Sustained release pharmaceutical formulation comprising ropivacaine and preparation method thereof

Abstract

The present invention relates to sustained release microspheres and a preparation method thereof, the microsphere comprising ropivacaine having a sodium channel block effect, a salt thereof, a hydrate or solvate thereof, and a biodegradable polymer. In addition, the present invention relates to a pharmaceutical composition characterized by an improved sustained release profile for a sustained analgesic effect of ropivacaine.

Description

Sustained-release formulation containing ropivacaine and method for manufacturing the same

[0001] The present invention relates to microspheres comprising ropivacaine having a sodium channel blocking effect, a salt thereof, a hydrate thereof, or a solvate thereof, and a method for manufacturing the same.

[0002] The present invention relates to a pharmaceutical composition characterized by an improved sustained-release profile for the sustained analgesic effect of ropivacaine.

[0003] Local anesthetics are drugs widely used for the treatment of acute pain after surgery and as analgesic anesthetics during childbirth. Among these drugs, ropivacaine is an aminoamide-class drug that offers rapid analgesic effects and fewer side effects due to motor nerve blockade compared to bupivacaine, making it one of the most widely used drugs for the local control of major pain. However, commercially available ropivacaine injection (naropin ® Since it provides a nerve block effect that lasts only about 2 to 6 hours, it is difficult to obtain a desirable analgesic effect for postoperative pain treatment with a single dose. Accordingly, it is used in clinical practice through methods such as continuous infusion via a catheter or repeated infusion via a patient-controlled analgesia pump, but there are limitations such as limited efficacy, poor patient compliance, risk of infection, restricted mobility, and lack of portability.

[0004] Accordingly, there have been attempts to develop long-acting injectable formulations capable of maintaining drug concentrations for a long period with a single administration, such as oil depots (U.S. Patent Publication No. 2023 / 0080811), liposomes (U.S. Patent Publication No. 2022 / 0249375), and hydrogels (U.S. Patent Publication No. 2022 / 0241200). However, formulations containing these lipid components have several problems, including low drug content, low loading efficiency, limitations on sustained drug release of less than 3 days, and limitations on storage conditions due to oxidation of lipid components and stability of the lipid structure.

[0005] Meanwhile, attempts have been made to manufacture microspheres using emulsion-solvent evaporation (X. Li et al., Eur. J. Pharm. Biopharm. 160 (2021) 143-151.), but the microsphere manufacturing method described in the above literature is a multi-step process involving the steps of dissolving a drug and a biodegradable polymer in an organic solvent to form an oil phase, dispersing the drug solution in a water phase to form microspheres, evaporating the organic solvent used as the oil phase, removing the surfactant used in the process of forming microspheres, and drying the obtained microspheres. As such, there are limitations such as high manufacturing costs, long manufacturing times, and high difficulty in scale-up and mass production, which have acted as major hurdles in product development.

[0006] Therefore, there is a continuous demand for research and development of manufacturing methods that can maintain the drug's effects for an extended period while also offering process simplification, reduced manufacturing costs, shortened manufacturing time, and ease of mass production.

[0007] The object of the present invention is to provide sustained-release microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a biodegradable polymer.

[0008] Another objective of the present invention is to provide a sustained-release formulation comprising the above-mentioned sustained-release microspheres.

[0009] Another objective of the present invention is to provide a pharmaceutical composition for pain suppression, prevention, or treatment comprising the sustained-release formulation.

[0010] Another object of the present invention is to provide a method for producing sustained-release microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a biodegradable polymer.

[0011] To achieve the above objective, the present invention provides sustained-release microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a biodegradable polymer, characterized in that they substantially do not contain a surfactant.

[0012] Specifically, the above ropivacaine may be ropivacaine base or ropivacaine hydrochloride, but is not limited thereto; any form of ropivacaine applicable to sustained-release microspheres according to the present invention, such as salts, hydrates, or solvates prepared according to conventional methods in the art, may be modified and applied as needed.

[0013] Additionally, specifically, the biodegradable polymer may be one or more selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof, but is not limited thereto. More specifically, the biodegradable polymer may include poly(lactide-co-glycolide) (PLGA).

[0014] Additionally, specifically, the biodegradable polymer may include a low-viscosity biodegradable polymer with an intrinsic viscosity of 0.14-0.24 dL / g, a high-viscosity biodegradable polymer with an intrinsic viscosity of 0.32-0.44 dL / g, or a mixture thereof, but is not limited thereto.

[0015] Additionally, specifically, the biodegradable polymer may include a low-viscosity biodegradable polymer with an intrinsic viscosity of 0.16-0.24 dL / g, a low-viscosity biodegradable polymer with an intrinsic viscosity of 0.14-0.22 dL / g, a high-viscosity biodegradable polymer with an intrinsic viscosity of 0.32-0.44 dL / g, or a mixture thereof, but is not limited thereto.

[0016] The above intrinsic viscosity may be measured at a concentration of 0.5 (w / v%) in chloroform at 25°C using a Brookfield viscometer.

[0017] More specifically, the weight ratio of the low-viscosity biodegradable polymer and the high-viscosity biodegradable polymer in the mixture may be 1:0.1 to 1.5, but is not limited thereto, and may be modified as necessary as long as the weight of the combination allows for the formation of sustained-release microspheres.

[0018] For example, the weight ratio of the low-viscosity biodegradable polymer and the high-viscosity biodegradable polymer in the mixture may be 1:0.3 to 1.5, and preferably 1:0.3 to 1.

[0019] In this way, when two or more types of biodegradable polymers with different intrinsic viscosities are mixed and applied, they can show superior effects in terms of drug release control compared to using only a polymer of a single viscosity.

[0020] More specifically, the difference in the degradation rate of biodegradable polymers can be controlled by using a mixture of low-viscosity and high-viscosity biodegradable polymers. Consequently, not only can the initial rapid release phenomenon, where the drug is released all at once at the beginning of administration, be effectively suppressed, but the duration of drug release can also be improved to maintain a uniform and constant release profile over a long period.

