Sustained-release microspheres comprising ropivacaine and nonsteroidal Anti-inflammatory agent, and preparation method therefor

Abstract

The present invention relates to microspheres and a preparation method therefor, the microspheres comprising: ropivacaine, a salt thereof, a hydrate or a solvate thereof, which have the effect of regulating acute pain after surgery; a nonsteroidal anti-inflammatory drug (NSAID); and a biodegradable polymer. The present invention provides a pharmaceutical composition for providing sustained and effective analgesic effects of ropivacaine and a nonsteroidal anti-inflammatory agent. The preparation of the present invention is applicable to all diseases in which acute pain control effects can be exhibited, and, particularly, has an improved sustained-release profile of ropivacaine and a nonsteroidal anti-inflammatory agent and simultaneously controls the release of the two drugs, can continuously provide effective analgesic effects, and can significantly increase medication compliance. In addition, conversion from a liquid solution to dry powder proceeds in a single step, and thus the microsphere preparation method of the present invention has advantages in terms of cost, scaling up, and process simplification.

Description

Long-acting microspheres containing ropivacaine and nonsteroidal anti-inflammatory drugs and method for preparing the same

[0001] The present invention relates to microspheres comprising ropivacaine, a salt thereof, a hydrate or a solvate thereof, a nonsteroidal anti-inflammatory drug (NSAID), and a biodegradable polymer, which have an acute pain control effect after surgery, and a method for preparing the same.

[0002] The present invention provides an improved sustained release profile for the sustained analgesic effect of ropivacaine and a non-steroidal anti-inflammatory drug, and simultaneously controlled release of the two drugs.

[0003] Local anesthetics are widely used for acute pain control after surgery and as analgesic anesthesia during labor. Among these drugs, ropivacaine, an amino amide drug, is one of the most widely used drugs for local control of major pain due to its rapid analgesic effect and fewer side effects from motor nerve block than bupivacaine. However, ropivacaine injection (naropin) on the market ® ) provides a nerve blocking effect that lasts only about 2-6 hours, making it difficult to achieve the desired analgesic effect for postoperative pain treatment with a single administration. Therefore, continuous infusion through a catheter or repeated infusion through a patient-controlled analgesia pump are used clinically, but there are limitations such as limited efficacy, poor patient compliance, risk of infection, restricted movement, and lack of portability.

[0004] Accordingly, there have been attempts to develop long-acting injections that can maintain drug concentration for a long time with only a single administration, such as oil depots (US Patent Publication No. 2023 / 0080811), liposomes (US Patent Publication No. 2022 / 0249375), and hydrogels (US Patent Publication No. 2022 / 0241200). However, these formulations containing lipid components have several problems, such as low drug content and low loading efficiency, limitations in sustained drug release of less than 3 days, and restrictions on storage conditions due to lipid component oxidation and lipid structure stability issues.

[0005] Meanwhile, the manufacture of microspheres using biodegradable polymers such as PLGA (Poly(lactide-co-glycolide)) (X. Li et al., Eur. J. Pharm. Biopharm. 160 (2021) 143-151.; K. Wen et al., Colloids Surf. B: Biointerfaces. 210(2022) 112215) was attempted, and sustained release of more than 3 days was achieved, including a low initial burst of drug release even at a high drug content of more than 30%. However, the analgesic effect of the microsphere composition in the above literature was found to be less than 24 hours in animals and did not have a sufficient analgesic effect. In addition, the manufacturing method of the above document is a multi-step process that involves a step of dissolving a drug and a biodegradable polymer in an organic solvent by emulsion-solvent evaporation to form an oil phase, a step of dispersing the drug solution in a water phase to form microspheres, a step of evaporating the organic solvent used as the oil phase, a step of removing a surfactant used in the process of forming microspheres, and a step of drying the obtained microspheres. As a result, there are limitations such as high manufacturing cost, long manufacturing time, and high difficulty in scale-up and mass production, which can act as a major hurdle in product development.

[0006] Meanwhile, nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that relieve the body's inflammatory response and have anti-inflammatory, analgesic, and antipyretic effects. They are widely used as combination drugs for postoperative acute pain control along with local anesthetics. However, the only sustained-release combination product containing a local anesthetic and a nonsteroidal anti-inflammatory drug commercialized for postoperative acute pain control is Zynrelef. ®(FDA approved in 21 years) is the only product in the form of an instillation containing bupivacaine and meloxicam, and is used only for pain in soft tissues and some joints, such as wounds. Currently, there is no sustained-release combination product containing ropivacaine and a non-steroidal anti-inflammatory drug.

[0007] Accordingly, there is a continuous need for research and development of a microsphere manufacturing method that can maintain the drug effect for a long time and exhibit the combined therapeutic effect of ropivacaine and non-steroidal anti-inflammatory drugs, while simplifying the process, reducing manufacturing costs, shortening manufacturing time, and facilitating mass production.

