical fluid technology. The emulsion-solvent evaporation technique emulsifies a dispersed phase in a continuous phase solution in an O / W, W / O / W, or S / O / W emulsion method, and the organic solvent in the emulsion is extracted toward the continuous phase, thereby forming microspheres.

[0004] In the manufacturing process of the above microspheres, various types of organic solvents are used to dissolve biodegradable polymers and drugs, but it is desirable to minimize the amount of the solvent used in the final microsphere product, and furthermore, organic solvents remaining in the final microspheres have a negative effect on the stability of the product, such as by promoting the decomposition of the polymer during the distribution period.

[0005] Additionally, during the microsphere manufacturing process, the organic solvent is removed by diffusion from the emulsion into the continuous phase, and this rate is affected by the concentration of the organic solvent present in the continuous phase. For example, the lower the concentration of the organic solvent mixed in the continuous phase compared to the concentration of the organic solvent within the emulsion, the faster the extraction rate of the organic solvent from the emulsion into the continuous phase. If the concentration of the organic solvent in the continuous phase is high, the extraction rate slows or stops, which may result in deformation or agglomeration of the soft microspheres.

[0006] Accordingly, in order to increase the extraction rate of the organic solvent from the emulsion to the continuous phase, it is desirable to lower the concentration of the organic solvent in the continuous phase, and one such method may be a method of exchanging a portion of the continuous phase with a new continuous phase, and a related technology is Korean Patent No. 10-2047983. Specifically, Korean Patent No. 10-2047983 proposes a method of exchanging the continuous phase 5 minutes after the surface of the microparticles begins to harden, preferably 10 to 60 minutes later, and states that exchanging the continuous phase earlier than the above time point has the disadvantage of deforming the microparticles, and that time for the injected emulsion solution to settle is essential.

[0007] As in the above prior art, if a time (more than 5 minutes, preferably 10 to 60 minutes) for the emulsion solution initially injected into the emulsion storage tank to settle is essential, the amount of microspheres that can be produced in an emulsion storage tank of limited capacity becomes limited.

[0008] An object of the present invention is to provide an improved method for producing biodegradable microspheres with increased production per batch using an emulsion-solvent evaporation technique.

[0009] Another object of the present invention is to provide a dispersed phase (DP) storage tank (1);

[0010] Continuous phase (CP) storage tank (2);

[0011] An emulsion storage tank (3) having a stirrer inside;

[0012] An emulsion forming device (4) that forms an emulsion by supplying a dispersed phase and a continuous phase from the dispersed phase storage tank (1) and the continuous phase storage tank (2), respectively;

[0013] A first continuous phase supply pipe (5a) that supplies the continuous phase by connecting the continuous phase storage tank (2) and the emulsion forming device (4);

[0014] An emulsion supply pipe (6) for transporting the emulsion formed in the emulsion forming device (4) to the emulsion storage tank (3); and

[0015] The present invention provides a biodegradable microparticle manufacturing device, which includes a second continuous phase supply pipe (5b) that directly supplies the continuous phase by connecting the continuous phase storage tank (2) and the emulsion storage tank (3).

[0016]

[0017] The present inventors, while devising a method for increasing the production volume of microspheres per batch, found that by supplying a fresh continuous phase from the start of the emulsion injection process and simultaneously discharging a continuous phase mixed with an organic solvent, the concentration of the organic solvent in the entire solution during the emulsion injection process can always be maintained below an appropriate level, thereby enabling the continuous supply of an additional dispersed phase exceeding the capacity that can be supplied to the emulsion tank at one time in the conventional process, thereby increasing the production volume per batch, and also confirming the effect of preventing the occurrence of agglomeration or deformation of soft microspheres, thereby completing the present invention.

[0018] The present invention,

[0019] A method for producing biodegradable microspheres using an emulsion-solvent evaporation technique,

[0020] (a) preparing a dispersed solution containing a biodegradable polymer;

[0021] (b) In a continuous phase (CP) storage tank, a water phase (W) containing a surfactant dissolved in water c Prepare a fresh continuous phase solution (CP0) and pre-fill the fresh continuous phase solution (CP0) into the emulsion storage tank;

[0022] (c) supplying the above dispersed phase solution and the above fresh continuous phase solution (CP1) to an emulsion forming device to form an emulsion;

[0023] (d) Supplying the emulsion of step (c) to the emulsion storage tank while supplying a fresh continuous phase solution (CP2), and discharging a portion of the contaminated continuous phase mixed with the organic solvent to the outside of the emulsion storage tank;

[0024] (e) a step of performing microparticle generation while performing a continuous phase replacement process of supplying a fresh continuous phase (CP3) while removing a portion of the contaminated continuous phase mixed with the organic solvent when the supply of the emulsion of the above step (c) to the emulsion storage tank is completed;

[0025] It relates to a method for producing biodegradable microspheres.

[0026]

[0027] In a specific example, the present invention

[0028] (a)

[0029] (O / W dispersion phase i) Biodegradable polymer alone, or biodegradable polymer and drug dissolved in an organic solvent (O d Prepare the phase as a dispersed phase, or

[0030] (W / O / W dispersion phase for preparation ii) Water phase (W) in which the drug is dissolved in an aqueous solution d phase) and an oil phase (O) in which biodegradable polymers are dissolved in an organic solvent d W mixed with phase d / Od Prepare an emulsion in a dispersed form, or

[0031] (S / O / W dispersion phase for the preparation method iii) Suspension phase (S) in which a biodegradable polymer and a powdered drug are mixed in an organic solvent that dissolves the biodegradable polymer d / O d A step of preparing a dispersed phase;

[0032] (b) In a continuous phase (CP) storage tank, a water phase (W) containing a surfactant dissolved in water c A step of preparing a fresh continuous phase solution (CP0) and pre-filling the fresh continuous phase solution (CP0) into an emulsion storage tank;

[0033] (c) a step of forming an emulsion by supplying the (dispersed phase i for O / W preparation), (dispersed phase ii for W / O / W preparation) or (dispersed phase iii for S / O / W preparation) of step (a) and the fresh continuous phase solution (CP1) of step (b) to an emulsion forming device;

[0034] (d) a step of supplying a fresh continuous phase solution (CP2) while supplying the emulsion of step (c) to the emulsion storage tank, and discharging a portion of the contaminated continuous phase mixed with the organic solvent to the outside of the emulsion storage tank; and

[0035] (e) A method for producing biodegradable microspheres, comprising: a step of performing microsphere production while performing a continuous phase replacement process of removing a portion of the contaminated continuous phase mixed with the organic solvent and supplying a fresh continuous phase solution (CP3) when the supply of the emulsion of the above step (c) to the emulsion storage tank is completed;

[0036] As a specific example,

[0037] The fresh continuous phase solution (CP0) of the above step (b) may be pre-injected into the emulsion storage tank through the continuous phase supply pipe (5b) before preparing the emulsion (see Fig. 1b). In addition, it may be pre-injected into the emulsion storage tank through the paths of the continuous phase supply pipe (5a), the emulsion forming device (4), and the emulsion supply pipe (6) (see Figs. 1a, 1b, and 1c). Furthermore, it may be pre-injected into the emulsion storage tank through the paths of the continuous phase supply pipe (5b) and the emulsion supply pipe (6) (see Fig. 1a).

[0038] As a specific example,

[0039] The emulsion of the above step (c) can be injected into the emulsion storage tank (3) through the emulsion supply pipe (6). In addition, the emulsion supply pipe and the continuous phase supply pipe may each be connected to the emulsion storage tank, or the continuous phase supply pipe may be connected to the emulsion supply pipe and connected to the emulsion storage tank through an integrated pipe.

[0040]

[0041] As a specific example,

[0042] In the above step (d), the contaminated continuous phase mixed with the organic solvent, which is equal to the sum of the amount of fresh continuous phase solution (CP1) supplied to the emulsion forming device and the amount of fresh continuous phase solution (CP2) supplied separately, can be continuously discharged to the outside of the emulsion storage tank.

[0043]

[0044] As a specific example,

[0045] In the emulsion of the above step (d), the organic solvent in the emulsion is diluted by the fresh continuous phase (CP2) additionally supplied while being supplied to the emulsion storage tank, thereby lowering the concentration of the organic solvent.

[0046]

[0047] As a specific example,

[0048] In the above step (e), a portion of the contaminated continuous phase mixed with the organic solvent is continuously discharged to the outside of the emulsion storage tank, while a fresh continuous phase solution (CP3) is continuously supplied to the emulsion storage tank, so that the contaminated continuous phase and the uncontaminated fresh continuous phase can be continuously replaced.

[0049] The method for producing biodegradable microspheres with increased production per batch according to the present invention uses a continuous process in which a fresh continuous phase is supplied from the time of injecting emulsion into an emulsion storage tank, while continuously discharging a continuous phase mixed with an organic solvent, thereby keeping the concentration of the organic solvent contained in the continuous phase low, thereby increasing the amount of emulsion that can be supplied to the emulsion storage tank, particularly the amount of the dispersed phase, compared to a conventional process in which there is no replacement of the continuous phase when injecting the emulsion, thereby increasing the production per batch, and also having the effect of preventing agglomeration or deformation of soft microspheres.

[0050]

[0051] Figures 1a, 1b, and 1c are schematic diagrams of a method for producing biodegradable microspheres with increased production per batch according to the present invention. Figure 1a shows a configuration in which a continuous phase (CP) supply pipe is connected to an emulsion supply pipe, and the emulsion supply pipe is connected to an emulsion storage tank. Figure 1b shows a configuration in which the continuous phase supply pipe and the emulsion supply pipe are each separately connected to an emulsion storage tank. Figure 1c shows a configuration in which two separate continuous phase supply pipes are each connected to an emulsion supply pipe and an emulsion storage tank.

[0052] In the above drawings, 1: dispersed phase (DP) storage tank, 2: continuous phase (CP) storage tank, 3: emulsion storage tank, 4: emulsion solution forming device (membrane emulsification using a porous filter, inline mixer, static mixer, or microfluidic), 5a: CP supply first pipe (for CP1 supply), 5b: CP supply second pipe (for CP2 supply), and 6: emulsion solution supply pipe are shown.

[0053] Figures 2a, 2b, and 2c are schematic diagrams of a method for producing biodegradable microspheres with increased production per batch according to the present invention, and are schematic diagrams of a production method additionally using a tangential flow filtration (TFF) device. Figure 2a shows a form in which a continuous phase (CP) supply pipe is connected to an emulsion supply pipe, and the emulsion supply pipe is connected to an emulsion storage tank. Figure 2b shows a form in which the continuous phase supply pipe and the emulsion supply pipe are each separately connected to the emulsion storage tank. Figure 2c shows a form in which two separate continuous phase supply pipes are each connected to the emulsion supply pipe and the emulsion storage tank. In the above drawings, 1: dispersed phase (DP) storage tank, 2: continuous phase (CP) storage tank, 3: emulsion storage tank, 4: emulsion solution forming device (membrane emulsification using a porous filter, inline mixer, static mixer, or microfluidic), 5a: CP supply first pipe (for CP1 supply), 5b: CP supply second pipe (for CP2 supply), 6: emulsion solution supply pipe, 7: first tangential flow filtration device (TFF-1), 8: second tangential flow filtration device (TFF-2), and 9: waste are shown.

[0054] Figure 3a is a photograph taken with an optical microscope of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization is completed by the manufacturing method according to Example 1.

[0055] Figure 3b is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization was completed, confirmed by an optical microscope, using the manufacturing method according to Comparative Example 1-1.

[0056] Figure 3c is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization was completed, confirmed by an optical microscope, using the manufacturing method according to Comparative Example 1-2.

[0057] Figure 3d is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization was completed, taken using an optical microscope, according to the manufacturing method according to Comparative Example 1-3.

[0058] Figure 4a is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization was completed, confirmed by an optical microscope, according to the manufacturing method according to Example 2.

[0059] Figure 4b is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization was completed, confirmed by an optical microscope, using the manufacturing method according to Comparative Example 2-1.

[0060] Figure 4c is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization is completed, confirmed by an optical microscope, using the manufacturing method according to Comparative Example 2-2.

[0061] Figure 5a is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization is completed, confirmed by an optical microscope, according to the manufacturing method according to Example 3.

[0062] Figure 5b is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization is completed, confirmed by an optical microscope, using the manufacturing method according to Comparative Example 3-1.

[0063] Figure 5c is a photograph of the shape of the emulsion droplets immediately after injection of the emulsion and the microparticles after volatilization is completed, confirmed by an optical microscope, using the manufacturing method according to Comparative Example 3-2.

[0064] Hereinafter, the present invention will be described in detail.

[0065] The term "one or more" in the present invention means "number" corresponding to one or more. In the present invention, when a certain configuration is one or more, it may preferably be one, two or more, three or more, one to three, or one to two, but is not limited thereto. The term "one or more" may be used interchangeably with the term "one or more" in the present invention.

[0066] The term "polymer blending" of the present invention means that two or more types of polymers are used in one microparticle.

[0067] The term "microsphere blending" of the present invention means a blend of two or more types of microspheres having different compositions, and may be, for example, a microsphere blending including the same drug but different types of biodegradable polymers, or may also be a microsphere blending including different drugs.

[0068] The term "dispersed phase (DP)" of the present invention means an oily solution containing a biodegradable polymer and an organic solvent; an oily solution containing a drug, a biodegradable polymer, and an organic solvent; a primary emulsion solution formed by a primary aqueous phase containing a drug and an oily solution containing a biodegradable polymer and an organic solvent; or an oily suspension containing a powdered drug, a biodegradable polymer, and an organic solvent.

[0069] The term "paid (O)" of the present invention d "phase" means a solution containing a biodegradable polymer and an organic solvent used in the manufacture of a dispersed phase, or a solution further containing a drug, wherein 'O' is an abbreviation for 'oil' and the subscript 'd' is an abbreviation for 'dispersed'.

[0070] The term "award (W) of the present invention d"phase" means a solution containing the drug and aqueous solvent used in the preparation of the dispersed phase, where 'W' is an abbreviation for 'water' and the subscript 'd' is an abbreviation for 'dispersed'.

[0071] The term "suspension (S) of the present invention d / O d "Phase" means an oily suspension containing a powdered drug, a biodegradable polymer, and an organic solvent.

[0072] The term "continuous phase (CP)" of the present invention refers to an aqueous solution containing a surfactant that forms an emulsion with the dispersed phase and serves to disperse fine droplets of the dispersion.

[0073] The term “fresh continuous phase” of the present invention refers to a continuous phase prepared in the following step (b), in which an organic solvent is not mixed, and “W c It is also expressed as "phase", where the subscript 'c' is an abbreviation for 'continuous'. The above "fresh continuous phase" is mixed with the emulsion solution after being injected into the emulsion storage tank, and changes into a "continuous phase mixed with organic solvent" as the organic solvent is extracted from the fine droplets of the dispersed phase suspended in the emulsion solution.

[0074] The terms CP0 to CP3 of the present invention mean the “fresh continuous phase” solutions described above, which have the same composition and are indicated by different subscript numbers to distinguish the process points used.

[0075]

[0076] The term "continuous phase mixed with organic solvent" in the present invention means that the organic solvent is mixed with the continuous phase by extracting the dispersed organic solvent in the emulsion from the emulsion storage tank toward the continuous phase. Here, since the continuous phase mixed with the organic solvent is selectively heated to evaporate the organic solvent, the continuous phase mixed with the organic solvent may have only a portion or a trace concentration of the organic solvent remaining, or the organic solvent may be completely evaporated.