[0021] Additionally, specifically, the biodegradable polymer may be a polymer containing a carboxylic acid terminal group (-COOH).

[0022] In addition, the biodegradable polymer may be included in an amount of 50 to 95 weight% of the total weight of the sustained-release microspheres, preferably 50 weight% or more, 55 weight% or more, 60 weight% or more, 65 weight% or more, 70 weight% or more, or 75 weight% or more, 80 weight% or more, 85 weight% or more, or 90 weight% or more, and 95 weight% or less, 85 weight% or less, 80 weight% or less, 75 weight% or less, 70 weight% or less, 65 weight% or less, 60 weight% or less, or 55 weight% or less.

[0023] Additionally, specifically, the ropivacaine or its pharmaceutically acceptable salt, its hydrate, or its solvate may be included in an amount of 5 to 50 weight% of the total weight of the sustained-release microspheres, preferably 20 to 40 weight%, and more preferably 30 to 40 weight%. However, it is not limited thereto and may be applied in a range of less than 5 weight% or more than 50 weight% depending on the required drug concentration.

[0024] For example, the above ropivacaine or its pharmaceutically acceptable salt, its hydrate, or its solvate may be 5% by weight or more, 10% by weight or more, 15% by weight or more, 20% by weight or more, 25% by weight or more, or 30% by weight or more of the total weight of the sustained-release microspheres, and 50% by weight or less, 45% by weight or less, 40% by weight or less, or 35% by weight or less.

[0025] In addition, the above-mentioned sustained-release microspheres substantially do not contain a surfactant.

[0026] Here, “surfactant” refers to a substance that has both a hydrophilic part and a lipophilic part within a single molecule, thereby lowering the surface tension of a liquid and reducing the interfacial energy between two immiscible substances. Such surfactants are not limited to a specific type and any substance that can be used for particle stabilization and emulsification during the microsphere manufacturing process may be used. For example, polymeric materials such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl cellulose, or carboxymethyl cellulose (CMC) may be used.

[0027] The term “substantially not included” above means that such surfactants are included in an amount of 5,000 ppm or less, 4,000 ppm or less, 3,000 ppm or less, 2,000 ppm or less, 1,000 ppm or less, 500 ppm or less, or 100 ppm or less based on sustained-release microspheres, and particularly includes cases where surfactants are not used in the microsphere manufacturing process.

[0028] Conventional emulsion-solvent evaporation often uses surfactants such as polyvinyl alcohol (PVA) in the process of dispersing an organic phase in an aqueous phase to form and stabilize microspheres, and it is common to perform a multi-stage washing process to remove them afterwards.

[0029] In contrast, the sustained-release microspheres according to the present invention are formed by spray-drying a mixed solution in which an active ingredient and a biodegradable polymer are dissolved in a single step, so there is no need to use a separate surfactant for particle formation and stabilization. Microspheres prepared in this manner can reduce the possibility of potential toxicity or immune reactions caused by surfactant residue and can form a high-purity, dense matrix structure.

[0030] However, pharmaceutically acceptable surfactants used in solvents or in vitro release test solutions to reconstitute the manufactured microsphere powder into a suspension form immediately before administration can be understood as having different uses and roles from surfactants used in the microsphere manufacturing process and contained within the microspheres.

[0031] Additionally, specifically, the average particle size (D50) of the above-mentioned Western-type microspheres may be 1 μm to 100 μm.

[0032] For example, the average particle size (D50, μm) of the above-mentioned Western-type microsphere may be 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 12 or more, 14 or more, 16 or more, 18 or more, 20 or more, 21 or more, or 22 or more, and may be 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 29 or less, 28 or less, 27 or less, 26 or less, 25 or less, 24 or less, 22 or less, or 20 or less, but is not limited thereto.

[0033] In addition, the above-mentioned sustained-release microspheres have a span value of 1.0 to 3.5, preferably 1.2 or more, 1.3 or more, 1.4 or more, 1.45 or more, 1.5 or more, 1.55 or more, 1.6 or more, 1.65 or more, 1.7 or more, or 1.75 or more, and may be 3.5 or less, 3.4 or less, 3.3 or less, 3.2 or less, or 3.1 or less. Here, the “span value” refers to a value obtained according to the following Equation 1, which is an indicator representing the width of the particle size distribution of the microspheres, i.e., the uniformity of particle size:

[0034] [Equation 1]

[0035] Span=(D90-D10) / D50

[0036] It is generally known that when conventional emulsion-solvent evaporation, particularly membrane emulsification technology, is applied, microspheres with a narrow particle size distribution with a span value of 0.8 or less, more specifically 0.5 to 0.7, are produced. However, obtaining such a narrow particle size distribution requires the use of surfactants (such as PVA), multi-stage washing processes, and long-term evaporation of organic solvents, which can act as a significant technical burden in terms of mass production and process simplification.

[0037] Here, the statement “average particle size (DX) = Y (where X and Y are positive numbers)” means that when the average particle size distribution obtained by measuring the diameter of the particles is represented by a cumulative curve, the particle diameter at the point where X% (where % is calculated based on number, volume, or weight) is accumulated in order of smallest average particle size is Y. Accordingly, the average particle size (D10) represents the diameter of the particle at the point that is 10% of the average particle size distribution cumulative curve, the average particle size (D50) represents the diameter of the particle at the point that is 50% of the average particle size distribution cumulative curve, and the average particle size (D90) represents the diameter of the particle at the point that is 90% of the average particle size distribution cumulative curve. Furthermore, the average particle size (DX) may vary depending on whether the percentage of the total accumulated particles is represented based on number, volume, or weight, and methods for measuring the average particle size distribution and types of % related thereto are known in the art.

[0038] At this time, it is preferable that the average particle size of the above-mentioned Western-type microspheres be measured by a laser diffraction method that records the average particle size as the diameter of a volume-equivalent sphere. In other words, when measuring the average particle size distribution by the laser diffraction method, the value of X in the average particle size represents the percentage calculated by the volume average. Therefore, the laser diffraction method provides a volume-averaged particle size in response to the volume of the particle, which corresponds to the weight-averaged particle size when the density is constant.