[0008] An object of the present invention is to provide sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer.

[0009] Another object of the present invention is to provide a sustained-release preparation comprising the above-described sustained-release microparticles.

[0010] Another object of the present invention is to provide a pharmaceutical composition for suppressing, preventing or treating pain, comprising the above-described sustained-release formulation.

[0011] Another object of the present invention is to provide a method for preparing sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer.

[0012] Another object of the present invention is to provide a method for alleviating or treating pain, comprising administering to a subject sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer.

[0013] Another object of the present invention is to provide sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer for use in pain relief or treatment.

[0014] One aspect of the present invention for achieving the above object relates to sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer.

[0015] Specifically, the ropivacaine may be a ropivacaine base, but is not limited thereto, and any form of ropivacaine that can be applied to the sustained-release microspheres according to the present invention, such as a salt, hydrate, or solvate prepared according to a method conventional in the art, may be modified and applied as needed.

[0016] In addition, specifically, the non-steroidal anti-inflammatory agent may be one or more selected from the group consisting of ibuprofen, naproxen, ketorolac, and diclofenac, but is not limited thereto, and may be changed and applied as needed.

[0017] In addition, specifically, the non-steroidal anti-inflammatory agent may be a base, but is not limited thereto, and any form of the non-steroidal anti-inflammatory agent that can be applied to the sustained-release microspheres according to the present invention, such as a salt, hydrate, or solvate prepared according to a method conventional in the art, may be changed and applied as needed.

[0018] More specifically, the non-steroidal anti-inflammatory agent may be a drug having acid properties, and more specifically, may be an acidic non-steroidal anti-inflammatory agent having a carboxylic acid structure, and more specifically, may be an acidic non-steroidal anti-inflammatory agent having a salicylic acid, acetic acid, propionic acid, mefenamic acid, or oxicam structure, but is not limited thereto.

[0019] Also specifically, the biodegradable polymer may be at least one 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, but is not limited to, poly(lactide-co-glycolide) ((Poly(lactide-co-glycolide, PLGA).

[0020] Also, specifically, the intrinsic viscosity of the biodegradable polymer may be, but is not limited to, 0.1-1.0 dL / g. More specifically, it may have an intrinsic viscosity of, but is not limited to, 0.1-0.5 dL / g, or most specifically, an intrinsic viscosity in the range of 0.15-0.45 dL / g.

[0021] More specifically, the biodegradable polymer may include, but is not limited to, a low viscosity biodegradable polymer having an intrinsic viscosity of 0.1-0.25 dL / g, more specifically 0.16-0.24 dL / g, or a high viscosity biodegradable polymer having an intrinsic viscosity of 0.30-0.5 dL / g, more specifically 0.32-0.44 dL / g, or a mixture thereof. The intrinsic viscosity can be appropriately controlled by selecting a low viscosity biodegradable polymer, a high viscosity biodegradable polymer, and / or a mixture thereof to control the drug release of the sustained-release microspheres.

[0022] Also, specifically, the ropivacaine may be included in the sustained-release microspheres at 10 to 40% (w / w), but is not limited thereto. More specifically, it may be included in 10 to 40% (w / w), and most specifically, it may be included in 20 to 30% (w / w), but is not limited thereto. In particular, when included together with a non-steroidal anti-inflammatory drug in the sustained-release microspheres, the content of ropivacaine may be changed to control appropriate drug release.

[0023] Also, specifically, the non-steroidal anti-inflammatory agent may be included in the sustained-release microspheres at a content of, but not limited to, 10 to 40% (w / w). More specifically, the non-steroidal anti-inflammatory agent may be included in the sustained-release microspheres at a content of, but not limited to, 10 to 40% (w / w), and most specifically, the non-steroidal anti-inflammatory agent may be included in the sustained-release microspheres at a content of, but not limited to, 20 to 30% (w / w). When included together with ropivacaine in the sustained-release microspheres, the content of the non-steroidal anti-inflammatory agent may be varied to control appropriate drug release.

[0024] Also specifically, ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and the non-steroidal anti-inflammatory agent may be included in the sustained-release microspheres at a molar ratio of 1:0.5 to 1:2, specifically at a molar ratio of 1:0.5 to 1:1.5, and most specifically at a molar ratio of 1:0.5 to 1:1, but is not limited thereto. The molar ratio may be changed as needed within a range where the formation of sustained-release microspheres and the release of each drug are appropriately controlled.

[0025] Also specifically, the ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; and the biodegradable polymer may be included in a weight ratio of 1:1 to 1:20, specifically in a weight ratio of 1:1 to 1:10, and most specifically in a weight ratio of 1:1 to 1:5, but is limited thereto. The weight ratio may be changed as needed within a range in which the formation of sustained-release microspheres and the release of ropivacaine are appropriately controlled.