[0077]

[0078] In general, it takes about 1-2 days to produce one batch of microspheres (emulsion storage tank) excluding the drying process. In the conventional method, in order to have a gradient of residual concentration of organic solvent mixed in the continuous phase, an amount of dispersed phase that can be supplied at one time is supplied to the emulsion tank, for example, at a volume ratio of dispersed phase to continuous phase of 1:50 to 1:1000, and then the organic solvent is extracted from the emulsion toward the continuous phase to produce microspheres. If the volume of the continuous phase in the conventional method is lowered to less than 50, the residual concentration of the organic solvent mixed in the continuous phase increases, making it difficult to extract the organic solvent from the emulsion to the continuous phase, which makes it difficult to form microspheres in an initially soft state from the emulsion. Here, the volume ratio of the dispersed phase to the continuous phase may vary depending on the type of solvent and / or the emulsion type.

[0079] That is, the amount of dispersed phase that can be injected into an emulsion storage tank with a limited volume is limited, and for example, the dispersed phase can only be injected in a volume of 1 / 50 to 1 / 1000 of the capacity of the emulsion storage tank. Since most of the major components of microspheres are contained in the dispersed phase, the amount of dispersed phase that can be injected into the emulsion storage tank is directly related to the microsphere production amount per batch. Here, the term 'batch' means one microsphere production cycle.

[0080] The present invention uses a continuous process in which a fresh continuous phase and an emulsion solution are continuously supplied during the emulsion injection process (corresponding to step d) while a continuous phase mixed with an organic solvent is continuously discharged, thereby continuously maintaining the freshness of the continuous phase in the emulsion injection process (i.e., the continuous phase maintains a low level of residual concentration of the mixed organic solvent), thereby increasing the amount of the dispersed phase that can be additionally injected compared to the conventional production process, which in turn leads to an improvement in the production volume per batch.

[0081] Meanwhile, in the Korean Patent No. 10-2047983 of the present applicant, although it is described that the continuous phase is continuously removed, in the detailed description of the invention, it is described that the continuous phase exchange time is preferably more than 5 minutes from the time when the surface of the generated microspheres begins to harden, and more preferably 10 to 60 minutes, and it is stated that if the continuous phase is exchanged earlier than the above time, there is a problem that the microspheres in the initial soft state cannot maintain their spherical shape and become deformed.

[0082] In other words, in the above Korean registered patent, the continuous phase displacement process is first performed after the end of the emulsion injection process, and the continuous phase displacement process is not performed during the emulsion injection process. That is, in the above Korean registered patent, since the concentration of the organic solvent increases rapidly depending on the amount of the dispersed phase injected during the emulsion injection process, there is a limit to the total amount of the dispersed phase that can be injected into the emulsion storage tank at one time. This is because if the concentration of the organic solvent is excessively high during the emulsion injection process, there is a problem that the polymer and / or drug are dissolved again in the formed emulsion. Therefore, in the conventional emulsion injection process, the total amount of the dispersed phase is limited and injected within a level that does not cause problems, taking the organic solvent concentration into consideration.

[0083]

[0084] However, the present invention can maintain the concentration of the organic solvent in the entire solution during the emulsion injection process below a certain level by replacing the continuous phase by adding a separate fresh continuous phase from the start of the emulsion injection process, thereby increasing the total amount of the dispersed phase that can be injected. Since the amount of dispersed phase that can be injected into an emulsion storage tank with a limited volume is directly related to the amount of microspheres produced per batch, the present invention has the advantage of showing a high amount of microspheres produced per batch.

[0085]

[0086] Below, steps (a) to (e) are described in detail.

[0087] In the production method according to the present invention, step (a) prepares a dispersed phase (DP), wherein the dispersed phase contains a biodegradable polymer,

[0088] More specifically, as a dispersion phase for O / W formulation, i) an oil phase (O) in which a biodegradable polymer alone or a biodegradable polymer and a drug are dissolved in an organic solvent d Prepare the phase as a dispersed phase, or

[0089] As a dispersion phase for W / O / W formulation, ii) a water phase (W) in which the drug is dissolved in an aqueous solution d phase) and an oil phase (O) in which biodegradable polymers are dissolved in an organic solvent d W mixed with phase d / O d Prepare an emulsion in a dispersed form, or

[0090] iii) A suspension phase (S) in which a biodegradable polymer and a powdered drug are mixed in an organic solvent that dissolves the biodegradable polymer as a dispersion phase for the S / O / W method. d / O d This is the step of preparing the phase as a dispersed phase.

[0091]

[0092] Preparation of dispersion phase for O / W method

[0093] In the above step a), as a dispersion phase for the O / W method, i) an oil phase (O) in which a biodegradable polymer alone or a biodegradable polymer and a drug are dissolved in an organic solvent d Prepare the dispersed phase.

[0094] The above-mentioned dispersed phase (DP) storage tanks may be prepared singly or in multiples. For example, when producing one type of biodegradable microsphere, one dispersed phase (DP) storage tank may be used, and when producing two types of biodegradable microspheres simultaneously, two dispersed phase storage tanks may be used. Here, the two types of biodegradable microspheres may be microsphere blends containing the same drug but different types of biodegradable polymers, or may be microsphere blends containing different drugs.

[0095]

[0096] In addition, when the drug and polymer are to be dissolved in one solvent, they can be mixed in a dispersion storage tank, and when the drug and polymer must be dissolved in separate solvents, a drug storage tank and a polymer storage tank can be configured separately and used by connecting them to the dispersion storage tank.

[0097]

[0098] Furthermore, the dispersed phase storage tank, continuous phase storage tank, and emulsion storage tank used in the present invention can be connected in parallel in multiple numbers, allowing for an expanded design for mass production. For example, the dispersed phase and continuous phase used can be the same, but 1-3 continuous phase storage tanks, 2-3 dispersed phase storage tanks, and 2-3 emulsion storage tanks can be designed by connecting them in parallel at the same time.

[0099]

[0100] The weight average molecular weight (Mw) of the above biodegradable polymer is not particularly limited, but the lower limit may be 5,000 Mw or more, 6,000 Mw or more, 7,000 Mw or more, 8,000 Mw or more, 9,000 Mw or more, 10,000 Mw or more, 15,000 Mw or more, 20,000 Mw or more, 25,000 Mw or more, 30,000 Mw or more, 40,000 Mw or more, or 50,000 Mw or more, and the upper limit may be 500,000 Mw or less, 450,000 Mw or less, 400,000 Mw or less, 350,000 Mw or less, 300,000 Mw or less, 250,000 Mw or less, 240,000 Mw or less, It may be 230,000 Mw or less, 220,000 Mw or less, 210,000 Mw or less, 200,000 Mw or less, 190,000 Mw or less, 180,000 Mw or less, 170,000 Mw or less, 160,000 Mw or less, 150,000 Mw or less, 140,000 Mw or less, 130,000 Mw or less, 120,000 Mw or less, 110,000 Mw or less, or 100,000 Mw or less. The weight average molecular weight (Mw) of the biodegradable polymer may be included in a range by a combination of the lower and upper limits above, but is not limited thereto. The lower the weight average molecular weight of the polymer, the lower the intrinsic viscosity, and the higher the weight average molecular weight, the higher the intrinsic viscosity.

[0101]

[0102] The types of the above biodegradable polymers are not particularly limited, but include polylactide (PLA), polyglycolide (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), A polymer selected from the group consisting of polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide and poly(butylene succinate-co-lactic acid) (PBSLA); a simple mixture of two or more kinds (specifically two to three kinds, more specifically two kinds) of the above-mentioned selected polymers;It may be at least one selected from the group consisting of a copolymer of the above-mentioned selected polymer and polyethylene glycol (PEG); and a polymer-sugar complex in which the above-mentioned selected polymer or copolymer is bound to a sugar (specifically, 1 to 3 types, more specifically, 1 to 2 types). Specifically, polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polycaprolactone (PCL), etc. may be used alone or in a mixture of two or more types. More specifically, polylactide (PLA), poly(lactide-co-glycolide) (PLGA), etc. may be used alone or in a mixture of two or more types.;

[0103]

[0104] The biodegradable polymer having an intrinsic viscosity of 0.08 to 1.7 dL / g may be used. Specifically, the intrinsic viscosity of the biodegradable polymer may be used in a wide range, taking into account the type of drug, the release characteristics of the drug, the manufacturing process, and other manufacturing conditions. The lower limit of the intrinsic viscosity of the above biodegradable polymer may be 0.08 or more, 0.14 or more, 0.15 or more, 0.16 or more, 0.20 or more, 0.25 or more, 0.26 or more, 0.32 or more, 0.33 or more, 0.39 or more, 0.40 or more, 0.45 or more, 0.50 or more, 0.55 or more, 0.61 or more, 0.70 or more, 0.71 or more, 0.76 or more, 0.80 or more, 0.83 or more, 0.90 or more, 0.95 or more, 1.00 or more, or 1.30 or more, and the upper limit may be 0.16 or less, 0.20 or less, 0.22 or less, 0.24 or less, 0.25 or less, 0.35 or less, 0.40 or less, 0.42 or less, It may be 0.44 or less, 0.49 or less, 0.50 or less, 0.54 or less, 0.60 or less, 0.68 or less, 0.70 or less, 0.74 or less, 0.75 or less, 0.85 or less, 0.90 or less, 0.93 or less, 0.94 or less, 1.00 or less, 1.20 or less, 1.30 or less, or 1.70 or less. The intrinsic viscosity of the biodegradable polymer may be used in a range by a combination of the lower and upper limits, but is not limited thereto. The intrinsic viscosity refers to that measured at a concentration of 0.1% (w / v) in chloroform at 25°C using an Ubbelohde viscometer.

[0105]

[0106] Depending on the type of drug, the release characteristics of the drug, the manufacturing process, and other manufacturing conditions, the intrinsic viscosity can be used in a wide range. From this perspective, if it exceeds the upper limit, there may be problems such as excessive delay in drug release (occurrence of lag phase) or deterioration in the reproducibility of microsphere manufacturing, and excessive use of organic solvent due to high viscosity. If it is below the lower limit, there may be problems such as insufficient molecular weight of the polymer, resulting in burst release of the drug, or difficulty in exhibiting a long-term sustained-release pattern. In one embodiment, in the case of a polymer blend in which two or more polymers are mixed and used, a polymer having a low intrinsic viscosity and a polymer having a high intrinsic viscosity may be mixed so that the mixed intrinsic viscosity falls within a desirable range of the intrinsic viscosity.

[0107]

[0108] When poly(lactide-co-glycolide) is used as the biodegradable polymer, the molar ratio of lactide to glycolide in the copolymer may be 40:60 to 90:10, 45:55 to 85:15, 50:50 to 85:15, or 50:50 to 75:25, for example, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, or 90:10.

[0109]

[0110] Examples of commercially available biodegradable polymers that can be used in the present invention include the Resomer® series from Evonik and the PURASORB® series from Corbion. For example, the biodegradable polymers of the Resomer series of Evonik include RG501H, RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, RG858S, R202H, R203H, R202S, R203S, R205H, R205S, etc., and the biodegradable polymers of the PURASORB series of Corbion include PDL 02A, PDL 02, PDL 04A, PDL 04, PDL 05, PDLG 7502A, PDLG 7502, PDLG 7507, PDLG 7510, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG 5004, PDLG 5010, PDLG 5505G, PL 10, PL 18, PL 24, PL 32, PL 38, PL 65, PLDL 7024, PLDL, 7028, PLDL, 7038, PLDL 7060, PLDL 8038, PLDL 8058, PG 20, PLG 1017, PLG 8218, PLG 8523, PLG 8531, PC 02, PC 04, PC 08, PC 12, PC 17, PLC 7015, etc. can be used.

[0111]

[0112] In addition, the biodegradable polymer being a simple mixture of two or more (i.e., a simple mixture including two or more of the polymers selected above) may include two or more different types of polymers among the non-limiting examples, or may be a combination or blend of polymers of the same type. If the same type of polymer is used, a combination of polymers having different intrinsic viscosities, different repeat unit molar ratios, and different terminal groups may be used. For example, a combination or blend of two or more PLA or PLGA having different intrinsic viscosities, or a combination or blend of two or more PLGA having different repeat unit molar ratios, or a combination or blend of two or more PLA or PLGA having different terminal groups (e.g., terminal groups that are carboxylic acids or terminal groups blocked with methyl, ester, etc.) may be used. For example, a simple mixture of RG502H and RG503H may be used as two or more biodegradable polymers used in the present invention, wherein both RG502H and RG503H have a lactide:glycolide molar ratio of 50:50 and the same polymer type as PLGA, but have different intrinsic viscosities of 0.16-0.24 dL / g and 0.32-0.44 dL / g.

[0113]

[0114] In addition, as a specific example, when there are two types of biodegradable polymers that are different from each other, they can be mixed and used in various content ratios. For example, the content ratio may be, but is not limited to, a weight ratio of 0.5:10 to 10:0.5, 0.5:8 to 8:0.5, 1:10 to 10:1, 1:4 to 4:1, 1:3 to 3:1, or 1:2 to 2:1.

[0115]

[0116] The content of the biodegradable polymer in the microspheres according to the present invention can be selected as 20 wt% or more, 25 wt% or more, 26 wt% or more, 27 wt% or more, 28 wt% or more, 29 wt% or more, 30 wt% or more, 35 wt% or more, 40 wt% or more, 45 wt% or more, 50 wt% or more, 55 wt% or more, 60 wt% or more, 65 wt% or more, 70 wt% or more, 75 wt% or more, 80 wt% or more, 85 wt% or more, 90 wt% or more or 95 wt% or more, with respect to the total weight of the microspheres, and the lower limit can be selected as 95 wt% or less, 90 wt% or less, 85 wt% or less, 80 wt% or less, 75 wt% or less, 70 wt% or less, 65 wt% or less, 60 wt% or less, 55 wt% or less, 50 wt% or less, 45 wt% or less. The upper limit may be selected as 40 wt% or less, 35 wt% or less, 30 wt% or less, 29 wt% or less, 28 wt% or less, 27 wt% or less, 26 wt% or less, 25 wt% or less, or 20 wt% or less. The content of the biodegradable polymer in the microparticles may be included in a range consisting of a combination of the upper and lower limits with respect to the total weight of the microparticles. For example, it may be, but is not limited to, 20 wt% to 95 wt%, 25 wt% to 95 wt%, 30 wt% to 95 wt%, 35 wt% to 95 wt%, 40 wt% to 95 wt%, 45 wt% to 95 wt%, 50 wt% to 95 wt%, 55 wt% to 95 wt%, 60 wt% to 95 wt%, 65 wt% to 95 wt%, 70 wt% to 95 wt%, 75 wt% to 95 wt%, 80 wt% to 95 wt%, or 85 wt% to 95 wt%.