[0039] The measurement of the volume-average particle size distribution of the sustained-release microspheres by such laser diffraction method can be performed using a commercially available device known to be based on the laser diffraction and scattering method based on Mie theory. For example, the average particle size of the sustained-release microspheres can be measured using the Mastersizer laser diffraction device from Malvern Instruments. The device utilizes the fact that scattering occurs when a helium-neon laser beam and a blue light-emitting diode are irradiated onto the particles, causing a light scattering pattern to appear on the detector, and calculates the particle diameter distribution by interpreting this light scattering pattern according to Mie theory. It has the advantage of being capable of both dry and wet measurements.

[0040] In addition, the sustained-release microspheres may have a spherical shape with a smooth surface. That is, the sustained-release microspheres may exhibit a smooth surface shape in which no visible pores or cracks are observed on the surface when observed with a scanning electron microscope (SEM).

[0041] This surface structure is believed to be due to the spray drying process of the present invention. In the case of a general emulsion-solvent evaporation method, fine channels or pores may be formed on the surface of microspheres as the organic solvent slowly diffuses and evaporates through the aqueous phase, whereas in the case of the present invention, a relatively smooth matrix structure can be formed as the droplets of the mixed solution are rapidly dried and solidified by hot air.

[0042] Such a smooth surface structure can contribute to inhibiting the early release of drugs by reducing defects on the surface of microspheres.

[0043] In an in vitro experiment of sustained-release microspheres according to the present invention, the drug release pattern may be such that, when ropivacaine salt-free is applied, the cumulative drug release rate up to day 1 is 10 to 50 weight% and the cumulative drug release rate up to day 2 is 20 to 65 weight%, and when ropivacaine hydrochloride is applied, the cumulative drug release rate up to day 1 is 50 to 85 weight% and the cumulative drug release rate up to day 2 is 65 to 85 weight%.

[0044] The sustained-release microspheres according to the present invention can exhibit a pharmacokinetic profile in which a blood drug concentration of 10 ng / mL or higher is continuously maintained for more than 96 hours (4 days) after administration in an in vivo experiment in which sustained-release microspheres with ropivacaine-free formulation are subcutaneously administered to SD rats (Sprague-Dawley rats) at a ropivacaine dosage of 40 mg / kg.

[0045] Additionally, specifically, the sustained-release microspheres may be prepared by dissolving ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and a biodegradable polymer in a solvent and then spray-drying.

[0046] The emulsion-solvent evaporation method, which was conventionally used for the manufacture of microspheres, had limitations in mass production and cost reduction due to a complex multi-step process involving the use of surfactants and washing.

[0047] On the other hand, since the sustained-release microspheres according to the present invention are manufactured by spray drying, process simplification and scale-up are easy, which is highly advantageous for commercial mass production and securing manufacturing economics.

[0048] The above spray drying can, for example, form fine droplets using high-pressure gas or ultrasonics and form microspheres through drying with hot air, and the nozzle type, nozzle temperature, spray flow rate, solution composition, and drying conditions can be changed and applied as needed.

[0049] In one embodiment of the present invention, it was confirmed that sustained-release microspheres are manufactured normally even when the nozzle spray pressure is varied during spray drying.

[0050] Another aspect of the present invention relates to a sustained-release formulation comprising the above-mentioned sustained-release microspheres.

[0051] In one embodiment of the present invention, sustained-release microspheres containing ropivacaine were prepared through a spray drying step using a biodegradable polymer with different intrinsic viscosities, and it was confirmed that the initial rapid release of these sustained-release microspheres was suppressed and the sustained release was improved. Furthermore, it was confirmed that microspheres containing ropivacaine hydrochloride and a biodegradable polymer provide uniform and constant drug release over a period of 7 days or more, so the sustained-release formulation containing the sustained-release microspheres of the present invention can also provide uniform and constant drug release over a long period.

[0052] Another aspect of the present invention relates to a pharmaceutical composition for pain suppression, prevention, or treatment comprising the sustained-release formulation.

[0053] In the present invention, the term “pain” includes acute pain, chronic pain, and breakthrough pain, and may include, without limitation, locally manifested pain or widely manifested pain.

[0054] In the present invention, “prevention” refers to any action in which the composition of the present invention delays the occurrence of pain.

[0055] In the present invention, “treatment” means any act in which the composition of the present invention causes symptoms caused by pain to improve or become beneficial.

[0056] Specifically, the pharmaceutical composition of the present invention may be a parenteral formulation, and more specifically, may be administered subcutaneously, intramuscularly, or locally.

[0057] For example, the above pharmaceutical composition may be administered subcutaneously.

[0058] The pharmaceutical composition of the present invention may include pharmaceutically acceptable additives such as thickeners, surfactants, isotonic agents, buffers, and pH adjusters within a range that does not impair the effects of the present invention.

[0059] However, the above surfactant is distinguished from surfactants used for the formation and stabilization of microspheres in the manufacturing process of sustained-release microspheres. For example, the above surfactant may be a pharmaceutically acceptable surfactant used to reconstitute microspheres into a suspension form immediately before administration or to improve the dispersion stability of the formulation, and may include polysorbate-based nonionic surfactants.

[0060] In addition, the pharmaceutical composition of the present invention may be applied in a pharmaceutically effective amount, and a "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including the patient's gender, age, type and severity of the disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0061] Another aspect of the present invention relates to a method for producing sustained-release microspheres, comprising the steps of: a) preparing a mixed solution by dissolving ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a biodegradable polymer in a solvent; and b) spray-drying the mixed solution to obtain microspheres.

[0062] Specifically, the biodegradable polymer may be one or more selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof, but is not limited thereto.

[0063] Additionally, specifically, the biodegradable polymer may include a low-viscosity biodegradable polymer with an intrinsic viscosity of 0.14-0.24 dL / g, a high-viscosity biodegradable polymer with an intrinsic viscosity of 0.32-0.44 dL / g, or a mixture thereof, but is not limited thereto.