[0026] Also, specifically, the non-steroidal anti-inflammatory agent and the biodegradable polymer may be included in a weight ratio of 1:1 to 1:20, specifically, may be included in a weight ratio of 1:1 to 1:10, and most specifically, may be included in a weight ratio of 1:1 to 1:5, but is limited thereto. The weight ratio may be changed as needed within a range in which the formation of sustained-release microspheres and the release of the non-steroidal anti-inflammatory agent are appropriately controlled.

[0027] Also specifically, the above-mentioned western-type microspheres may be manufactured by dissolving ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; a non-steroidal anti-inflammatory agent; and a biodegradable polymer in a solvent and then spray-drying the resulting solution.

[0028] The solvent may be a volatile solvent, for example, a volatile organic solvent such as dichloromethane, acetone, chloroform, methanol, ethanol, or a volatile organic acid such as acetic acid, but is not limited thereto.

[0029] The above spray drying can be performed by forming fine droplets through, for example, high-pressure gas or ultrasonic waves, and forming microspheres through drying using hot air. The nozzle type, nozzle temperature, spray flow rate, solution composition, and drying conditions can be changed and applied as needed.

[0030] The above-mentioned western-type microspheres may have an average particle size of 1 to 100 um, and specifically may have an average particle size of 5 to 20 um.

[0031] In addition, the above-mentioned western-type microspheres can have a drug encapsulation efficiency of 95% or more, and specifically, can have a drug encapsulation efficiency of 97% or more.

[0032] In addition, the above-mentioned western-type microspheres can be stored at room temperature or refrigerated in the form of a lyophilized powder, and can be reconstituted into a suspension-type preparation by adding a solvent before use (administration), and the composition of the lyophilized powder and the solvent can include pharmaceutically acceptable additives such as thickeners, surfactants, isotonic agents, buffers, and pH regulators within a range that does not impair the effects of the present invention.

[0033] Another aspect of the present invention relates to sustained-release microspheres comprising ropivacaine base, a hydrate thereof or a solvate thereof; an organic acid; and a biodegradable polymer.

[0034] The above 'organic acid' is a general term for organic compounds that are acidic. For example, organic acids may be, but are not limited to, lactic acid, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, carboxylic acid, propionic acid, glutaric acid, adipic acid, formic acid, toluic acid, or naphthoic acid.

[0035] More specifically, the organic acid may be, but is not limited to, lactic acid or 1-hydroxy-2-naphthoic acid.

[0036] In addition, the above ropivacaine anhydride, its hydrate or its solvate; and the organic acid may be included in the sustained-release microspheres at a mass ratio of 10:1 to 1:1, specifically at a mass ratio of 8:1 to 1:1, and most specifically at a mass ratio of 6:1 to 1:1, but is not limited thereto. The mass ratio may be changed as needed within a range where the formation of sustained-release microspheres and the release of each drug are appropriately controlled.

[0037] In one embodiment of the present invention, it was confirmed that the release rate was improved in both low-viscosity and high-viscosity biodegradable polymers when an organic acid was added (Fig. 13), and the release rate can be controlled by adding an organic acid.

[0038] Another aspect of the present invention relates to a sustained-release formulation comprising the above-described sustained-release microparticles.

[0039] The sustained-release formulation of the present invention exhibits an improved sustained-release profile for maintaining the sustained and effective analgesic and anti-inflammatory effects of ropivacaine and a non-steroidal anti-inflammatory agent, and is particularly characterized by simultaneous controlled release of different drugs.

[0040] Another aspect of the present invention relates to a pharmaceutical composition comprising the sustained-release formulation for pain suppression, prevention, or treatment. Specifically, the pharmaceutical composition may further comprise an anti-inflammatory agent.

[0041] In the present invention, the “pain” includes acute pain, chronic pain, breakthrough pain, and may include, without limitation, locally expressed pain or widely expressed pain.

[0042] In the present invention, the term “anti-inflammation” refers to suppressing the process of inflammation or the inflammation itself, and also includes suppressing or soothing pain caused by inflammation.

[0043] In the present invention, “prevention” means any action by which the composition of the present invention delays the onset of pain.

[0044] In the present invention, “treatment” means any action that causes the composition of the present invention to improve or benefit symptoms caused by pain.

[0045] Specifically, the pharmaceutical composition of the present invention may be a parenteral administration preparation, and more specifically, may be administered subcutaneously, intramuscularly, or by local infiltration.

[0046] The pharmaceutical composition of the present invention may include pharmaceutically acceptable additives such as thickeners, surfactants, isotonic agents, buffers, and pH regulators, within a range that does not impair the effects of the present invention.

[0047] In addition, the pharmaceutical composition of the present invention can be applied in a pharmaceutically effective amount, and the "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the patient's sex, age, type and severity of the disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.