[0117]

[0118] The concentration of the biodegradable polymer in the above-mentioned dispersed phase can be used in a wide range considering the type of drug, the release characteristics of the drug, the manufacturing process, and other manufacturing conditions. The lower limit of the concentration of the biodegradable polymer in the above-mentioned dispersed phase may be 1 w / v% or more, 2 w / v% or more, 3 w / v% or more, 4 w / v% or more, 5 w / v% or more, 10 w / v% or more, 15 w / v% or more, 20 w / v% or more, 25 w / v% or more, 30 w / v% or more, 35 w / v% or more, 40 w / v% or more, 41 w / v% or more, 42 w / v% or more, 43 w / v% or more, 44 w / v% or more, or 45 w / v% or more, and the upper limit may be 50 w / v% or less, 49 w / v% or less, 48 ​​w / v% or less, 47 w / v% or less, 46 w / v% or less, 45 w / v% or less, 40 w / v% or less, 35 w / v% or less, 30 w / v% or less, 25 w / v% or less, 20 w / v% or less, 15 w / v% or less, 14 w / v% or less, 13 w / v% or less, 12 w / v% or less, 11 w / v% or less, 10 w / v% or less, 9 w / v% or less, 8 w / v% or less, 7 w / v% or less, 6 w / v% or less, or 5 w / v% or less. The concentration of the biodegradable polymer in the dispersed phase may be used in a range by a combination of the lower and upper limits, but is not limited thereto.

[0119] If the concentration of the biodegradable polymer in the above-mentioned dispersed phase exceeds the upper limit, the viscosity may become excessively high, which may cause difficulties in manufacturing microspheres. If it is less than the lower limit, the emulsion may not be formed or the amount of organic solvent used may become excessive, which may cause difficulties in removing it from the microspheres and may cause environmental pollution.

[0120]

[0121] The types of the above drugs are not particularly limited, and water-soluble drugs, fat-soluble drugs, and poorly soluble drugs can all be used. Specifically, small molecule therapeutics, synthetic compound therapeutics, peptide therapeutics, antibody therapeutics, protein therapeutics, nucleic acid therapeutics, gene therapeutics, cell therapeutics, antibody-drug conjugates (ADCs), and radiopharmaceuticals (RPTs) can be used alone or in combination of two or more. Here, when two or more drugs are used in combination, they can be co-encapsulated microspheres.

[0122]

[0123] The nucleic acid therapeutic agent may be at least one selected from the group consisting of DNA, RNA, microRNA (miRNA), small RNA (smRNA), small interfering RNA (siRNA), Piwi-interacting RNA (piRNA), small nucleolar RNA (snoRNA), tRNA-derived small RNA (tsRNA), small rDNA-derived RNA (srRNA), small nuclear RNA (U-RNA), and long noncoding RNA (lncRNA).

[0124]

[0125] The above drugs include, for example, dementia treatment drugs; Parkinson's disease treatment drugs; anticancer drugs; antipsychotic drugs such as antianxiety drugs, antidepressants, tranquilizers, and psychotropic drugs; cardiovascular treatment drugs such as hyperlipidemia treatment drugs, hypertension treatment drugs, hypotension treatment drugs, antithrombotic drugs, vasodilators, and arrhythmia treatment drugs; epilepsy treatment drugs; epilepsy treatment drugs; gastrointestinal treatment drugs such as antiulcer drugs; rheumatism treatment drugs; antispasmodics; tuberculosis treatment drugs; muscle relaxants; osteoporosis treatment drugs; erectile dysfunction treatment drugs; hemostatic drugs; hormonal drugs such as sex hormones; diabetes treatment drugs; obesity treatment drugs; nonalcoholic steatohepatitis treatment drugs; antibiotics; antifungal drugs; antiviral drugs; antipyretics, analgesics, anti-inflammatory drugs; autonomic nervous system regulators; steroidal anti-inflammatory drugs such as corticosteroids; diuretics; antidiuretics; analgesics; anesthetics; antihistamines; antiprotozoal drugs; antianemia drugs; antiasthmatic drugs; antispasmodics; antitoxins; antimigraine drugs; Antiemetics; anti-Parkinsonian drugs; anti-epileptics; antiplatelet agents; expectorants; bronchodilators; cardiotonic agents; immunomodulators; protein drugs; genetic drugs, etc. can be used alone or in combination of two or more. Specifically, dementia treatment drugs, Parkinson's disease treatment drugs, anticancer drugs, antipsychotic drugs, hyperlipidemia treatment drugs, hypertension treatment drugs, epilepsy treatment drugs, gastrointestinal treatment drugs, rheumatism treatment drugs, antispasmodics, tuberculosis treatment drugs, muscle relaxants, arrhythmia treatment drugs, osteoporosis treatment drugs, erectile dysfunction treatment drugs, hemostatic agents, antiviral agents, hormone drugs, antibiotics, diabetes treatment drugs, obesity treatment drugs, non-alcoholic steatohepatitis treatment drugs, antifungal agents, antithrombotic agents, antipyretics, analgesics, anti-inflammatory drugs, steroidal anti-inflammatory drugs, etc. can be used alone or in combination of two or more.

[0126]

[0127] Specific examples of the above drugs include donepezil, memantine, rivastigmine, entecavir, lamivudine, rotigotine, ropinirole, bupivacaine, ropivacaine, meroxicam, buprenorphine, fentanyl, nimodipine, granisetron, dexamethasone, triamcinolone, cytarabine, carmustine, tamsoleucine, polmacoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, goserelin, leuprolide, triptorelin, buserelin, nafarelin, deslorelin, octreotide, pasireotide, lanreotide, vapretide, exenatide, liraglutide, lixisenatide, semaglutide, capriglintide, terzepatide, Dulaglutide, letaturutide, mazdutide, 5-alpha reductase inhibitors (e.g., finasteride, dutasteride, etc.), brexpiprazole, insulin glargine, insulin degludec, insulin icodec, steroidal anti-inflammatory drugs, amycretin, monlunabant (INV-202, Novo Nordisk), orforglipron, eloralintide (LY-3841136, Eli Lilly), DACRA QW II (LY-3541105, Eli Lilly), nisotirostide (LY-3457263, Eli Lilly), survodutide, Ecnoglutide, dapiglutide, ZP8396 from Zealand, VK2735 from Viking therapeutics, pembidutide, bamadutide, cotadutide, utreglutide, PYY1875 from Novo Nordisk, CT-388 from Roche / Carmot therapeutics, etc. can be used alone or in combination of two or more.As an example of a combination of two drugs, semaglutide and caprylintide can be used together.

[0128]

[0129] Specific examples of the above steroidal anti-inflammatory agents include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximethasone, dexamethasone, dexamethasone acetate, dexamethasone phosphate, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone Acetonide, fluocinonide, flucortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, Prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide,Beclomethasone dipropionate, betamethasone, budesonide, deflazacort, dexamethasone, dexamethasone acetate, dexamethasone phosphate, difluprednate, epinephrine, fludrocortisone, fluocinolone acetonide, fluocortin, fluorometholone, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, Triamcinolone, etc. can be used alone or in combination of two or more.

[0130]

[0131] Additionally, the above-mentioned drugs may be used as derivatives or in the form of pharmaceutically acceptable salts. Salts commonly used in the art may be used without limitation. The term "pharmaceutically acceptable salt" of the present invention refers to any organic or inorganic addition salt of the above-mentioned compound, which is relatively non-toxic and harmless to the patient, has an effective effect, and the side effects caused by the salt do not diminish the beneficial effects of the active ingredient. For example, pamoate may be used as the pharmaceutically acceptable salt.

[0132]

[0133] Furthermore, the content of the drug in the microspheres according to the present invention can be selected as a lower limit of 5 wt% or more, 10 wt% or more, 15 wt% or more, 20 wt% or more, 25 wt% or more, 30 wt% or more, 35 wt% or more, 40 wt% or more, 45 wt% or more, 50 wt% or more, 55 wt% or more, 60 wt% or more, 65 wt% or more, 70 wt% or more, 71 wt% or more, 72 wt% or more, 73 wt% or more, 74 wt% or more, or 75 wt% or more, based on the total weight of the microspheres, and 80 wt% or less, 75 wt% or less, 74 wt% or less, 73 wt% or less, 72 wt% or less, 71 wt% or less, 70 wt% or less, 65 wt% or less, 60 wt% or less, 55 wt% or less, 50 wt% or less, 45 wt% or less, The upper limit can be selected as 40 wt% or less, 35 wt% or less, 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, or 10 wt% or less. The content of the drug in the microparticles can be included in a range consisting of a combination of the lower and upper limits with respect to the total weight of the microparticles. For example, it may be 5 wt% to 80 wt%, 5 wt% to 75 wt%, 5 wt% to 74 wt%, 5 wt% to 73 wt%, 5 wt% to 72 wt%, 5 wt% to 71 wt%, 5 wt% to 70 wt%, 5 wt% to 65 wt%, 5 wt% to 60 wt%, 5 wt% to 55 wt%, 5 wt% to 50 wt%, 5 wt% to 45 wt%, 5 wt% to 40 wt%, 5 wt% to 35 wt%, 5 wt% to 30 wt%, 5 wt% to 25 wt%, 5 wt% to 20 wt%, 5 wt% to 15 wt%, or 5 wt% to 10 wt%, but is not limited thereto.

[0134]

[0135] The above organic solvent may be dichloromethane, dimethyl carbonate, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, n-methyl pyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, benzyl alcohol, etc., which may be used alone or in combination of two or more. For example, two or more mixed organic solvents may be used. In a specific embodiment, the mixed organic solvent may be a mixed organic solvent of an organic solvent that is miscible with water and an organic solvent that is not miscible with water. In this case, it is preferable to use an organic solvent that is immiscible with water in an amount of at least 50% (v / v), 60% (v / v), 50 to 99.9% (v / v), 50 to 90% (v / v), 50 to 80% (v / v), 50 to 70% (v / v), 60 to 90% (v / v), or 60 to 80% (v / v). Specifically, dichloromethane or ethyl acetate may be used alone, or dichloromethane or ethyl acetate may be used in combination with at least one of dimethyl sulfoxide, N-methylpyrrolidone, methyl alcohol, benzyl alcohol, and acetic acid. More specifically, dichloromethane may be used alone or in combination with one or more of dichloromethane, dimethyl sulfoxide, n-methylpyrrolidone, methyl alcohol, benzyl alcohol, and acetic acid.

[0136]

[0137] Optionally, the above-described dispersion phase may further include a release-controlling agent, such as butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, napadicylic acid, naphthalene sulfonic acid, or pamoic acid, alone or in combination of two or more. Specifically, pamoic acid may be used alone, but is not limited thereto.

[0138]

[0139] Preparation of dispersion phase for W / O / W method

[0140] In the above step a), as a dispersion phase for the W / O / W method, ii) a water phase (W) in which the drug is dissolved in an aqueous solvent d phase) and an oil phase (O) in which biodegradable polymers are dissolved in an organic solvent d W mixed with phase d / O d Prepare the emulsion in a dispersed form.

[0141]

[0142] Specifically, the above step a) for the dispersion phase for the W / O / W method can be performed by a process comprising the following steps:

[0143]

[0144] (a1) In the water storage tank, the drug is dissolved in an aqueous solvent and the water (W d Step for preparing the phase);

[0145] (a2) In the oil storage tank, the biodegradable polymer is dissolved in an organic solvent to form an oil phase (O d Step for preparing the phase); and

[0146] (a3) The award (W) prepared in the above step (a1) d phase) and the oil phase (O) prepared in the above step (a2) d W mixed with phase d / O d Step of preparing an emulsion in a dispersed form.

[0147]

[0148] As a dispersion phase for W / O / W method, water phase (W) d phase) can be prepared, for example, by dissolving the drug in an aqueous solvent in a water storage tank.

[0149] The above award (W dThe phase) storage tank can be prepared in single or multiple phases. For example, when producing biodegradable microspheres containing one type of drug, one phase storage tank can be used, and when producing biodegradable co-encapsulated microspheres containing two types of drugs, two phase storage tanks can be used.

[0150] Examples of the above aqueous solvent include water, PBS (Phosphate buffered saline), TBS (Triss buffered saline), acetate buffer, citrate buffer, glycine-HCl buffer, ammonium bicarbonate buffer, sodium hydroxide aqueous solution, urea aqueous solution, etc., which may be used alone or in combination of two or more. The water may be purified water, distilled water, water for injection, etc.

[0151] A detailed description of the above drug is replaced by a description of the method for producing biodegradable microspheres using the O / W method described above.

[0152]

[0153] In the production method according to the present invention, the oil phase (O d phase) can be prepared by dissolving a biodegradable polymer in an organic solvent in a storage tank as in the above step (a2).

[0154] Detailed descriptions of the above biodegradable polymer and organic solvent are replaced with descriptions of the preparation of the dispersion phase for the above-described O / W method.

[0155]

[0156] In the production method according to the present invention, the above-prepared water (W d phase) and the oil phase (O) prepared in the above step (a2) d W mixed with phase d / O d When preparing an emulsion in a dispersed form, for example, the above water (W d phase) and oil phase (O dphase) is supplied to a separate emulsion forming device. d / O d Forming an emulsion, the above W d / O d The emulsion can be stored in a dispersed phase (DP) storage tank.

[0157] As another example, the dispersed storage tank is omitted, and the first phase (W d phase) and oil phase (O d phase) is supplied to a separate emulsion forming device. d / O d Forming an emulsion, the above W d / O d Emulsion continuous phase (W c It can also be used by supplying it directly to the emulsion forming device (4) where the phase is supplied. An inline mixer, a static mixer, etc. can be used as the 'separate emulsion forming device'. In FIGS. 1a-c to 2a-c of the present invention, the use of a dispersion phase storage tank is disclosed as an example, but in the case of the W / O / W manufacturing method as described above, it is also possible to omit the dispersion phase storage tank.

[0158]

[0159] Preparation of dispersion phase for S / O / W method

[0160] In the above step a), as a dispersion phase for the S / O / W method, iii) a suspension phase (S) in which a biodegradable polymer and a powdered drug are mixed in an organic solvent that dissolves the biodegradable polymer d / O d Prepare the dispersed phase.

[0161] The above suspension is not in the form of an emulsion, but rather represents a state in which a powdered drug is suspended in an organic solvent in which a biodegradable polymer is dissolved.

[0162] The average particle size of the above-mentioned powdered drug may be, but is not limited to, an upper limit of 10 ㎛ or less, 8 ㎛ or less, 6 ㎛ or less, 5 ㎛ or less, 4 ㎛ or less, or 3 ㎛ or less, and a lower limit of 0.0001 ㎛ or more, 0.005 ㎛ or more, 0.01 ㎛ or more, 0.05 ㎛ or more, 0.1 ㎛ or more, or 0.2 ㎛ or more, or a range combining the upper and lower limits of the above-mentioned particle sizes.

[0163] For example, a biodegradable polymer can be dissolved in an organic solvent, then mixed with a powdered drug to prepare a suspension. Another example is a powdered drug suspended in an organic solvent, then mixed with a biodegradable polymer to prepare a suspension. Yet another example is a suspension prepared by simultaneously mixing a biodegradable polymer and a powdered drug in an organic solvent.

[0164] Detailed descriptions of the above drugs, biodegradable polymers and organic solvents are replaced by descriptions in the preparation of the dispersion phase for the above-described O / W method.

[0165]

[0166] In the production method according to the present invention, the step (b) comprises dissolving a surfactant in water in a continuous phase (CP) storage tank. cThis is a step of preparing a fresh continuous phase solution (CP0) as a fresh continuous phase, and pre-filling the fresh continuous phase solution (CP0) into an emulsion storage tank. The fresh continuous phase solution prepared in step (b) can be used as a fresh continuous phase (CP0) that is pre-filled before supplying the emulsion to the emulsion storage tank, a fresh continuous phase (CP1) that forms an emulsion together with the dispersed phase in step (c), a fresh continuous phase (CP2) that is supplied together with the emulsion injection through a separate pipe in step (d), and a fresh continuous phase (CP3) that is supplied in step (e). Here, the terms CP0 to CP3 are all the same as the fresh continuous phase solution prepared in step (b), and different subscript numbers are written to distinguish the process points used.