[0064] Additionally, specifically, the biodegradable polymer may be included in the mixed solution at a concentration of 1 to 20 (w / v%), preferably 5 to 20 (w / v%), but is not limited thereto and may be modified as needed as long as the concentration allows for the formation of sustained-release microspheres. For example, the biodegradable polymer may be included in an amount of 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, 6 (w / v%) or more, 7 (w / v%) or more, 8 (w / v%) or more, 9 (w / v%) or more, or 10 (w / v%) or more, based on the total volume of the mixed solution, and 20 (w / v%) or less, 19 (w / v%) or less, 18 (w / v%) or less, 17 (w / v%) or less, 16 (w / v%) or less, or 15 (w / v%) or less.

[0065] And, the above mixed solution may substantially not contain a surfactant.

[0066] Here, the surfactant refers to a component intentionally added during the microsphere manufacturing process for the formation and stabilization of particles, as previously described in the composition of sustained-release microspheres; it should be understood as distinct from pharmaceutically acceptable surfactants used in solvents or in vitro release test solutions to reconstitute the manufactured microsphere powder into a suspension form immediately before administration.

[0067] The term “substantially not included” above means that the surfactant is included in the mixed solution at a concentration of 5000 ppm or less, 4000 ppm or less, 3000 ppm or less, 2000 ppm or less, 1000 ppm or less, 500 ppm or less, or 100 ppm or less, based on the mixed solution, and particularly includes the case where the surfactant is not used in the preparation of the mixed solution of step a).

[0068] Additionally, specifically, in step a), the solvent may be a volatile solvent capable of dissolving both the active ingredient and the biodegradable polymer, and more specifically, volatile organic solvents such as dichloromethane, acetone, chloroform, methanol, and ethanol; or volatile organic acids such as acetic acid may be used, but are not limited thereto.

[0069] For example, the solvent may be one or more selected from the group consisting of dichloromethane and acetic acid.

[0070] Additionally, specifically, the spray drying in step b) above can form fine droplets through, for example, high-pressure gas or ultrasonic waves, and form microspheres through drying with hot air, and the nozzle type, nozzle temperature, spray flow rate, composition of the solution, and drying conditions can be changed as needed. More specifically, the nozzle spray pressure of the spray drying above can be applied at 300 to 650 L / h, but is not limited thereto.

[0071] The method of manufacturing microspheres through spray drying in the present invention can form microspheres of various shapes depending on the nozzle type, nozzle temperature, spray flow rate, composition of the solution, and drying conditions.

[0072] Additionally, it can be stored at room temperature and can be reconstituted into a suspension formulation by adding a solvent prior to use (administration). The composition of the solvent may include pharmaceutically acceptable additives such as thickeners, surfactants, isotonic agents, buffers, and pH adjusters, within a range that does not impair the effects of the present invention.

[0073] However, the above surfactant is distinguished from the surfactant used for the formation and stabilization of microspheres in the manufacturing process of sustained-release microspheres.

[0074] The present invention provides a formulation that has a high drug content of ropivacaine and can maintain a blood drug concentration for a long period of time. It is applicable to all diseases for which ropivacaine is effective, and in particular, the formulation of the present invention can significantly increase analgesic effects and medication compliance by maintaining the blood drug concentration for a long period of time.

[0075] In addition, the manufacturing method of the present invention has advantages in terms of cost, scale-up, and process simplification because the conversion from a liquid solution to a dry powder proceeds in a single step.

[0076] Figure 1 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 3.

[0077] Figure 2 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 6.

[0078] Figure 3 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 7.

[0079] Figure 4 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 12.

[0080] Figure 5 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 13.

[0081] Figure 6 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 15.

[0082] Figure 7 is a scanning electron microscope image showing the characteristics of microspheres prepared according to Example 16.

[0083] Figure 8 shows the results of the in vitro drug release profiles of microspheres prepared according to Examples 3, 6, 7, and 11.

[0084] Figure 9 shows the results of the in vitro drug release profiles of microspheres prepared according to Examples 6 and 8.

[0085] Figure 10 shows the results of the in vitro drug release profiles of microspheres prepared according to Examples 14, 15, and 16.

[0086] Figure 11 shows the in vivo pharmacokinetic profiles up to 24 hours after administering microspheres prepared according to Examples 3, 6, and 7 to rats.

[0087] Figure 12 shows the results (semi-log scale) of the in vivo pharmacokinetic profiles up to 336 hours after administering microspheres prepared according to Examples 3, 6, and 7 to rats.

[0088] Figure 13 is a graph showing a one-to-one correspondence between the time taken for 80% drug release (T_80% release) in the in vitro drug release evaluation of microspheres prepared according to Examples 3, 6, and 7 and the time taken for the drug to be lost to 10 ng / mL or less (T_10 ng / mL) in the pharmacokinetic evaluation.

[0089] Figure 14 shows the results (semi-log scale) of the in vivo pharmacokinetic profile up to 24 hours after administering microspheres prepared according to Example 16 to a rat.

[0090] Figure 15 shows the results (semi-log scale) of the in vivo pharmacokinetic profile up to 168 hours after administering microspheres prepared according to Example 16 to a rat.

[0091] The present invention will be explained in detail below by way of examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.

[0092]

[0093] Preparation Example. Preparation of microspheres containing ropivacaine

[0094] (1) Preparation of mixed solution

[0095] Ropivacaine base (Ropivacaine base, Apothecon, India) or ropivacaine hydrochloride (Ropivacaine hydrochloride, Apothecon, India) was mixed with a biodegradable polymer (Poly(D,L-lactide-co-glycolide), PLGA) according to the composition listed in Table 1 below, and then dichloromethane was added as a solvent and completely dissolved.

[0096] At this time, in the process of preparing the above mixed solution, no separate surfactant, such as polyvinyl alcohol (PVA), which is commonly used for particle formation and stabilization in conventional emulsion-solvent evaporation methods, was added, thereby producing a uniform mixed solution that substantially does not contain surfactant.

[0097] As an example of the above-mentioned biodegradable polymer, Poly(lactide-co-glycolide) utilized Evonik's Resomer, and the low-viscosity (intrinsic viscosity 0.16-0.24 dL / g) PLGA was Resomer ® RG 502H, high viscosity (intrinsic viscosity 0.32-0.44 dL / g) PLGA is a Resomer ® I purchased and used the RG 503H.

[0098] Ingredients Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Ropivacaine base (w / w%) 10 20 30 40 50 30 30 Ropivacaine hydrochloride (w / w%) ------- Low viscosity PLGA (w / v%) 5 5 5 5 5 -- 1:1 mixture of low viscosity and high viscosity PLGA (w / v%) --- 5 -- 3:1 mixture of low viscosity and high viscosity PLGA (w / v%) --- ---- High viscosity PLGA (w / v%) --- 5 Ingredients Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Ropivacaine base (w / w%) 30 40 30 --- Ropivacaine hydrochloride (Ropivacaine hydrochloride, w / w%)---15.6 1030 Low-viscosity PLGA(w / v%)--15 15 15 15 15 1:1 mixture of low-viscosity and high-viscosity PLGA(w / v%)----3:1 mixture of low-viscosity and high-viscosity PLGA(w / v%)5-----High-viscosity PLGA(w / v%)------

[0099]

[0100] Ropivacaine base or ropivacaine hydrochloride was mixed with a biodegradable polymer according to the composition listed in Table 2 below, and then acetic acid was added as a solvent and completely dissolved.

[0101] At this time, in the process of preparing the above mixed solution, no separate surfactant, such as polyvinyl alcohol (PVA), which is commonly used for particle formation and stabilization in conventional emulsion-solvent evaporation methods, was added, thereby producing a uniform mixed solution that substantially does not contain surfactant.

[0102] As an example of the above-mentioned biodegradable polymer, poly(lactide-co-glycolide) utilized Evonik’s Resomer, and more specifically, a low-viscosity (intrinsic viscosity 0.14-0.22 dL / g) PLGA Resomer. ® I purchased and used the RG 752H.

[0103] Ingredients Example 14 Example 15 Example 16 Ropivacaine base (w / w%) 30 --Ropivacaine hydrochloride (w / w%) 30 40 Low viscosity PLGA (w / v%) 55 10

[0104]

[0105] (2) Preparation of microspheres

[0106] Microspheres were prepared by spray-drying the solution shown in Table 1 above using a spray dryer (Mini Spray Dryer B-290, Buchi, Switzerland) according to the following spray-drying conditions 1 (Table 3) or spray-drying conditions 2 (Table 4).

[0107] Nozzle typeTwo-fluid nozzle, Ø0.7mmAtomization gashigh purity nitrogen gasInlet temperature(℃)50Outlet temperature(℃)38Aspirator(%)100Flowmeter (L / h)357Feed flow (mL / min)6

[0108] Nozzle typeTwo-fluid nozzle, Ø0.7mmAtomization gashigh purity nitrogen gasInlet temperature(℃)50Outlet temperature(℃)37Aspirator(%)100Flowmeter (L / h)601Feed flow (mL / min)6

[0109]

[0110] Microspheres were prepared by spray-drying the solution shown in Table 2 above using a spray dryer (sodeva, France) according to the following spray-drying conditions 3 (Table 5).

[0111] Inlet temperature(℃)150~200Outlet temperature(℃)50~70

[0112]

[0113] Experimental Example 1. Evaluation of particle size of manufactured microspheres

[0114] To evaluate the particle size of the microspheres, the average particle size of the microspheres prepared in Preparation Example (spray drying condition 1) was measured using a particle size analyzer (Mastersizer 3000, Malvern Panalytical, UK) according to the conditions in Table 6 below. At this time, the unit of the measured average particle size is μm.

[0115] Dispersion Solvent Stirring RPM 2800 Shielding (%) 20 Particle Refractive Index 1.5 2 Measurement Time (sec) 10 Number of Measurements (times) 3

[0116]

[0117] 1-1. Evaluation of Microsphere Particle Size According to Type of Biodegradable Polymer

[0118] To evaluate the particle size of microspheres according to the type of biodegradable polymer, the average particle size was measured for microspheres prepared with the compositions of Examples 3, 6, and 7 (spray drying condition 1) according to the conditions of Table 6 above.

[0119] As a result, as shown in Table 7, there was no significant difference in the change in particle size of microspheres depending on the type of biodegradable polymer.

[0120] Example 3 Example 6 Example 7 D [4,3]20.0023.2022.80Span2.4642.7692.992D102.161.911.64D5016.518.116.5D9042.852.050.9

[0121]

[0122] 1-2. Evaluation of Microsphere Particle Size According to Changes in Active Ingredient Content When Applying Low-Viscosity Biodegradable Polymers

[0123] To evaluate the particle size of microspheres according to changes in the content of the active ingredient when applying a low-viscosity biodegradable polymer, the average particle size was measured for microspheres prepared with the compositions of Examples 1 to 5 (spray drying condition 1) according to the conditions of Table 6 above.

[0124] As a result, as shown in Table 8, it was confirmed that the particle size of the microspheres increased as the ropivacaine-free content increased from 10% to 50%.

[0125] Example 1 Example 2 Example 3 Example 4 Example 5D [4,3]18.0019.3020.0021.2023.90Span3.0202.5082.4642.1221.789D101.982.232.162.336.81D5013.215.916.519.021.2D9041.742.042.842.744.9

[0126]

[0127] 1-3. Evaluation of Microsphere Particle Size According to Changes in Active Ingredient Content When Applying High-Viscosity Biodegradable Polymers

[0128] To evaluate the particle size of microspheres according to changes in the content of the active ingredient when applying a high-viscosity biodegradable polymer, the average particle size was measured for microspheres prepared with the compositions of Examples 7 and 9 (spray drying condition 1) according to the conditions of Table 6 above.

[0129] As a result, as shown in Table 9, it was confirmed that the particle size of the microspheres increased as the ropivacaine-free content increased from 30% to 40%.