[0167]

[0168] The type of the above surfactant is not particularly limited, and any surfactant that can help the dispersed phase form a stable droplet emulsion within the continuous phase can be used. Specifically, the surfactant may be polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, etc., used alone or in combination of two or more. More specifically, the surfactant may be polyvinyl alcohol.

[0169]

[0170] The content of the surfactant in the continuous phase may be 0.01 w / v% to 20 w / v%, specifically 0.03 w / v% to 18 w / v%, 0.05 w / v% to 15 w / v%, 0.07 w / v% to 10 w / v%, or 0.1 w / v% to 5 w / v%, based on the total volume of the continuous phase including the surfactant, and may be a combination of the lower and upper limits of the above-described ranges. When the content of the surfactant is less than 0.01 w / v%, a dispersed phase emulsion in the form of droplets may not be formed in the continuous phase, and when the content of the surfactant exceeds 20 w / v%, after microspheres are formed in the continuous phase due to an excess of surfactant, it may be difficult to remove the surfactant.

[0171]

[0172] The above continuous phase may further include methyl alcohol, ethyl alcohol, propyl alcohol, ethyl acetate, etc., either singly or in combination of two or more, for the purpose of controlling the extraction rate of the organic solvent from the dispersed phase in the emulsion state. In addition, the above continuous phase may further include sodium chloride, etc., for the purpose of controlling the osmotic pressure.

[0173]

[0174] The continuous phase (CP0) of the above step (b), the continuous phase (CP1) of the above step (c), the continuous phase (CP2) of the above step (d), or the continuous phase (CP3) of the above step (e) may further include an early release inhibitor for the purpose of inhibiting the early release of the drug.

[0175]

[0176] Specifically, the above early release inhibitor may be a phosphate salt, a hydroxide salt, a phosphide salt, a phosphite salt, a carbonate salt, a bicarbonate salt, a chromate salt, a dichromate salt, an oxide, an oxalate salt, a silicate salt, a sulfate salt, a sulfide salt, a sulfite salt, a tartrate salt, a tetraborate salt, a thiosulfate salt, an arsenate salt, an arsenite salt, a citrate salt, a ferricyanide salt, a nitride salt, etc. of an alkali metal, an alkaline earth metal, or an ammonium, which may be used alone or in combination of two or more. More specifically, the above early release inhibitor may be monosodium phosphate (NaH2PO4), disodium phosphate (Na2HPO4), monopotassium phosphate (KH2PO4), dipotassium phosphate (K2HPO4), diammonium phosphate ((NH4)2HPO4), sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), diammonium sulfate ((NH4)2SO4), etc., used alone or in combination of two or more.

[0177]

[0178] The lower limit of the concentration of the early release inhibitor in the above continuous phase may be 0.1 (w / v)% or more, 0.2 (w / v)% or more, 0.3 (w / v)% or more, 0.4 (w / v)% or more, 0.5 (w / v)% or more, 0.6 (w / v)% or more, 0.7 (w / v)% or more, 0.8 (w / v)% or more, 0.9 (w / v)% or more, 1.0 (w / v)% or more, 1.2 (w / v)% or more, 1.4 (w / v)% or more, 1.6 (w / v)% or more, 1.8 (w / v)% or more, or 2.0 (w / v)% or more, and the upper limit may be 10.0 (w / v)% or less, 9.0 (w / v)% or less, 8.0 (w / v)% or less, 7.0 (w / v)% or less, 6.0 (w / v)% or less, 5.0 (w / v)% or less, 4.5 (w / v)% or less, 4.0 (w / v)% or less, 3.5 (w / v)% or less, 3.4 (w / v)% or less, 3.3 (w / v)% or less, 3.2 (w / v)% or less, 3.1 (w / v)% or less, 3.0 (w / v)% or less, 2.9 (w / v)% or less, 2.8 (w / v)% or less, 2.7 (w / v)% or less, 2.6 (w / v)% or less, 2.5 (w / v)% or less, 2.4 (w / v)% or less, 2.3 (w / v)% or less, 2.2 (w / v)% or less, or 2.1 (w / v)% or less, and the initial release in the continuous phase The concentration of the inhibitor can be used as a combination of the lower and upper limits described above. For example, 0.1 to 10.0 (w / v)%, 0.1 to 9.0 (w / v)%, 0.1 to 8.0 (w / v)%, 0.1 to 7.0 (w / v)%, 0.1 to 6.0 (w / v)%, 0.1 to 5.0 (w / v)%, 0.2 to 10.0 (w / v)%, 0.2 to 9.0 (w / v)%, 0.2 to 8.0 (w / v)%, 0.2 to 7.0 (w / v)%, 0.2 to 6.0 (w / v)%, 0.2 to 5.0 (w / v)%, 0.3 to 10.0 (w / v)%, 0.3 to 9.0 (w / v)%, 0.3 to 8.0 (w / v)%, 0.3 to 7.0 (w / v)%, 0.3 to 6.It can be 0 (w / v)%, 0.3 to 5.0 (w / v)%, 0.4 to 10.0 (w / v)%, 0.4 to 9.0 (w / v)%, 0.4 to 8.0 (w / v)%, 0.4 to 7.0 (w / v)%, 0.4 to 6.0 (w / v)%, 0.4 to 5.0 (w / v)%, 0.5 to 10.0 (w / v)%, 0.5 to 9.0 (w / v)%, 0.5 to 8.0 (w / v)%, 0.5 to 7.0 (w / v)%, 0.5 to 6.0 (w / v)% or 0.5 to 5.0 (w / v)%.

[0179] The concentration range of the above early-release inhibitor can be used in a wide range, taking into account manufacturing conditions such as the type of drug, the release characteristics of the drug, the manufacturing process, and the type of polymer. From this perspective, if the upper limit of the concentration range of the above early-release inhibitor is exceeded, there may be a problem in which the emulsion droplets burst during the manufacturing process, resulting in failure in forming microspheres. If it is below the lower limit, there is no significant effect in inhibiting early-release.

[0180] Low-drug-loaded microspheres typically do not have a high initial release, but high-drug-loaded microspheres may have a high initial release problem, so drug-loaded microsphere manufacturers set a limit on the drug loading content.

[0181] When the above early release inhibitor is used in a continuous phase or mixed continuous phase during the manufacture of microspheres, the early release rate on the first day in high-drug loading microspheres can be reduced to 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less.

[0182] The above-mentioned Day 1 initial release rate refers to the cumulative release amount up to Day 1 among the total amount of drug loaded into the microspheres. If the Day 1 initial release rate is 10%, it means that in the case of a 1-month (approximately 30-day) formulation, approximately 3 days' worth of drug is released in one day, in the case of a 3-month (approximately 90-day) formulation, approximately 9 days' worth of drug is released in one day, and in the case of a 6-month (approximately 180-day) formulation, approximately 18 days' worth of drug is released in one day. In other words, a lower Day 1 initial release rate may be desirable for a longer-release formulation.

[0183]

[0184] The above early release inhibitor may be injected at the time of preparing the continuous phase of the above step (b), or the early release inhibitor may be injected at any time during the supply of the continuous phase of the above step (d), and the timing and method of injection are not limited.

[0185]

[0186] The temperature of the continuous phase is not particularly limited, but it may be heated to a level close to the boiling point of the organic solvent used in the preparation of the dispersed phase, or it may be used at room temperature without heating. If heated to a level close to the boiling point of the organic solvent, it may be advantageous for the selective evaporation of the organic solvent mixed into the continuous phase after the organic solvent in the dispersed phase is extracted from the emulsion suspended in the continuous phase. If the drug used is sensitive to high temperatures, it may be used by heating to a level that does not affect the activity of the drug. In addition, the continuous phase may be prepared at room temperature, and heating may be performed in the emulsion storage tank.

[0187]

[0188] In the production method according to the present invention, the step (c) supplies the dispersed phase and the fresh continuous phase (CP1) to an emulsion forming device to form an emulsion solution,

[0189] The above step (d) is characterized in that a fresh continuous phase solution (CP2) is supplied while supplying the emulsion formed in the above step (c) to the emulsion storage tank, and a portion of the contaminated continuous phase mixed with the organic solvent due to contact with the emulsion is discharged to the outside of the emulsion storage tank.

[0190] As a specific example, the fresh continuous phase (CP1) used in step (c) is a part of the continuous phase prepared in step (b), and the i) O / W dispersion phase (biodegradable polymer alone or biodegradable polymer and drug dissolved in an organic solvent) prepared in step (a) d ) form), ii) Dispersed phase for W / O / W method (water phase (W d ) / paid (O d ) emulsion form), or iii) dispersed phase for S / O / W formulation (water phase (S) / oil phase (O d ) and are supplied to an emulsion forming device, respectively, to form an emulsion solution within the emulsion forming device, and then are moved to an emulsion storage tank through a pipe in a subsequent step.

[0191] In the above step (d), the emulsion formed in the above step (c) is supplied to an emulsion storage tank through a pipe, and at this time, a fresh continuous phase solution (CP2) may be supplied together through a separate pipe. The emulsion supply pipe and the continuous phase (CP2) supply pipe may be separately connected to the emulsion storage tank, or the continuous phase (CP2) supply pipe may be connected to the emulsion supply pipe and connected to the emulsion storage tank as a single integrated pipe.

[0192] At this time, the fresh continuous phase (CP2) supplied together through a separate pipe is a part of the continuous phase prepared in step (b), and is supplied together from the time the emulsion solution is injected into the emulsion storage tank in step (d).

[0193]

[0194] In a specific embodiment, by supplying fresh continuous phase (CP2) together during the emulsion injection process of step (d), the maximum usable capacity of the dispersed phase per batch can be increased. If the maximum capacity of the dispersed phase is exceeded, a 'process failure' criterion may occur.

[0195]

[0196] At this time, the above 'process failure' criterion is when drug crystals or powder are generated together with microspheres in the optical microscope image of microspheres manufactured when using the 0 / W method dispersion phase or the S / O / W method dispersion phase.

[0197] When using the dispersion phase for W / O / W method, the encapsulation rate may be less than 70%.

[0198] Microspheres manufactured using a dispersed phase for 0 / W formulation or a dispersed phase for S / O / W formulation may have an excessively high concentration of organic solvent in the emulsion if the process fails, i.e., if the maximum capacity of the dispersed phase is exceeded, the drug may dissolve before the formation of microspheres, resulting in the formation of drug crystals or powder together with the manufactured microspheres. In addition, microspheres manufactured using a dispersed phase for W / O / W formulation may have an excessively high concentration of organic solvent in the emulsion, resulting in the formation of drug crystals or powder together with the manufactured microspheres if the process fails, since the drug is water-soluble, crystallization does not occur and the drug escapes outside the microspheres, resulting in a low encapsulation rate.

[0199] In this way, while the emulsion formed in step (c) is supplied (injected) into the emulsion storage tank through the emulsion supply pipe, the fresh continuous phase (CP2) additionally supplied through the separate pipe is supplied at the time of injection of the emulsion solution, thereby diluting and greatly reducing the organic solvent concentration in the emulsion.

[0200] In a specific embodiment, the organic solvent concentration reduction rate when using the fresh continuous phase (CP2) compared to when not using the fresh continuous phase (CP2) may be, but is not limited to, 40% or more based on the end point of emulsion supply (injection).

[0201] The production method according to the present invention can achieve a 40% reduction in the organic solvent concentration in the entire solution in the emulsion storage tank at the end of the emulsion injection process by controlling the injection speeds of the continuous phase (CP1) and the continuous phase (CP2). Here, the 'organic solvent concentration reduction rate' refers to a reduction rate compared to a conventional process that does not use a fresh continuous phase (CP2) during the emulsion injection process of step (d).

[0202]

[0203] As a concrete example,

[0204] In order to achieve a reduction rate of organic solvent concentration of 40% or more at the end point of the above emulsion injection process, the continuous phase (CP1) injection rate and the continuous phase (CP2) injection rate can be controlled using the following mathematical expression 1.

[0205] [Mathematical Formula 1]

[0206] (V CP2 / V CP1 ) × k ≥ organic solvent concentration reduction rate 40%

[0207] (In the above mathematical formula 1,

[0208] V CP1 is the injection rate (mL / min) of the continuous phase (CP1),

[0209] V CP2 is the injection rate (mL / min) of the continuous phase (CP2),

[0210] k is a proportionality constant, k=η / R,

[0211] η is the standard organic solvent concentration reduction rate, η(%)={(C con -C add ) / C con}×100, where C con is the reference concentration of organic solvent at the end of emulsion injection when continuous phase (CP2) is not used, and C add is the reference concentration of the organic solvent at the end of emulsion injection when using the continuous phase (CP2).

[0212] R is the reference injection rate ratio when using continuous phase (CP2), R=V CP2기준 / V CP1기준 and here V CP1기준 is the standard continuous phase (CP1) injection rate (mL / min), and V CP2기준 is the standard continuous phase (CP2) injection rate (mL / min).

[0213]

[0214] For example, the manufacturing conditions of Example 1 and Comparative Example 1-1 of the present invention (Tables 1 and 2) and the results of measuring the organic solvent concentration at the end of the emulsion injection process (Table 8) are substituted into the above mathematical expression 1 as follows.

[0215] k= η / R = [{(21688-8721) / 21688}

[0216] (V CP2 / V CP1 ) × k ≥ (organic solvent concentration reduction rate 40%)

[0217] (V CP2 / V CP1 ) ≥ (organic solvent concentration reduction rate 40%) / k

[0218] (V CP2 / V CP1 ) ≥ 40% / 71.78% = 0.557 = 668 / 1200

[0219] That is, in order to satisfy the organic solvent concentration reduction rate of 40% or more in the O / W manufacturing method using dichloromethane (DCM) as an organic solvent, (V CP2 / V CP1 ) ≥ 668 / 1200 to satisfy the condition V CP1 Wow V CP2 must be adjusted.

[0220] The injection rate ratio of Example 1 (V CP2 / V CP1 ) = 1000 / 1200, which satisfies the condition of the above mathematical expression 1.

[0221]

[0222] For example, the manufacturing conditions of Example 2 and Comparative Example 2-1 of the present invention (Tables 3 and 4) and the results of measuring the organic solvent concentration at the end of the emulsion injection process (Table 8) are substituted into the above mathematical expression 1 as follows.

[0223] k= η / R = [{(28430-13694) / 28430}

[0224] (V CP2 / V CP1 ) × k ≥ (organic solvent concentration reduction rate 40%)

[0225] (V CP2 / V CP1 ) ≥ (organic solvent concentration reduction rate 40%) / k

[0226] (V CP2 / V CP1 ) ≥ 40% / 97.24% = 0.411 = 493 / 1200

[0227] That is, in order to satisfy the organic solvent concentration reduction rate of 40% or more in the O / W manufacturing method using ethyl acetate (EA) as an organic solvent, (V CP2 / V CP1 ) ≥ 493 / 1200 to satisfy the condition V CP1 Wow V CP2 must be adjusted.

[0228] Example 2: Injection rate ratio (V CP2 / V CP1 ) = 640 / 1200, which satisfies the condition of the above mathematical expression 1.

[0229]

[0230] For example, the manufacturing conditions of Example 3 and Comparative Example 3-1 of the present invention (Tables 5 and 6) and the results of measuring the organic solvent concentration at the end of the emulsion injection process (Table 8) are substituted into the above mathematical expression 1 as follows.

[0231] k= η / R = [{(8195-4734) / 8195}

[0232] (V CP2 / V CP1 ) × k ≥ (organic solvent concentration reduction rate 40%)

[0233] (V CP2 / V CP1 ) ≥ (organic solvent concentration reduction rate 40%) / k

[0234] (V CP2 / V CP1 ) ≥ 40% / 50.678% = 0.789 = 2367 / 3000

[0235] That is, in order to satisfy the organic solvent concentration reduction rate of 40% or more in the W / O / W manufacturing method using dichloromethane (DCM) as an organic solvent, (V CP2 / V CP1 ) ≥ 2367 / 3000 to satisfy the condition V CP1 Wow V CP2 must be adjusted.

[0236] Example 3: Injection rate ratio (V CP2 / V CP1 ) = 2500 / 3000, which satisfies the condition of the above mathematical expression 1.

[0237]

[0238] If the pipe length of the above step (d) is set sufficiently long, some or all of the "hard microspheres" may be formed while the emulsion solution is being transferred to the emulsion storage tank, and especially if the pipe is additionally provided with a "permeable membrane" selective for the organic solvent used in the preparation of the dispersed phase, the "hard microspheres" may be further formed. The "permeable membrane" is described below.

[0239] In addition, when the pipe length of the above step (d) is set short, the emulsion solution may remain in an “emulsion” state or some or all of the “soft microparticles” may be formed while being transferred to the emulsion storage tank.

[0240]

[0241] The volume ratio of the dispersed phase and the continuous phase (Wc) in the above emulsion solution may be 1:1 to 1:100 at the time of forming the emulsion in the emulsion forming device, and may be 1:50 to 1:1000 at the time of extracting the organic solvent from the dispersed phase of the emulsion solution to the continuous phase. The emulsion forming device may use a membrane emulsification device using a porous filter, an inline mixer, a static mixer, a microfluidic device, or the like.

[0242]

[0243] The emulsion storage tank may be provided with a filter net that does not allow the emulsion and microparticles to pass through, and the emulsion storage tank may also be provided with a continuous phase discharge port through which the organic solvent is mixed and discharged through the filter net.

[0244]

[0245] The above pipe and / or filter net may additionally be equipped with an organic solvent selective permeable membrane used in the dispersion phase production. For example, a hydrophobic polymer permeable membrane, an organic-inorganic composite permeable membrane, etc. may be used, and a permeable membrane (porous or non-porous), hollow fiber membrane, etc. used in a known membrane evaporation separation may also be used. For reference, the membrane evaporation separation method is a method of separating components of a liquid mixture by using partial vaporization through a porous or non-porous membrane. It consists of a membrane separation, evaporation, and condensation process, in which a specific component is passed through the membrane and then condensed in a gaseous state to be recovered. For example, a hydrophilic membrane is used to remove a trace amount of moisture from alcohol, and a hydrophobic membrane is used to remove organic substances from a solution.

[0246]

[0247] Specifically, an organic solvent selective permeable membrane tube may be further provided longitudinally inside the pipe. For example, when a membrane emulsification method or a microfluidic system using a porous filter is used as the emulsion forming device (4), the organic solvent selective permeable membrane may be provided inside the pipe connecting from the starting point of the end of the emulsion forming device (4) where the dispersed phase and the continuous phase meet to form droplets to the emulsion storage tank. As another example, when an inline mixer or a static mixer is used as the emulsion forming device (4), the organic solvent selective permeable membrane may be provided inside the pipe connecting from the starting point where the dispersed phase and the continuous phase pass through the inline mixer or the static mixer to the emulsion storage tank.

[0248]

[0249] At this time, a space is formed between the inner surface of the permeable membrane tube and the pipe, and by applying negative pressure to the space, the permeation flux value of the organic solvent through the permeable membrane tube can be improved. In addition, the permeable membrane tube can be processed in a shape to increase the surface area (effective area), or can be used in multiples to improve the organic solvent separation efficiency.

[0250]

[0251] In addition, the filter net installed on a part of the inner surface of the emulsion storage tank containing the emulsion solution may further be equipped with an organic solvent selective permeable membrane. A space is formed on the outside of the filter net, and by applying negative pressure to the space, the permeation flux value of the organic solvent through the permeable membrane can be improved. In addition, the permeable membrane can be processed in a shape to increase the surface area (effective area), thereby improving the organic solvent separation efficiency. Here, when the filter net is equipped with a permeable membrane, a filter net equipped with a permeable membrane and a filter net not equipped with a permeable membrane for discharging a continuous phase mixed with the organic solvent can be installed separately. Meanwhile, when the organic solvent selective permeable membrane is used in the filter net while discharging the continuous phase mixed with the organic solvent as described above, the discharge port for discharging the continuous phase mixed with the organic solvent can be provided so as to be directly connected to the filter net not equipped with the organic solvent selective permeable membrane, and the organic solvent separated through the organic solvent selective permeable membrane can be discharged through a separate discharge port.

[0252]

[0253] When the above organic solvent selective permeable membrane is used, only the organic solvent used in the production of the dispersed phase can be selectively separated through the permeable membrane, so that the concentration of the organic solvent in the continuous phase mixed with the organic solvent can be further reduced.

[0254] The above permeation flux can be calculated using the following mathematical formula 2.

[0255] [Equation 2]

[0256] Permeation flux (kg / m 2 h)= Q / AT

[0257] In the above mathematical expression 2,

[0258] Q is the amount of organic solvent that permeates through the membrane over a certain period of time,

[0259]

[0260] A is the effective area of ​​the membrane,

[0261] T is the separation time.

[0262]

[0263] In the above step (c), the emulsion forming device may utilize a membrane emulsification method using a porous filter, an inline mixer, a static mixer, a microfluidic system, etc. The material of the porous filter is not limited, but from the perspective of reusability, it is preferable to use a stainless steel material rather than a polymer membrane.

[0264] As an example of a method for forming the above emulsion solution, when a membrane emulsification method using a porous filter is used, the porous filter is provided in a part of a pipe connected to a dispersion phase storage tank, and the dispersion phase passing through the porous filter is continuously injected in the form of droplets to form an emulsion.

[0265] As another example of a method for forming the above emulsion solution, when using a microfluidic system, the microfluidic system is connected to a dispersed phase storage tank and a continuous phase storage tank, and the dispersed phase can be injected while the continuous phase is flowing to form an emulsion.

[0266] As another example of a method for forming the above emulsion solution, when an inline mixer or a static mixer is used, a dispersed phase injection part is installed in a part of a pipe connected so that the continuous phase flows from a continuous phase storage tank to an emulsion storage tank, so that a mixture of the dispersed phase and the continuous phase flows, and the inline mixer or the static mixer is provided in a part of the pipe through which the mixture flows, so that the mixture passing through the inline mixer can form an emulsion solution.

[0267] In one aspect of the present invention, when an organic solvent selective permeable membrane is provided in the pipe as described above, a portion of the organic solvent can be removed in the process of the emulsion solution in the pipe reaching the emulsion storage tank in the step (d), which has the effect of lowering the concentration of residual organic solvent in the emulsion and improving productivity.

[0268]

[0269] In the production method according to the present invention, the step (e) is a step of extracting the dispersed organic solvent in the emulsion solution toward the continuous phase to produce microspheres, specifically, a step of extracting the dispersed organic solvent in the emulsion toward the continuous phase in an emulsion storage tank to produce microspheres, and at this time, includes a substitution process of removing a portion of the contaminated continuous phase containing the extracted organic solvent and supplying a fresh continuous phase (CP3).

[0270]

[0271] The above step (e) may further include a heating treatment for evaporating the organic solvent.

[0272]

[0273] The above step (e) is characterized in that, when the emulsion supply (injection) is completed, a fresh continuous phase (CP3) is continuously supplied, and the continuous phase mixed with the organic solvent is continuously discharged from the emulsion storage tank to perform a continuous phase replacement process, thereby performing microparticle generation. Through this, the residual organic solvent concentration in the continuous phase mixed with the organic solvent stored in the emulsion storage tank can be maintained below a certain level.

[0274] By continuously supplying the above continuous phase (CP3) and setting it to continuously discharge a continuous phase solution mixed with the same amount of organic solvent, the total volume of the solution flowing into the emulsion storage tank can be maintained constant.

[0275]

[0276] The total capacity of the dispersed phase used in the present invention can be calculated through the volume ratio of the total capacity of the continuous phase in the emulsion storage tank to the total capacity of the dispersed phase used in the present invention, so that the 'process failure' criterion per batch does not occur (see the last row of Table 2, Table 4, or Table 6), and since all of the main components constituting the microspheres are included in the dispersed phase, the production per batch can increase as the total capacity of the dispersed phase used increases.

[0277]

[0278] The production method according to the present invention uses a 'continuous process' that discharges a continuous phase mixed with an organic solvent in the step (e) and simultaneously supplies a fresh continuous phase (CP3), which is different from the conventional 'static process' and 'substitution process' configurations.

[0279] The conventional 'political process' can be implemented as a one-time process of extracting the organic solvent of the dispersed phase toward the initially supplied continuous phase, i.e., a 'political process' without a replacement process of the fresh continuous phase.

[0280] The conventional "substitution process" can also be implemented as a "substitution process" that discharges the continuous phase mixed with the organic solvent and supplies a fresh continuous phase. This substitution process is a discontinuous process and can be performed multiple times.

[0281] The above "continuous phase mixed with organic solvent" means that the organic solvent is mixed in the continuous phase as the dispersed organic solvent in the emulsion is extracted from the emulsion storage tank toward the continuous phase. Here, since the continuous phase mixed with organic solvent is selectively heated to evaporate the organic solvent, the continuous phase mixed with organic solvent may have only a small or trace concentration of organic solvent remaining, or the organic solvent may be completely evaporated.

[0282]

[0283] In one aspect of the present invention, when an organic solvent selective permeable membrane is provided in the filter net of the emulsion storage tank as described above, there is an effect of further reducing the residual concentration of the organic solvent in the continuous phase mixed with the organic solvent in the step (e) process.

[0284]

[0285] Furthermore, the continuous phase mixed with the organic solvent can be separated from the organic solvent, and the organic solvent and the continuous phase can be recycled separately. Adding a recycling process can be significant in that it allows for the production of microspheres through an environmentally friendly process. Any known technology can be used to separate the organic solvent. For example, organic solvent evaporation-condensation recovery, organic solvent reverse osmosis (OSRO), organic solvent nanofiltration (OSN), and solvent-resistant nanofiltration (SRNF) can be used.

[0286]

[0287] In the production method according to the present invention, after the step (e), the following steps (f-1) to (i-1) using known technology may be further included.

[0288] (f-1) A step of removing surfactant remaining on the surface of microparticles through washing;

[0289] (g-1) Step of recovering microspheres;

[0290] (h-1) a step of drying the obtained microspheres; and

[0291] (i-1) Step of filling dried microparticles into a container.

[0292]

[0293] Additionally, a sieving process may be additionally employed between steps (f-1) and (g-1) to obtain uniform microspheres. The sieving process may be performed using known techniques, and microspheres of uniform size may be obtained by filtering out small and large particles using sieves of different sizes.

[0294] The above step (f-1) can use various known techniques, for example, washing using water can be performed, and the washing can be repeated several times.

[0295] The above step (g-1) can utilize various known technologies, and for example, the microspheres can be recovered using methods such as filtration and centrifugation. For example, the microspheres can be recovered using a hydrocyclone method using centrifugation, a tangential flow filtration (TFF) method having a porous filter structure, or a method of connecting a hydrocyclone and a TFF in series.

[0296]

[0297] In another aspect of the present invention, a tangential flow filtration (TFF) device may be additionally included on at least one side of a pipe connecting the emulsion forming device and the emulsion storage tank; and on at least one side of a pipe provided to circulate the emulsion storage tank. Examples of additionally connecting such a tangential flow filtration device are schematically illustrated in FIGS. 2a, 2b, and 2c.

[0298] Tangential flow filtration (TFF) devices can be equipped with various types of membranes depending on the intended use. These membranes can be expected to reduce the organic solvent content in emulsion solutions. For example, if a general-purpose filtration membrane is equipped, a portion of the mixed continuous phase containing the organic solvent can be discharged. In another example, if the aforementioned organic solvent-selective permeable membrane is equipped, only a portion of the organic solvent can be selectively discharged.

[0299] For example, the tangential flow filtration (TFF) device (7) may be connected to one side of a pipe connecting the emulsion forming device (4) and the emulsion storage tank (see Figs. 2a-c). In this case, a portion of the organic solvent may be reduced while the emulsion solution is being transferred from the emulsion forming device to the emulsion storage tank.

[0300] As another example, the tangential flow filtration (TFF) device (8) is connected to one side of a pipe provided to circulate through an emulsion storage tank, so that the solution passing through the tangential flow filtration device (8) can be returned to the emulsion storage tank (see Figs. 2a-c). In this case, a portion of the organic solvent can be reduced while the continuous phase mixed with the organic solvent circulates through the tangential flow filtration device (8).

[0301]

[0302] The above step (h-1) can use various known technologies, and for example, the microspheres can be dried using methods such as freeze-drying, vacuum freeze-drying, low-temperature drying, room-temperature drying, hot-air drying, ventilation drying, pressurized-reduced-pressure drying, fluidized bed drying, vacuum drying, infrared drying, and suction drying.

[0303] The above step (i-1) can obtain a final product in the form of dried microparticles filled in a suitable container. For example, a final product in the form of dried microparticles filled in a container such as a syringe, cartridge, or vial can be obtained.

[0304]

[0305] In another aspect, the present invention,

[0306] Dispersed phase (DP) storage tank (1);

[0307] Continuous phase (CP) storage tank (2);

[0308] An emulsion storage tank (3) having a stirrer inside;

[0309] An emulsion forming device (4) that forms an emulsion by supplying a dispersed phase and a continuous phase from the dispersed phase storage tank (1) and the continuous phase storage tank (2), respectively;

[0310] A first continuous phase supply pipe (5a) that supplies the continuous phase by connecting the continuous phase storage tank (2) and the emulsion forming device (4);

[0311] An emulsion supply pipe (6) for transporting the emulsion formed in the emulsion forming device (4) to the emulsion storage tank (3); and

[0312] It includes a second continuous phase supply pipe (5b) that connects the continuous phase storage tank (2) and the emulsion storage tank (3) to directly supply the continuous phase;

[0313] It relates to a biodegradable microparticle manufacturing device.

[0314]

[0315] In a specific aspect,

[0316] The second continuous phase supply pipe (5b) may be connected in series to the emulsion supply pipe (6), connected in series to the emulsion storage tank (3), or connected in parallel to the emulsion supply pipe (6) and the emulsion storage tank (3).

[0317]

[0318] In addition, the manufacturing device according to the present invention

[0319] A tangential flow filtration (TFF) device may be additionally included on at least one side of the above emulsion supply pipe (6); and one side of the pipe provided to circulate the above emulsion storage tank.

[0320]

[0321] In addition, the emulsion forming device (4) may be, but is not limited to, a membrane emulsifying device using a porous filter, an in-line mixer, a static mixer, or a microfluidics device.