[0130] Example 7 Example 9 D [4,3] 2 2.80 3 2.50 Span 2.99 2 2.97 2D 10 1.64 3.33D 50 16.52 3.4D 90 50.97 2.9

[0131]

[0132] 1-4. Evaluation of Microsphere Particle Size According to Changes in Biodegradable Polymer Concentration (w / v%)

[0133] To evaluate the particle size of microspheres according to changes in the concentration (w / v%) of the biodegradable polymer in the manufacturing solution, the average particle size was measured for microspheres prepared with the compositions of Examples 3 and 10 (spray drying condition 1) according to the conditions of Table 6 above.

[0134] As a result, as shown in Table 10, it was confirmed that the particle size of the microspheres increased as the concentration (w / v%) of the biodegradable polymer increased from 1% to 5%.

[0135] Example 3 (5 w / v%) Example 10 (1 w / v%) D [4,3] 20.00 3.47 Span 2.46 41.90 8 D 10 2.16 1.28 D 50 16.5 2.71 D 90 42.8 6.44

[0136]

[0137] 1-5. Evaluation of Microsphere Particle Size According to Changes in Nozzle Pressure During Spray Drying

[0138] To evaluate the particle size of microspheres according to changes in nozzle spray pressure (Flowmeter) during spray drying, microspheres were prepared by spray drying the composition of Example 7 according to spray drying condition 1 (Table 3) or spray drying condition 2 (Table 4). Subsequently, the average particle size was measured according to the conditions in Table 6.

[0139] As a result, as shown in Table 11, microspheres were manufactured normally even with different spray drying conditions, and it was confirmed that the particle size of the microspheres decreased as the nozzle spray pressure (Flowmeter) during spray drying increased from 357 L / h to 601 L / h.

[0140] Spray drying condition 1 Spray drying condition 2D [4,3]22.8014.60Span2.9922.299D101.641.80D5016.512.4D9050.930.4

[0141]

[0142] 1-6. Evaluation of Microsphere Particle Size According to Change in Active Ingredient Salt

[0143] To evaluate the particle size of microspheres according to the change in the salt of the active ingredient, the average particle size was measured for microspheres prepared with the compositions of Examples 3 and 11 (spray drying condition 1) and the compositions of Examples 14 and 15 (spray drying condition 2) according to the conditions of Table 6 above.

[0144] Example 3 Example 11 Example 14 Example 15D [4,3]20.0028.519.118.2Span2.4642.2831.8441.487D102.166.066.116.2D5016.522.216.417.2D9042.856.736.431.8

[0145]

[0146] 1-7. Evaluation of Microsphere Particle Size According to Mixing Ratio of Low-Viscosity and High-Viscosity Biodegradable Polymers

[0147] To evaluate the particle size of microspheres according to the mixing ratio of low-viscosity and high-viscosity polymers of biodegradable polymers, microspheres were prepared by spray-drying the compositions of Examples 6 and 8 according to spray-drying condition 1 (Table 3). Subsequently, the average particle size was measured according to the conditions in Table 6.

[0148] As a result, as shown in Table 13, it was confirmed that the particle size increased as the proportion of high-viscosity polymers in the biodegradable polymers increased.

[0149] Example 6 Example 8D [4,3]23.2019.2Span2.7692.870D101.911.67D5018.114.6D9052.043.6

[0150]

[0151] Experimental Example 2. Evaluation of Appearance

[0152] To evaluate the characteristics of microspheres prepared according to Examples 3, 6, and 7, in which ropivacaine salt-free was used as the active ingredient, and Examples 12 and 13, in which ropivacaine hydrochloride was used as the active ingredient, using dichloromethane as the solvent, the characteristics were evaluated according to the conditions of Table 14 below using a scanning electron microscope (TM4000Plus, Hitachi, Japan).

[0153] Accelerating voltage (kV)10Magnification2000

[0154]

[0155] The results of the evaluation of the properties of the microspheres are shown in FIGS. 1 to 5. As a result of the evaluation of properties, the surface of the microspheres prepared with ropivacaine salt-free as the active ingredient in Examples 3, 6, and 7 was smooth, and the microspheres prepared with ropivacaine hydrochloride as the active ingredient in Examples 12 and 13 also showed a relatively smooth surface in which no significant pores or cracks were observed.

[0156] Additionally, the properties of microspheres prepared according to Examples 15 and 16, in which ropivacaine hydrochloride was used as the active ingredient and acetic acid was used as the solvent, were evaluated.

[0157] The results of the evaluation of the characteristics of the microspheres are shown in Figures 6 and 7. Examples 15 and 16, which contained ropivacaine hydrochloride as an active ingredient, had a smooth surface.

[0158]

[0159] Experimental Example 3. Evaluation of in vitro drug release

[0160] To evaluate the drug release of microspheres prepared according to Examples 3, 6, and 7, in which ropivacaine salt-free was used as the active ingredient, and Example 11, in which ropivacaine hydrochloride was used as the active ingredient, in vitro drug release evaluations were conducted under bio-mimicking conditions. Microspheres corresponding to 3 mg of ropivacaine were placed in a 120 mL glass vial, and drug release evaluations were performed in a shaking water bath according to the conditions in Table 15. The concentration of ropivacaine in the release solution was analyzed using HPLC-UV.

[0161] Apparatusshaking water bath with 120mL Glass vialMedium100mL, pH 7.4 PBS with 0.02% polysorbate 20temperature(℃)37Shaking RPM100

[0162]

[0163] The results of the in vitro drug release evaluation of microspheres prepared according to Examples 3, 6, 7, and 11 are shown in Fig. 8. As a result of the in vitro drug release evaluation, microspheres prepared with ropivacaine-free as the active ingredient, as in Examples 3, 6, and 7 of the present invention, exhibited a lower initial rapid drug release than microspheres prepared with ropivacaine hydrochloride as the active ingredient in Example 11. In addition, different drug release rates were observed depending on the type of biodegradable polymer, and a continuous linear (zero-order) drug release profile was shown for 4 to 9 days or more.

[0164] In particular, in the case of Example 6, in which two types of biodegradable polymers with different intrinsic viscosities were mixed in a 1:1 weight ratio, it was confirmed that the drug release behavior can be controlled through the combination of polymers with different viscosities. For example, a formulation using a low-viscosity polymer (Example 3) exhibits relatively fast initial release characteristics, and a formulation using a high-viscosity polymer (Example 7) exhibits a more gradual release behavior, whereas a formulation applying a mixture of these (Example 6) can exhibit a release profile that reflects the two characteristics.