[0322]

[0323] In the manufacturing device according to the present invention, an emulsion is formed using a dispersed phase and a continuous phase supplied through a first continuous phase supply pipe (5a) in the emulsion forming device (4), and while the formed emulsion is supplied to an emulsion storage tank (3) through an emulsion supply pipe (6), the concentration of the organic solvent in the emulsion solution is diluted by a fresh continuous phase additionally supplied through the second continuous phase supply pipe (5b).

[0324] In the manufacturing device according to the present invention, it is also possible to omit the dispersion phase storage tank in the case of the W / O / W manufacturing method as described above.

[0325] Matters not mentioned separately for each component of the above manufacturing device can be applied as described in the above manufacturing method.

[0326]

[0327] Hereinafter, the present invention will be described in more detail with reference to the following manufacturing examples. However, the following manufacturing examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following manufacturing examples.

[0328] [Example]

[0329] Example 1: Preparation of drug microspheres using 0 / W emulsion

[0330] The equipment for manufacturing donepezil biodegradable polymer microspheres used in this example includes a dispersed phase storage tank, a continuous phase storage tank, an emulsion forming device, and an emulsion storage tank. In this example, donepezil biodegradable polymer microspheres were manufactured according to a 0 / W emulsion microsphere manufacturing method in which the continuous phase is continuously replaced from the start of injection of the emulsion into the emulsion storage tank.

[0331] In detail,

[0332] Step (a):

[0333] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 27.5 g of a biodegradable polymer, Resomer RG203H (manufactured by Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000) and 11.79 g of donepezil base (manufactured by Neuland Laboratories, India) with 125 g of dichloromethane (manufactured by JT Baker, USA). The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0334] Step (b):

[0335] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of fresh continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0336] Step (c):

[0337] The dispersed phase and continuous phase prepared above were injected into the membrane emulsification device as an emulsion forming device at a ratio of 1:40 in the total volume of the dispersed phase used: the volume ratio of the continuous phase maintained in the emulsion tank, at an injection rate of 50 mL / min, and at an injection rate of 1,200 mL / min for 150 seconds to form an emulsion.

[0338] Step (d):

[0339] While the above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), a fresh continuous phase (CP2) was also supplied to the emulsion storage tank through a separate pipe (second pipe, 5b) at an injection rate of 1,000 mL / min. During the injection, the continuous phase contaminated with dichloromethane, an organic solvent, was discharged at a flow rate of 2,200 mL / min, and the total discharge amount of the contaminated continuous phase during the emulsion injection was 5,500 mL.

[0340] Step (e):

[0341] Afterwards, the organic solvent was removed while maintaining the temperature of the emulsion storage tank at 25℃ for 3 hours while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank to be 5125.0 mL. At this time, the exchange rate of the fresh continuous phase (CP3) was 69.44 mL / min, and the ratio of the total capacity (volume) of the continuous phase maintained in the emulsion tank to the total capacity (volume) of the dispersed phase used (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 2. Afterwards, the volatilization process was performed at 44℃, and after cooling the temperature to 25℃, the residual polyvinyl alcohol was removed using triple-distilled water, filtered, and freeze-dried.

[0342]

[0343] Comparative Example 1-1: Preparation of drug microspheres using 0 / W emulsion

[0344] The same drug, polymer, and organic solvent as in the manufacturing method of Example 1 were used to manufacture the dispersed phase and continuous phase with the contents described in Table 1. However, unlike Example 1, the continuous phase was not replaced when supplying the emulsion to the emulsion storage tank.

[0345] Specifically,

[0346] Step (a):

[0347] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 27.5 g of a biocompatible polymer, Resomer RG203H (manufactured by Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000) and 11.79 g of donepezil base (manufactured by Neuland Laboratories, India) with 125 g of dichloromethane (manufactured by JT Baker, USA). The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0348] Step (b):

[0349] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0350] Step (c):

[0351] The dispersed phase and continuous phase prepared above were injected into a membrane emulsifying device as an emulsion forming device at a ratio of 1:40 (total capacity of the dispersed phase used: total capacity of the continuous phase maintained in the emulsion storage tank), at an injection rate of 50 mL / min, and at an injection rate of 1,200 mL / min, for 150 seconds to form an emulsion.

[0352] Step (d):

[0353] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 1 was not used.

[0354] Step (e):

[0355] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank to be 5125.0 mL, and the temperature of the emulsion storage tank was maintained at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 69.44 mL / min, and the ratio of the total capacity (volume) of the dispersed phase used to the total capacity (volume) of the continuous phase maintained in the emulsion storage tank (total capacity of the dispersed phase: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 2. Afterwards, the volatilization process was performed at 44℃, and after cooling the temperature to 25℃, the residual polyvinyl alcohol was removed using triple-distilled water, filtered, and freeze-dried.

[0356]

[0357] Comparative Example 1-2: Preparation of drug microspheres using 0 / W emulsion

[0358] The same drug, polymer, and organic solvent as in the manufacturing method of Example 1 were used to manufacture the dispersed phase and continuous phase with the contents described in Table 1. However, unlike Example 1, the continuous phase was not exchanged when supplying the emulsion to the emulsion storage tank.

[0359] Specifically,

[0360] Step (a):

[0361] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 18.33 g of a biocompatible polymer, Resomer RG203H (manufacturer: Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000), 7.86 g of donepezil base (manufacturer: Neuland Laboratories, India), and 83.33 g of dichloromethane (manufacturer: JT Baker, USA). The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0362] Step (b):

[0363] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of fresh continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0364] Step (c):

[0365] The dispersed phase and continuous phase prepared above were injected into a membrane emulsifying device as an emulsion forming device at a ratio of 1:60 (total volume of dispersed phase used): total volume of continuous phase maintained in an emulsion storage tank, at an injection rate of 50 mL / min, and at an injection rate of 1,200 mL / min for 100 seconds to form an emulsion.

[0366] Step (d):

[0367] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 1 was not used.

[0368] Step (e):

[0369] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the batch in the emulsion storage tank to 5083.3 mL and maintaining the temperature of the emulsion storage tank at 25°C for 3 hours.

[0370] At this time, the exchange rate of the fresh continuous phase (CP3) was 69.44 mL / min, and the ratio of the total capacity (volume) of the dispersed phase used to the total capacity (volume) of the continuous phase maintained in the emulsion storage tank (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 2. Afterwards, the volatilization process was performed at 44°C, and after cooling to 25°C, the temperature was filtered to remove the residual polyvinyl alcohol with triple-distilled water, and freeze-dried.

[0371]

[0372] Comparative Example 1-3: Preparation of drug microspheres using 0 / W emulsion

[0373] The same drug, polymer, and organic solvent as in the manufacturing method of Example 1 were used to manufacture the dispersed phase and continuous phase with the contents described in Table 1. However, unlike Example 1, the continuous phase was not exchanged when supplying the emulsion to the emulsion storage tank.

[0374] Specifically,

[0375] Step (a):

[0376] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 13.75 g of a biocompatible polymer, Resomer RG203H (manufactured by Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000), 5.89 g of donepezil base (manufactured by Neuland Laboratories, India), and 62.50 g of dichloromethane (manufactured by JT Baker, USA). The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0377] Step (b):

[0378] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0379] Step (c):

[0380] The dispersed phase and continuous phase prepared above were injected into a membrane emulsifying device as an emulsion forming device at a ratio of 1:80 (total volume of dispersed phase used): total volume of continuous phase maintained in an emulsion storage tank, at an injection rate of 50 mL / min, and at an injection rate of 1,200 mL / min for 75 seconds to form an emulsion.

[0381] Step (d):

[0382] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 1 was not used.

[0383] Step (e):

[0384] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank to be 5062.5 mL, and the temperature of the storage batch was maintained at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 69.44 mL / min, and the ratio of the total capacity (volume) of the dispersed phase used to the total capacity (volume) of the continuous phase maintained in the emulsion storage tank (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 2. Afterwards, the volatilization process was performed at 44℃, and after cooling the temperature to 25℃, the residual polyvinyl alcohol was removed using triple-distilled water, filtered, and freeze-dried.

[0385] The amounts and concentrations of drugs and polymers used in Example 1 and Comparative Examples 1-1, 1-2, and 1-3, as well as the amounts of each solvent, are summarized in Tables 1 and 2 below. Example 1 and Comparative Examples 1-1, 1-2, and 1-3 were all O / W emulsion types, the drug was donepezil, the drug theoretical loading amount (TL) was 30%, and the organic solvent used in the dispersed phase was dichloromethane (DCM). The continuous phase used was a 0.5% (w / v) aqueous solution of PVA.

[0386]

[0387] Classification Example 1 Comparative Example 1-1 Comparative Example 1-2 Comparative Example 1-3 Minute solution (O) Drug amount (g) 11.79 11.79 7.86 5.89 Polymer amount (g) 27.5 27.5 18.33 13.75 Organic solvent amount (g) 125 125 83.33 62.5 DP amount (mL) 125 125 83.33 62.5 Continuous phase solution (W c )CP1(mL)3,0003,0002,0001,500CP2(mL)2,500000CP3(mL)12,50012,50012,50012,500

[0388] Classification Example 1 Comparative Example 1-1 Comparative Example 1-2 Comparative Example 1-3 Emulsion injection stage DP injection speed (mL / min) 50 50 50 50 CP1 injection speed (mL / min) 1,200 1,200 1,200 CP2 injection speed (mL / min) 1,000 --- Injection time (sec) 150 150 100 75 Emulsion injection stage Contaminated CP discharge speed (mL / min) 2,200 --- Contaminated CP discharge amount (mL) 5,500 --- Stage after completion of emulsion injection CP maintenance volume (mL) 51 255 1255 0 83.3 50 62.5 DP total used volume: CP maintenance total volume ratio 1:40 1:40 1:60 1:80

[0389]

[0390] Example 2: Preparation of microspheres using 0 / W emulsion

[0391] Donepezil biodegradable polymer microspheres were manufactured according to a method for manufacturing 0 / W emulsion microspheres that continuously replace the continuous phase from the start of emulsion injection.

[0392] In detail,

[0393] Step (a):

[0394] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 25.00 g of Resomer RG203H (manufactured by Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000), a biocompatible polymer, and 10.70 g of donepezil base (manufactured by Neuland Laboratories, India) with 250 g of ethyl acetate. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0395] Step (b):

[0396] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0397] Step (c):

[0398] The dispersed phase and continuous phase prepared above were injected into the membrane emulsification device as an emulsion forming device at a ratio of 1:20 (total volume of dispersed phase used: total volume of continuous phase maintained in the emulsion storage tank), at an injection rate of 80 mL / min, and at an injection rate of 1,200 mL / min, for 187.50 seconds to form an emulsion.

[0399] Step (d):

[0400] While the above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), a fresh continuous phase (CP2) was also supplied to the emulsion storage tank at a rate of 640 mL / min through a separate pipe (second pipe, 5b). During the injection, the continuous phase contaminated with ethyl acetate, an organic solvent, was discharged at a rate of 1,840 mL / min, and the total discharge amount of the contaminated continuous phase during the emulsion injection was 5,750 mL.

[0401] Step (e):

[0402] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank at 5250.0 mL and the temperature of the emulsion storage tank at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 83.33 mL / min and the ratio of the total capacity (volume) of the dispersed phase used to the total capacity (volume) of the continuous phase maintained in the emulsion storage tank (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 4. Afterwards, the volatilization process was performed at 44℃, and after cooling the temperature to 25℃, the residual polyvinyl alcohol was removed using triple-distilled water through filtration, and freeze-dried.

[0403]

[0404] Comparative Example 2-1: Production of donepezil biodegradable polymer microspheres using a 0 / W emulsion microsphere production method that does not replace the continuous phase during emulsion injection.

[0405] Unlike the manufacturing method of Example 2, microspheres were manufactured by exchanging the continuous phase in the emulsion storage tank after injection. In other words, unlike Example 2, the continuous phase was not exchanged when supplying the emulsion to the emulsion storage tank.

[0406] Specifically,

[0407] Step (a):

[0408] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 25.00 g of Resomer RG203H (manufactured by Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000), a biocompatible polymer, and 10.70 g of donepezil base (manufactured by Neuland Laboratories, India) with 250 g of ethyl acetate. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0409] Step (b):

[0410] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0411] Step (c):

[0412] The dispersed phase and continuous phase prepared above were injected into the membrane emulsification device as an emulsion forming device at a ratio of 1:20 (total volume of the dispersed phase used): total volume of the continuous phase maintained in the emulsion storage tank, at an injection rate of 80 mL / min, and at an injection rate of 1,200 mL / min, to form an emulsion.

[0413] Step (d):

[0414] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 2 was not used.

[0415] Step (e):

[0416] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank at 5250.0 mL and the temperature of the storage batch at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 83.33 mL / min and the ratio of the total capacity (volume) of the dispersed phase used to the total capacity (volume) of the continuous phase maintained in the emulsion storage tank (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 4. Afterwards, the volatilization process was performed at 44℃, and after cooling the temperature to 25℃, the residual polyvinyl alcohol was removed by filtration with triple-distilled water, and freeze-dried.

[0417]

[0418] Comparative Example 2-2: Preparation of donepezil biodegradable polymer microspheres using a 0 / W emulsion microsphere preparation method that does not replace the continuous phase during emulsion injection.

[0419] Unlike the manufacturing method of Example 2, microspheres were manufactured by exchanging the continuous phase in the emulsion storage tank after injection. In other words, unlike Example 2, the supply of emulsion to the emulsion storage tank was performed without exchanging the continuous phase.

[0420] Specifically,

[0421] Step (a):

[0422] In a dispersed phase storage tank, the dispersed phase (DP) was prepared by mixing 12.50 g of Resomer RG203H (manufactured by Evonik, Germany; poly(D,L-lactide) Mw: 18,000–24,000), a biocompatible polymer, and 5.35 g of donepezil base (manufactured by Neuland Laboratories, India) with 125.00 g of ethyl acetate. The dispersed phase was used after stirring for more than 30 minutes to ensure sufficient dissolution.

[0423] Step (b):

[0424] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0425] Step (c):

[0426] The dispersed phase and continuous phase prepared above were injected into the membrane emulsification device as an emulsion forming device at a ratio of 1:40 (total volume of dispersed phase used): total volume of continuous phase maintained in the emulsion storage tank, at an injection rate of 80 mL / min, and at an injection rate of 1,200 mL / min for 93.75 seconds to form an emulsion.

[0427] Step (d):

[0428] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 2 was not used.

[0429] Step (e):

[0430] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank at 5125.0 mL and maintaining the temperature of the storage batch at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 83.33 mL / min and the ratio of the total capacity (volume) of the dispersed phase used to the total capacity (volume) of the continuous phase maintained in the emulsion storage tank (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 4. Afterwards, the volatilization process was performed at 44℃, and after cooling the temperature to 25℃, the residual polyvinyl alcohol was removed using triple-distilled water, filtered, and freeze-dried.

[0431]

[0432] The amounts and concentrations of drugs and polymers used in Example 2 and Comparative Examples 2-1 and 2-2, and the amounts of each solvent used, are summarized in Tables 3 and 4 below. Example 2 and Comparative Examples 2-1 and 2-2 were all O / W emulsion types, the drug was donepezil, the drug theoretical loading amount (TL) was 30%, and the organic solvent used in the dispersed phase was ethyl acetate (EA). The continuous phase used was a 0.5% (w / v) aqueous solution of PVA.

[0433] Classification Example 2 Comparative Example 2-1 Comparative Example 2-2 Dispersed phase solution (O) Drug amount (g) 10.7 10.7 5.35 Polymer amount (g) 25 25 12.5 Organic solvent amount (g) 250 250 125 DP amount (mL) 250 250 125 Continuous phase solution (W c )CP1(mL)3,7503,7501,875CP2(mL)2,00000CP3(mL)5,0005,0005,000

[0434] Classification Example 2 Comparative Example 2-1 Comparative Example 2-2 Emulsion injection conditions DP injection speed (mL / min) 808080 CP1 injection speed (mL / min) 1,2001,2001,200 CP2 injection speed (mL / min) 640--Injection time (sec) 187.5187.593.75 Contaminated CP discharge speed during emulsion injection (mL / min) 1,840--Contaminated CP discharge volume during emulsion injection (mL) 5,750--Stage CP maintenance volume after completion of emulsion injection (mL) 5,2505,2505,125 DP total used volume: CP maintenance total volume ratio 1:201:201:40

[0435]

[0436] Example 3: Production of leuprolide biodegradable polymer microspheres using a W / 0 / W emulsion microsphere production method in which the continuous phase is continuously replaced from the start of emulsion injection.

[0437] Step (a):

[0438] The first phase (W1 phase) was prepared by dissolving 3 g of leuprolide acetate (manufacturer: Zhejiang Peptides Biotech Co., Ltd) as a drug in 10 g of triple-distilled water (DW). The oil phase (O phase) was prepared by dissolving 27 g of Resomer RG752H (manufacturer: Evonik, Germany; poly(D,L-lactide) Mw: 4,000–15,000), a biodegradable polymer, in 50 g of dichloromethane (DCM), an organic solvent. A primary W / O emulsion (dispersed phase, DP) was prepared by dispersing the water phase in the oil phase using a homogenizer (manufacturer: IKA Works Inc., Germany, model name: T18 digtal ULTRA TURRAX) at 20,000 rpm for 5 minutes, and this was placed in a dispersed phase storage tank.

[0439] Step (b):

[0440] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of fresh continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0441] Step (c):

[0442] The dispersed phase and continuous phase prepared above were injected into a membrane emulsifying device as an emulsion forming device at a ratio of 1:50 (total volume of dispersed phase used: total volume of continuous phase maintained in an emulsion storage tank), at an injection rate of 120 mL / min, and at an injection rate of 3,000 mL / min for 30 seconds to form a W / O / W emulsion.

[0443] Step (d):

[0444] While the above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), a fresh continuous phase (CP2) was also supplied to the emulsion storage tank at a rate of 2,500 mL / min through a separate pipe (second pipe, 5b). During the injection, the continuous phase contaminated with dichloromethane, an organic solvent, was discharged at a rate of 5,500 mL / min, and the total discharge amount of the contaminated continuous phase during the emulsion injection was 2,750 mL.

[0445] Step (e):

[0446] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 41.67 mL / min, and the ratio of the total capacity (volume) of the continuous phase maintained in the emulsion storage tank to the total capacity (volume) of the dispersed phase used (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 6. Afterwards, the volatilization process was performed at 36℃, and after cooling to 25℃, the temperature was filtered to remove the residual polyvinyl alcohol with triple-distilled water, and freeze-dried.

[0447]

[0448] Comparative Example 3-1: Manufacturing of leuprolide biodegradable polymer microspheres using a W / 0 / W emulsion microsphere manufacturing method that does not replace the continuous phase during emulsion injection.

[0449] Unlike the manufacturing method of Example 3, microspheres were manufactured by exchanging the continuous phase in the emulsion storage tank after injection. In other words, unlike Example 3, the continuous phase was not exchanged when supplying the emulsion to the emulsion storage tank.

[0450] Specifically,

[0451] Step (a):

[0452] The first phase (W1 phase) was prepared by dissolving 3 g of leuprolide freebase (manufacturer: Zhejiang Peptides Biotech Co., Ltd) as a drug in 10 g of triple-distilled water (DW). The oil phase (O phase) was prepared by dissolving 27 g of Resomer RG752H (manufacturer: Evonik, Germany; poly(D,L-lactide) Mw: 4,000–15,000), a biodegradable polymer, in 50 g of dichloromethane (DCM), an organic solvent. A primary W / O emulsion (dispersed phase, DP) was prepared by dispersing the water phase in the oil phase using a homogenizer (manufacturer: IKA Works Inc., Germany, model name: T18 digtal ULTRA TURRAX) at 20,000 rpm for 5 minutes, and this was placed in a dispersed phase storage tank.

[0453] Step (b):

[0454] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of fresh continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0455] Step (c):

[0456] The dispersed phase and continuous phase prepared above were injected into a membrane emulsifying device as an emulsion forming device at a ratio of 1:50 (total volume of dispersed phase used: total volume of continuous phase maintained in an emulsion storage tank), at an injection rate of 120 mL / min, and at an injection rate of 3,000 mL / min for 30 seconds to form a W / O / W emulsion.

[0457] Step (d):

[0458] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 3 was not used.

[0459] Step (e):

[0460] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 41.67 mL / min, and the ratio of the total capacity (volume) of the continuous phase maintained in the emulsion storage tank to the total capacity (volume) of the dispersed phase used (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 6. Afterwards, the volatilization process was performed at 36℃, and after cooling to 25℃, the temperature was filtered to remove the residual polyvinyl alcohol with triple-distilled water, and freeze-dried.

[0461]

[0462] Comparative Example 3-2: Production of leuprolide biodegradable polymer microspheres using a W / 0 / W emulsion microsphere production method that does not replace the continuous phase during emulsion injection.

[0463] Unlike the manufacturing method of Example 3, microspheres were manufactured by exchanging the continuous phase in the emulsion storage tank after injection. In other words, unlike Example 3, the continuous phase was not exchanged when supplying the emulsion to the emulsion storage tank.

[0464] Specifically,

[0465] Step (a):

[0466] The first phase (W1 phase) was prepared by dissolving 1.5 g of leuprolide freebase (manufacturer: Zhejiang Peptides Biotech Co., Ltd) as a drug in 5 g of distilled water (DW). The oil phase (O phase) was prepared by dissolving 13.5 g of Resomer RG752H (manufacturer: Evonik, Germany; poly(D,L-lactide) Mw: 4,000–15,000), a biodegradable polymer, in 25 g of dichloromethane (DCM), an organic solvent. A primary W / O emulsion (dispersed phase, DP) was prepared by dispersing the water phase in the oil phase using a homogenizer (manufacturer: IKA Works Inc., Germany, model name: T18 digtal ULTRA TURRAX) at 20,000 rpm for 5 minutes, and this was placed in a dispersed phase storage tank.

[0467] Step (b):

[0468] In the continuous phase storage tank, the continuous phase (CP) was prepared by dissolving a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution. First, an appropriate amount of continuous phase (CP0) was pre-filled in the emulsion storage tank.

[0469] Step (c):

[0470] The dispersed phase and continuous phase prepared above were injected into a membrane emulsifying device as an emulsion forming device at a ratio of 1:100 (total volume of dispersed phase used: total volume of continuous phase maintained in an emulsion storage tank), at an injection rate of 120 mL / min, and at an injection rate of 3,000 mL / min for 15 seconds to form a W / O / W emulsion.

[0471] Step (d):

[0472] The above emulsion was supplied to the emulsion storage tank through the emulsion supply pipe (6), but the fresh continuous phase (CP2) used in Example 3 was not used.

[0473] Step (e):

[0474] Afterwards, the organic solvent was removed while stirring at a speed of 400 rpm while maintaining the total material capacity (volume) in the emulsion storage tank at 25℃ for 3 hours. At this time, the exchange rate of the fresh continuous phase (CP3) was 41.67 mL / min, and the ratio of the total capacity (volume) of the continuous phase maintained in the emulsion storage tank to the total capacity (volume) of the dispersed phase used (total capacity of the dispersed phase used: total capacity of the continuous phase maintained) was performed according to the conditions described in Table 6. Afterwards, the volatilization process was performed at 36℃, and after cooling to 25℃, the temperature was filtered to remove the residual polyvinyl alcohol with triple-distilled water, and freeze-dried.

[0475]

[0476] The amounts and concentrations of drugs and polymers used in Example 3 and Comparative Examples 3-1 and 3-2, and the amounts of each solvent used, are summarized in Tables 5 and 6 below. Example 3 and Comparative Examples 3-1 and 3-2 were both W / O / W emulsion types, the drug was leuprolide acetate, the drug theoretical loading amount (TL) was 10%, and the organic solvent used in the dispersed phase was dichloromethane (DCM). The continuous phase used was a 0.5% (w / v) aqueous solution of PVA.

[0477]

[0478] Classification Example 3 Comparative Example 3-1 Comparative Example 3-2 Minute Imaginary Solution W d Drug usage (g) 331.5 Distilled water usage (g) 10105O Polymer usage (g) 272713.5 Organic solvent usage (g) 505025 DP usage (mL) 606030 Continuous solution W c CP1(mL)1,5001,500750CP2(mL)1,25000CP3(mL)2,5002,5002,500

[0479] Classification Example 3 Comparative Example 3-1 Comparative Example 3-2 Emulsion injection conditions DP injection speed (mL / min) 120 120 120 CP1 injection speed (mL / min) 3,000 3,000 3,000 CP2 injection speed (mL / min) 2,500 -- Injection time (sec) 30 30 15 Contaminated CP discharge speed during emulsion injection (mL / min) 5,500 -- Contaminated CP discharge volume during emulsion injection (mL) 2,750 -- Stage after completion of emulsion injection CP maintenance volume (mL) 2,560 2,560 2,530 DP total used volume: CP maintenance total volume ratio 1:50 1:50 1:100

[0480]

[0481] Experimental Example 1: Measurement of drug encapsulation rate in microspheres

[0482] In order to measure the drug (donepezil and leuprolide acetate) content of the microspheres manufactured in the above examples and comparative examples, the microspheres were weighed so that 2 mg of the drug was used. This was dissolved in 1 mL of dimethyl sulfoxide (DMSO) and diluted to 200 μg / mL, which was used as a test solution. 20 μL of the test solution was injected into HPLC and measured at a detection wavelength of 280 nm. In this experimental example, a ZORBAX 300SB-C18, 5 μm, 4.6 × 150 mm column was used, and a 0.1% (w / w) trifluoroacetic acid aqueous solution was used as the mobile phase A, and acetonitrile (gradient: 40-60 (v / v)%) containing 0.1% (w / w) trifluoroacetic acid was used as the mobile phase B.

[0483] The drug encapsulation rate measurements are shown in Table 7 below.

[0484]

[0485] Experimental Example 2: Analysis of Residual Organic Solvent Concentration

[0486] The following test was conducted to confirm the storage stability of the microspheres by measuring the residual organic solvent concentration in the microspheres manufactured by the above examples and comparative examples.

[0487] 100 mg of microspheres prepared for the measurement of residual dichloromethane and ethyl acetate were placed in a volumetric flask, 10 mL of dimethylformamide was added, and the solution was diluted, transferred to a 5 mL vial, and placed in a gas chromatograph equipped with a headspace sampler to measure the residual solvent. The column used here was DB-624 (manufacturer: Agilent, USA) (30 mx 0.53 mm, 3 μm), the sample injection volume was 1 μL, and the flame ionization detector temperature was set to 250°C for measurement.

[0488] The results of the residual organic solvent analysis are shown in Table 7 below. As can be seen in Table 7, except for Comparative Example 2-2, the residual organic solvent concentration was low and thus did not affect storage stability.

[0489]

[0490] Experimental Example 3: Observation of microparticle morphology using an optical microscope (OM).

[0491] When manufacturing microspheres using the O / W emulsification method, drug crystals may form if the organic solvent concentration in the entire solution is excessive during the emulsion injection process or the continuous phase displacement process after the emulsion injection process. The reason drug crystals form is that if the organic solvent concentration is excessively high, the drug is not properly encapsulated in the microspheres and dissolves into the organic solvent in the continuous phase. After the organic solvent volatilization process, the drug crystallizes and forms when the organic solvent is removed. When drug crystals form around the manufactured microspheres, it is difficult to separate the microspheres and the drug crystals. Therefore, these drug crystals are included in the microsphere composition, which may cause a rapid increase in the initial blood concentration when administered to a body.

[0492] Meanwhile, when manufacturing microspheres using the W / O / W emulsification method, if the concentration of the organic solvent in the entire solution is excessive during the emulsion injection process or the continuous phase displacement process after the emulsion injection process, the drug will not be properly encapsulated in the microspheres and will dissolve into the continuous phase. Since the drug used in the W / O / W emulsification method is dissolved in an aqueous solution rather than an organic solvent, drug crystals do not form, but since it dissolves into the continuous phase, the drug encapsulation rate will be low.

[0493] In the examples and comparative examples, the shape of the manufactured microspheres and the formation of drug crystals around them were observed. Specifically, the microsphere suspension was dropped on a slide glass, the slide glass was placed on the stage of an optical microscope (manufacturer: Olympus BH-2, Japan), and at x100 magnification (objective lens x10, eyepiece lens x10), the formation of drug crystals on the surface of the emulsion immediately after injection and after volatilization was confirmed.

[0494] Encapsulation rate (%) Final particle residual solvent (ppm) Whether crystals occurred in the OM image CP (80) Maintenance Total capacity: DP Total capacity used **Example 194.56 1.8 None 2 Comparative Example 1-194.3 186 Yes 2 Comparative Example 1-285.2 150.4 Yes 1.33 Comparative Example 1-392.16 31 None 1 Example 284.1 186 None 4 Comparative Example 2-182 334 Yes 4 Comparative Example 2-292.8 25907 No 2 Example 385.03 443 None* 1.6 Comparative Example 3-161.37 347 No* 1.6 Comparative Example 3-285.7 380 No* 0.8

[0495] * In Example 3, Comparative Example 3-1 and Comparative Example 3-2, crystallization did not occur because the drug was water-soluble and dissolved in the continuous phase used in the manufacturing process.

[0496] ** CP(80) maintenance total capacity: DP usage total capacity volume ratio means the parts by volume of the total capacity of the dispersed phase (DP) used when the total capacity of the continuous phase (CP) in the emulsion storage tank is maintained at 80 parts by volume, for example. Taking Example 1 as an example, when the total capacity of CP is maintained at 80 mL, it means that 2 mL of the total capacity of DP is used, and when the total capacity of CP is maintained at 800 mL, it means that 20 mL of the total capacity of DP is used. In the above CP(80) maintenance total capacity: DP usage total capacity volume ratio, the larger the volume part of the total capacity of DP used, the larger the total amount of the dispersed phase (DP) injected into the emulsion storage tank. In the following description, it is also referred to simply as 'CP80:DP'.

[0497]

[0498] As shown in Table 7 and FIGS. 3a-c, 4a-c, and 5a-c, Examples 1 to 3 showed no drug crystals formed around the manufactured microspheres (FIGS. 3a, 4a, and 5a), whereas Comparative Examples 1-1, 1-2, and 2-1 (FIGS. 3b, 3c, and 4a) showed drug crystals formed around the microspheres. Since such drug crystals may be included in the microsphere composition, they may cause a rapid increase in the initial blood concentration upon in vivo administration.