[0165] In addition, in vitro drug release evaluations of the microspheres prepared according to Examples 6 and 8 were conducted, and the results are shown in Fig. 9. The in vitro drug release evaluation results confirmed that the drug release behavior can be controlled according to the ratio of low-viscosity polymers to high-viscosity polymers. In particular, Example 8, which had a high proportion of low-viscosity polymers, exhibited a more gradual release behavior than Example 6, which had a low proportion of low-viscosity polymers. These results suggest that the drug release characteristics of microsphere formulations can be designed in various ways by controlling the viscosity or composition of the biodegradable polymers.

[0166] Additionally, the in vitro drug release of the microspheres prepared according to Examples 14, 15, and 16 was evaluated, and the results are shown in Fig. 10. Example 14, containing ropivacaine salt-free as the active ingredient, exhibited a lower rapid drug release than Examples 15 and 16, containing ropivacaine hydrochloride as the active ingredient. Comparing Example 15 and Example 16, overall dissolution occurred more rapidly as the drug concentration increased.

[0167]

[0168] Experimental Example 4. Evaluation of Pharmacokinetics (PK) in Rat

[0169] 1-1. Evaluation of Pharmacokinetics of Microspheres Prepared with Ropivacaine-Free as Active Ingredient

[0170] Pharmacokinetic studies were conducted in rats to evaluate the pharmacokinetics of microspheres prepared with ropivacaine salt-free as the active ingredient in Examples 3, 6, and 7. Approximately 250 g of 9-week-old male SD rats, acclimatized for 7 days, were used, and they were fasted for 12 hours prior to administration. Pharmacokinetic analysis was performed on the animals after subcutaneous administration of the microspheres prepared in Examples 3, 6, and 7, which were suspended in physiological saline supplemented with 0.05% polysorbate 80 and 1% sodium carboxymethylcellulose. As a control, ropivacaine hydrochloride was dissolved in physiological saline at a concentration of 0.75 w / v% and administered subcutaneously. The composition of the test groups and administration conditions are shown in Table 16 below.

[0171] Test Group | Gender | Number of Animals (Heads) | Test Substance | Route of Administration | As Pivacaine | Dosage (mg / kg) G1 M4 | Pivacaine Hydrochloride Solution | Subcutaneous Administration (SC) | 10, Single Dose G2 M5 | Example 3 | Subcutaneous Administration (SC) | 40, Single Dose G3 M5 | Example 6 | Subcutaneous Administration (SC) | 40, Single Dose G4 M5 | Example 7 | Subcutaneous Administration (SC) | 40, Single Dose

[0172]

[0173] According to the above composition, it was administered subcutaneously to the cervix, and blood was collected for two weeks as shown in Table 17 below. The collected blood was centrifuged to separate the plasma, which was frozen at -70 °C until analysis. The concentration of ropivacaine in the plasma samples was analyzed using LC-MS / MS.

[0174] Blood Collection Site Jugular Vein Collection Time (h): 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 24, 48, 72, 96, 120, 168, 216, 264, and 336 (Total 19 points) Blood Volume (mL): 0.25 Blood Collection: Collected in a heparin-treated tube at 0℃ Plasma Separation: Centrifuged at 12,000 RPM at 4℃ Storage: -70℃

[0175]

[0176] The results of the analysis of the concentration of ropivacaine in plasma samples are shown in Figures 11, 12 and Table 18.

[0177] Test group Dose(mg / kg)T max (h)C max (ng / mL)C max / Dose (kg / L)AUC last (ng·h / mL)AUC last / Dose (kg·h / L)G1100.38 (±0.14)1497.70(±845.82)0.149(±0.085)2201.74(±467.87)0.220(±0.047)G2401.50 (±0.87)429.31(±112.45)0.011(±0.003)5762.78(±1210.98)0.144(±0.030)G3401.50 (±0.35)279.56(±101.37)0.007(±0.002)4544.83(±1036.22)0.114(±0.026)G4401.60 (±0.42)214.89(±43.47)0.005(±0.001)5054.60(±1266.44)0.126(±0.032)

[0178]

[0179] The maximum blood concentration of ropivacaine (C) when microspheres prepared according to Examples 3, 6, and 7 of the present invention are administered max ) was 3.5 to 7 times lower compared to when ropivacaine hydrochloride solution was administered.

[0180] In addition, it was confirmed that when a ropivacaine hydrochloride solution is administered, the blood concentration of ropivacaine rapidly decreases to 10 ng / mL or less after 4 hours, whereas in the case of microspheres prepared according to Examples 3, 6, and 7, sustained drug release under physiological conditions is exhibited as the drug is encapsulated in a biodegradable polymer, and depending on the type of biodegradable polymer, a sustained drug release profile of 4 to 9 days or more can be exhibited.

[0181] Meanwhile, Figure 13 shows a one-to-one correspondence graph between the time taken for 80% drug release (T_80% release) in the in vitro drug release evaluation of the microspheres prepared in Examples 3, 6, and 7 and the time taken for the drug to be eliminated to 10 ng / mL or less (T_10 ng / mL) in the pharmacokinetic evaluation, and there is a linear relationship between the two parameters (R 2 =0.9825) was confirmed.

[0182] From these results, it was confirmed that the microsphere formulation of the present invention, containing ropivacaine-free and biodegradable polymers, can exhibit an improved drug release profile of 3 days or more while containing a high drug content of 30% or more.

[0183]

[0184] 1-2. Evaluation of Pharmacokinetics of Microspheres Prepared with Ropivacaine Hydrochloride as Active Ingredient

[0185] Pharmacokinetic studies were conducted in rats to evaluate the pharmacokinetics of microspheres prepared with ropivacaine hydrochloride as the active ingredient. Approximately 250 g 9-week-old male SD rats, acclimatized for 7 days, were used, and they were fasted for 12 hours prior to administration. Pharmacokinetic analysis was performed on the animals after subcutaneous administration of the microspheres prepared in Example 16, which were suspended in physiological saline supplemented with 0.05% polysorbate 80 and 1% sodium carboxymethylcellulose. As a control group, ropivacaine hydrochloride was dissolved in physiological saline at a concentration of 0.75 w / v% and administered subcutaneously. The composition of the test groups and administration conditions are shown in Table 19 below.