[0499] As can be seen in Table 7,

[0500] Example 1 and Comparative Examples 1-1 to 1-3 all used DCM as an organic solvent in the O / W emulsification method.

[0501] In Example 1, drug crystals did not form around the microspheres manufactured using 2 parts by volume of DP in CP80:DP, whereas in Comparative Example 1-1, drug crystals formed around the microspheres manufactured using 2 parts by volume of DP in the same amount, which corresponded to a 'process failure'. In addition, in Comparative Example 1-2, drug crystals formed around the microspheres manufactured even when the amount used was reduced to 1.33 parts by volume of DP, which also corresponded to a 'process failure'. In Comparative Example 1-3, drug crystals did not form around the microspheres manufactured only when 1 part by volume, which is half the amount of DP used in Example 1, was used. In other words, compared to Comparative Example 1-3, drug crystals, which are the criterion for a 'process failure', were not formed in Example 1 even when at least twice the amount of DP was used, which confirmed that the production volume per batch could be increased by at least twice.

[0502] Example 2 and Comparative Examples 2-1 to 2-2 all used EA as an organic solvent in the O / W emulsification method.

[0503] In Example 2, drug crystals did not form around the microspheres manufactured using 4 parts by volume of DP in CP80:DP, whereas in Comparative Example 2-1, drug crystals formed around the microspheres manufactured using 4 parts by volume of the same amount of DP, which corresponded to a 'process failure'. In Comparative Example 2-2, drug crystals did not form around the microspheres manufactured only when 2 parts by volume, which was half the amount of DP used in Example 2, was used. In other words, compared to Comparative Example 2-2, Example 2 did not form drug crystals, which is the criterion for 'process failure', even when at least twice the amount of DP was used, confirming that the production volume per batch could be increased at least twice.

[0504] In Example 3 and Comparative Examples 3-1 to 3-2, DCM was used as an organic solvent in the W / O / W emulsification method.

[0505] Example 3 showed a good drug encapsulation rate of 85.03% even when using 1.6 parts by volume of DP in CP80:DP, whereas Comparative Example 3-1 showed a drug encapsulation rate of 61.37%, which corresponds to a 'process failure', when using the same amount of 1.6 parts by volume of DP. Comparative Example 3-2 showed a good recovery to a drug encapsulation rate of 85.7% only when using 0.8 parts by volume, which is half the amount of DP used in Example 3. In other words, Example 3 did not fall below the drug encapsulation rate of 80%, which is the 'process failure' criterion, even when using at least twice the amount of DP compared to Comparative Example 3-2, confirming that the production volume per batch could be increased by at least twice.

[0506] Here, the reason why there is no significant difference in the encapsulation rate of Comparative Examples 1-1 and 1-2 in which drug crystals are formed compared to Example 1 is because, when measuring the encapsulation rate, the drug crystals are measured together with the microspheres in the samples of Comparative Examples 1-1 and 1-2, and thus the actual content of the drug encapsulated in the microspheres decreases to an amount similar to the amount of drug crystals formed. This also applies to Example 2 and Comparative Example 2-1.

[0507]

[0508] In light of these results, the production method according to the present invention can increase batch production by at least two times compared to conventional techniques that do not utilize a continuous phase displacement process in the emulsion injection process. In other words, this is a significantly advantageous effect for the mass production of biodegradable microspheres, meaning that the production volume per microsphere production cycle (per batch), which takes approximately one week, can be increased by at least two times.

[0509]

[0510] Experimental Example 4: Analysis of the concentration of organic solvent in the total solution in the emulsion storage tank according to the emulsion injection process point.

[0511] In Example 1 and Comparative Example 1-1, Example 2 and Comparative Example 2-1, and Example 3 and Comparative Example 3-1, which differ only in the use of a fresh continuous phase (CP2) in the emulsion injection process (corresponding to step (d)), the concentrations of organic solvents in the total solution in the emulsion storage tank at the 1 / 3 completion point, the 2 / 3 completion point, and the end point of the emulsion injection process (corresponding to step (d)) were measured, and the results are shown in Table 8. In Table 8, the organic solvent concentration reduction rate at the end point of the emulsion injection process represents a value calculated as a percentage of how much the organic solvent concentration measurement value of the Example was reduced based on the organic solvent concentration measurement value of the Comparative Example in the above set of Examples and Comparative Examples.

[0512] Organic solvent concentration (ppm) in the total solution in the emulsion storage tank according to the emulsion injection process point Reduction rate of organic solvent concentration at the end point Emulsion injection process 1 / 3 completion point Emulsion injection process 2 / 3 completion point Emulsion injection process end point Comparative example Example Example 14,4038,2468,72159.8% Comparative example 1-114,20019,72221,688 Example 210,43012,64913,69451.8% Comparative example 2-126,51428,07128,430 Example 31,2403,7094,73442.2% Example 3-11,8505,7988,195

[0513] As shown in Table 8, the organic solvent concentrations in the total solution in the emulsion storage tank at the end of the emulsion injection process of Example 1 and Comparative Example 1-1 were 8,721 ppm and 21,688 ppm, respectively, indicating a 59.8% reduction in the organic solvent concentration of Example 1 compared to Comparative Example 1-1.

[0514] At the end of the emulsion injection process of Example 2 and Comparative Example 2-1, the organic solvent concentrations in the total solution in the emulsion storage tank were 13,694 ppm and 28,430 ppm, respectively, indicating a 51.8% reduction in the organic solvent concentration of Example 2 compared to Comparative Example 2-1.

[0515] At the end of the emulsion injection process of Example 3 and Comparative Example 3-1, the organic solvent concentrations in the total solution in the emulsion storage tank were 4,734 ppm and 8,195 ppm, respectively, indicating a 42.2% reduction in the organic solvent concentration of Example 3 compared to Comparative Example 3-1.

[0516] This result of reducing the organic solvent concentration is the result of continuously supplying a fresh continuous phase (CP2) from the start point to the end point of the emulsion injection process in the production method according to the present invention while simultaneously continuously discharging the contaminated continuous phase to maintain a constant total solution volume in the emulsion storage tank.

[0517] That is, in the production method (embodiment) according to the present invention, the concentration of the organic solvent in the entire solution in the emulsion storage tank from the start point to the end point of the emulsion injection process is maintained lower than in the conventional method (comparative example), so that even if the total amount of the supplied dispersed phase increases compared to the conventional method, 'process failure' does not occur, which leads to an increase in production per batch.

Claims

1. A method for producing biodegradable microspheres using an emulsion-solvent evaporation technique, (a) Prepare a dispersed phase (DP) containing a biodegradable polymer; (b) In a continuous phase (CP) storage tank, a water phase (W) containing a surfactant dissolved in water c Prepare a fresh continuous phase solution (CP0) and pre-fill the fresh continuous phase solution (CP0) into the emulsion storage tank; (c) supplying the above dispersed phase solution and the above fresh continuous phase solution (CP1) to an emulsion forming device to form an emulsion; (d) Supplying the emulsion of step (c) to the emulsion storage tank while supplying a fresh continuous phase solution (CP2), and discharging a portion of the contaminated continuous phase mixed with the organic solvent to the outside of the emulsion storage tank; (e) a step of performing microparticle generation while performing a continuous phase replacement process of supplying a fresh continuous phase (CP3) while removing a portion of the contaminated continuous phase mixed with the organic solvent when the supply of the emulsion of the above step (c) to the emulsion storage tank is completed; Method for producing biodegradable microspheres.

2. A method for producing biodegradable microspheres, wherein in the step (d) of paragraph 1, the contaminated continuous phase solution is continuously discharged from the emulsion storage tank in a volume equal to the total volume of the continuous phase solution (CP1) supplied to the emulsion forming device in the step (c) and the fresh continuous phase solution (CP2) supplied to the emulsion storage tank.

3. A method for producing biodegradable microspheres in the first paragraph, wherein step (e) continuously supplies a fresh continuous phase solution (CP3) while continuously discharging the same volume of contaminated continuous phase solution.

4. A method for producing biodegradable microspheres, wherein in step (d), a fresh continuous phase solution (CP2) is supplied to an emulsion storage tank through a separate pipe.

5. A method for producing biodegradable microspheres, wherein in the first paragraph, CP0 to CP3 are all the same as fresh continuous phase solutions prepared in step (b), and each of CP0 to CP3 distinguishes a process point at which it is used.

6. In paragraph 1, the dispersed phase is (O / W dispersion phase i) Biodegradable polymer alone, or biodegradable polymer and drug dissolved in an organic solvent (O d Prepare the phase as a dispersed phase, or (W / O / W dispersion phase for preparation ii) Water phase (W) in which the drug is dissolved in an aqueous solution d phase) and an oil phase (O) in which biodegradable polymers are dissolved in an organic solvent d W mixed with phase d / O d Prepare an emulsion in a dispersed form, or (S / O / W dispersion phase for the preparation method iii) Suspension phase (S) in which a biodegradable polymer and a powdered drug are mixed in an organic solvent that dissolves the biodegradable polymer d / O d A method for producing biodegradable microspheres, which comprises preparing a dispersed phase.

7. In paragraph 6, When using the above (dispersed phase ii for W / O / W method), Store and use in a dispersion storage tank; Omitting storage in the above-mentioned dispersion storage tank, the above-mentioned water (W d phase) and oil phase (O d phase) is supplied to a separate emulsion forming device. d / O d Forming an emulsion, the above W d / O d A method for producing biodegradable microspheres, wherein the emulsion is directly supplied to an emulsion forming device (4) that supplies a continuous phase (Wc phase).

8. In the first paragraph, the method for producing the biodegradable microspheres is as follows: A method for producing biodegradable microspheres, wherein the concentration of organic solvent in the entire solution in the emulsion storage tank at the end of the emulsion injection in step (d) is reduced by 40% or more, compared to a method for producing biodegradable microspheres, which includes a process for supplying an emulsion without performing a process for supplying a continuous phase solution (CP2) and a process for discharging a contaminated continuous phase in step (d).

9. In paragraph 8, In order to satisfy the condition of a reduction rate of organic solvent concentration of 40% or more in the total solution in the emulsion storage tank at the end point of the above emulsion injection, A production method for controlling the CP1 injection speed and CP2 injection speed using the following mathematical expression 1. [Mathematical Formula 1] (V CP2 / V CP1 ) × k ≥ organic solvent concentration reduction rate 40% (In the above mathematical formula 1, V CP1 is the continuous phase (CP1) injection rate (mL / min), V CP2 is the continuous phase (CP2) injection rate (mL / min), k is a proportionality constant, k=η / R, η is the standard organic solvent concentration reduction rate, η(%)={(C con -C add ) / C con }×100, where C con is the reference concentration of organic solvent at the end of emulsion injection when continuous phase (CP2) is not used, and C add is the standard concentration of organic solvent at the end of emulsion injection when using continuous phase (CP2). R is the standard injection rate ratio when using CP2, R=V CP2기준 / V CP1기준 and here V CP1기준 is the standard continuous phase (CP1) injection rate (mL / min), and V CP2기준 is the standard continuous phase (CP2) injection rate (mL / min).

10. In paragraph 1, The biodegradable polymer of the above step (a) is polylactide (PLA), polyglycolide (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), A polymer selected from the group consisting of polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate-co-lactic acid) (PBSLA); a simple mixture of two or more of the above-mentioned selected polymers; A copolymer of the above-mentioned selected polymer and polyethylene glycol (polyethylenglycol, PEG);And a production method, wherein the selected polymer or copolymer is at least one selected from the group consisting of a polymer-sugar complex in which a sugar is bonded.

11. In paragraph 1, A production method, wherein the drug of the above step (a) is at least one selected from the group consisting of small molecule therapeutic agents, synthetic compound therapeutic agents, peptide therapeutic agents, antibody therapeutic agents, protein therapeutic agents, nucleic acid therapeutic agents, gene therapeutic agents, cell therapeutic agents, antibody-drug conjugates (ADC) therapeutic agents, and radiopharmaceutical therapy (RPT).

12. In paragraph 1, A production method, wherein the organic solvent of the above step (a) is at least one selected from the group consisting of dichloromethane, ethyl acetate, dimethyl carbonate, chloroform, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, n-methylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol.

13. In paragraph 1, A production method, wherein the dispersed phase of the above step (a) further comprises at least one release controlling agent selected from the group consisting of butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, napadicylic acid, naphthalene sulfonic acid, and pamoic acid.

14. In paragraph 1, A production method, wherein the surfactant of the above step (b) is at least one selected from the group consisting of polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil derivatives.

15. In paragraph 1, A production method, wherein the continuous phase of the above step (b) further includes at least one selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate.

16. In paragraph 1, The continuous phase of the above step (b) or the continuous phase of the above step (e) is, A production method further comprising at least one early release suppressing agent selected from the group consisting of phosphate salts, phosphide salts, phosphide salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalate salts, silicate salts, sulfate salts, sulfide salts, sulfite salts, tartrate salts, tetraborate salts, thiosulfate salts, arsenate salts, arsenite salts, citrate salts, ferricyanide salts, and nitride salts of alkali metals, alkaline earth metals, or ammonium.

17. In paragraph 1, A production method wherein the emulsion forming device in the above step (c) is a membrane emulsifying device using a porous filter, an in-line mixer, a static mixer, or a microfluidics device.

18. In paragraph 1, A production method wherein the above step (e) further includes a heating treatment for evaporating an organic solvent.

19. In paragraph 1, One side of the pipe connecting the above emulsion forming device and the emulsion storage tank; and A production method, wherein one side of a pipe provided to circulate the above emulsion storage tank further includes a tangential flow filtration (TFF) device on at least one side thereof.

20. Dispersed phase (DP) storage tank (1); Continuous phase (CP) storage tank (2); An emulsion storage tank (3) having a stirrer inside; An emulsion forming device (4) that forms an emulsion by supplying a dispersed phase and a continuous phase from the dispersed phase storage tank (1) and the continuous phase storage tank (2), respectively; A first continuous phase supply pipe (5a) that supplies the continuous phase by connecting the continuous phase storage tank (2) and the emulsion forming device (4); An emulsion supply pipe (6) for transporting the emulsion formed in the emulsion forming device (4) to the emulsion storage tank (3); and It includes a second continuous phase supply pipe (5b) that connects the continuous phase storage tank (2) and the emulsion storage tank (3) to directly supply the continuous phase; Biodegradable microsphere manufacturing device.

21. In paragraph 20, The second continuous phase supply pipe (5b) is Connected in series to the emulsion supply pipe (6), or Connected in series to the emulsion storage tank (3), or A manufacturing device connected in parallel to an emulsion supply pipe (6) and an emulsion storage tank (3).

22. In paragraph 20, One side of the above emulsion supply pipe (6); and A manufacturing device further comprising a tangential flow filtration (TFF) device on at least one side of a pipe provided to circulate the emulsion storage tank (3).

23. In paragraph 20, A manufacturing device wherein the above emulsion forming device (4) is a membrane emulsifying device using a porous filter, an in-line mixer, a static mixer, or a microfluidics device.

24. In paragraph 20, A manufacturing device in which an emulsion is formed using a dispersed phase and a continuous phase supplied through a first continuous phase supply pipe (5a) in the above emulsion forming device (4), and the organic solvent concentration in the emulsion solution is diluted by a fresh continuous phase additionally supplied through the second continuous phase supply pipe (5b) while the formed emulsion is supplied to an emulsion storage tank (3) through the emulsion supply pipe (6).

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