[0186] Test Group | Gender | Number of Animals (Heads) | Test Substance | Route of Administration | Dosage (mg / kg) as Ropivacaine G1 M5 | Ropivacaine hydrochloride solution | Subcutaneous administration (SC) | 15, single dose G2 M5 | Example 16 | Subcutaneous administration (SC) | 15, single dose

[0187]

[0188] According to the above composition, it was administered subcutaneously to the cervix and back, and blood was collected for one week as shown in Table 20 below. The collected blood was centrifuged to separate the plasma, which was frozen and stored at -70°C until analysis. The concentration of ropivacaine in the plasma samples was analyzed using LC-MS / MS.

[0189] Blood Collection Site Jugular Vein Collection Time (h) 0, 0.083, 0.166, 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 24, 48, 72, 96, 120, 144, 168 (Total 18 points) Blood Volume (mL) 0.25 Blood Collection Collected in a heparin-treated tube at 0℃ Plasma Separation Centrifuged at 12,000 RPM at 4℃ Storage -70℃

[0190]

[0191] The results of the analysis of the concentration of ropivacaine in plasma samples are shown in Figures 14, 15 and Table 21.

[0192] Test group Dose(mg / kg)T max (h)C max (ng / mL)AUC last (ng·h / mL)G1152.3 (±0.5)342.8(±39.2)1632.84(±127.17)G2151.1 (±0.6)55.8(±7.2)385.89(±21.46)

[0193]

[0194] When microspheres prepared according to Example 16 of the present invention are administered, the peak blood concentration of ropivacaine (C max ) was 6 times lower compared to when ropivacaine hydrochloride solution was administered.

[0195] In addition, it was confirmed that while the blood concentration of ropivacaine disappears after 8 hours when a ropivacaine hydrochloride solution is administered, the microspheres prepared according to Example 16 exhibit sustained drug release under physiological conditions as the drug is encapsulated in a biodegradable polymer, and can exhibit a sustained drug release profile of 7 days or more.

[0196] From these results, it was confirmed that the microsphere formulation of the present invention, comprising ropivacaine hydrochloride and a biodegradable polymer, can exhibit an improved drug release profile of 7 days or more while containing a high drug content of 40%.

[0197]

[0198] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single unit may be implemented in a distributed manner, and components described as distributed may likewise be implemented in a combined form.

[0199] The scope of the present invention is defined by the claims set forth below, and all modifications or variations derived from the meaning and scope of the claims and equivalent concepts thereof should be interpreted as being included within the scope of the present invention.

Claims

1. Ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and sustained-release microspheres comprising a biodegradable polymer, Sustained-release microspheres characterized by the above microspheres substantially not containing a surfactant.

2. Sustained-release microspheres according to claim 1, wherein the ropivacaine is ropivacaine base or ropivacaine hydrochloride.

3. Sustained-release microspheres according to claim 1, wherein the biodegradable polymer is one or more selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof.

4. In Paragraph 1, Sustained-release microspheres comprising the above biodegradable polymer, which includes a low-viscosity biodegradable polymer with an intrinsic viscosity of 0.14-0.24 dL / g, a high-viscosity biodegradable polymer with an intrinsic viscosity of 0.32-0.44 dL / g, or a mixture thereof.

5. In Paragraph 4, Sustained-release microspheres, wherein the weight ratio of the low-viscosity biodegradable polymer and the high-viscosity biodegradable polymer in the above mixture is 1:0.1 to 1.

5.

6. In Paragraph 1, Sustained-release microspheres, wherein the above-mentioned ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is included in an amount of 5 to 50 weight% of the total weight of the sustained-release microspheres.

7. In Paragraph 1, The average particle size (D50) of the above sustained-release microspheres is 1 μm to 100 μm.

8. In Paragraph 1, Sustained-release microspheres, wherein the span value of the above sustained-release microspheres is 1.0 to 3.5, and the span value is calculated according to the following Equation 1: [Equation 1] Span=(D90-D10) / D50 9. In Paragraph 1, The above-mentioned sustained-release microsphere is a sustained-release microsphere having a spherical shape with a smooth surface.

10. In Paragraph 1, The sustained-release microspheres are prepared by dissolving ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and a biodegradable polymer in a solvent and then spray-drying.

11. A sustained-release formulation comprising the sustained-release microspheres of claim 1.

12. A pharmaceutical composition for pain suppression, prevention, or treatment comprising the sustained-release formulation of claim 11. 13.a) a step of preparing a mixed solution by dissolving ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and a biodegradable polymer in a solvent; and b) A method for manufacturing sustained-release microspheres comprising the step of spray-drying the above-mentioned mixed solution to obtain microspheres.

14. A method for manufacturing sustained-release microspheres according to claim 13, wherein the biodegradable polymer is one or more selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof.

15. A method for manufacturing sustained-release microspheres according to claim 13, wherein the biodegradable polymer comprises a low-viscosity biodegradable polymer with an intrinsic viscosity of 0.14-0.24 dL / g, a high-viscosity biodegradable polymer with an intrinsic viscosity of 0.32-0.44 dL / g, or a mixture thereof.

16. A method for manufacturing sustained-release microspheres according to claim 13, wherein the biodegradable polymer is included in an amount of 1 to 20 (w / v%) based on the total volume of the mixed solution.

17. In Paragraph 13, The above-mentioned mixed solution is a method for manufacturing sustained-release microspheres that substantially does not contain a surfactant.

18. A method for manufacturing sustained-release microspheres according to claim 13, wherein the nozzle spray pressure of the spray drying is 300 to 650 L / h.

19. A method for manufacturing sustained-release microspheres according to claim 13, wherein the solvent is one or more selected from the group consisting of dichloromethane and acetic acid.

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