[0048] In one embodiment of the present invention, it was confirmed that the release of ropivacaine and non-steroidal anti-inflammatory drugs was stably maintained over a long period of time, thereby maintaining the analgesic and anti-inflammatory effects for a long period of time (Figs. 18 to 21). In particular, the sustained-release microspheres of the present invention were confirmed to be able to maintain the release of each drug for a long period of time even when different types of drugs were encapsulated, thereby enabling sustained efficacy and improving medication compliance.

[0049] Another aspect of the present invention relates to a method for producing sustained-release microspheres, comprising the steps of: a) dissolving ropivacaine or a pharmaceutically acceptable salt thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer in a solvent to produce a mixed solution; and b) spray-drying the mixed solution to obtain microspheres.

[0050] Specifically, the non-steroidal anti-inflammatory agent may be one or more selected from the group consisting of ibuprofen, naproxen, ketorolac, and diclofenac, but is not limited thereto, and may be changed and applied as needed.

[0051] Also specifically, the biodegradable polymer may be at least one 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, but is not limited to, poly(lactide-co-glycolide) ((Poly(lactide-co-glycolide, PLGA).

[0052] Also, specifically, the intrinsic viscosity of the biodegradable polymer may be, but is not limited to, 0.1-1.0 dL / g. More specifically, it may have an intrinsic viscosity of, but is not limited to, 0.1-0.5 dL / g, or most specifically, an intrinsic viscosity in the range of 0.15-0.45 dL / g.

[0053] More specifically, the biodegradable polymer may include, but is not limited to, a low viscosity biodegradable polymer having an intrinsic viscosity of 0.1-0.25 dL / g, more specifically 0.16-0.24 dL / g, or a high viscosity biodegradable polymer having an intrinsic viscosity of 0.30-0.5 dL / g, more specifically 0.32-0.44 dL / g, or a mixture thereof. The intrinsic viscosity can be appropriately controlled by selecting a low viscosity biodegradable polymer, a high viscosity biodegradable polymer, and / or a mixture thereof to control the drug release of the sustained-release microspheres.

[0054] Specifically, in the step a), a volatile solvent capable of dissolving both the active ingredient and the biodegradable polymer may be used as the solvent, and more specifically, a volatile organic solvent such as dichloromethane, acetone, chloroform, methanol, ethanol, or a volatile organic acid such as acetic acid may be used, but is not limited thereto.

[0055] Additionally, specifically, an organic acid may be additionally mixed in step a). The organic acid may be, but is not limited to, lactic acid, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, carboxylic acid, propionic acid, glutaric acid, adipic acid, formic acid, toluic acid, or naphthoic acid.

[0056] The spray drying in step b) above can be performed by forming fine droplets, for example, using high-pressure gas or ultrasonic waves, and forming microspheres through drying using hot air. The nozzle type, nozzle temperature, spray flow rate, solution composition, and drying conditions can be changed and applied as needed.

[0057] The microspheres manufactured by the manufacturing method of the present invention may have an average particle size of 1 to 100 um, and specifically, an average particle size of 5 to 20 um. In addition, they may be stored at room temperature and may be reconstituted into a suspension-type preparation by adding a solvent before use (administration). The composition of the solvent may include pharmaceutically acceptable additives such as thickeners, surfactants, isotonic agents, buffers, and pH regulators, within a range that does not impair the effects of the present invention.

[0058] Specifically, in step a), ropivacaine may be mixed in an amount of 10 to 40% (w / w) of the sustained-release microspheres, but is not limited thereto. More specifically, it may be mixed in an amount of 10 to 40% (w / w), and most specifically, it may be mixed in an amount of 20 to 30% (w / w), but is not limited thereto. In particular, when included together with a non-steroidal anti-inflammatory drug in the sustained-release microspheres, the content of ropivacaine may be varied to control appropriate drug release.

[0059] Additionally, in step a), the non-steroidal anti-inflammatory agent may be mixed in an amount of 10 to 40% (w / w) of the sustained-release microspheres, but is not limited thereto. More specifically, it may be mixed in an amount of 10 to 40% (w / w), and most specifically, it may be mixed in an amount of 20 to 30% (w / w), but is not limited thereto. When included together with ropivacaine in the sustained-release microspheres, the content of the non-steroidal anti-inflammatory agent may be varied to control appropriate drug release.

[0060] In addition, in the step a), ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and the non-steroidal anti-inflammatory agent may be mixed in the sustained-release microspheres at a molar ratio of 1:0.5 to 1:2, specifically at a molar ratio of 1:0.5 to 1:1.5, and most specifically at a molar ratio of 1:0.5 to 1:1, but is not limited thereto. The molar ratio may be changed as needed within a range in which the formation of sustained-release microspheres and the release of each drug are appropriately controlled.

[0061] In addition, in the step a), ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and the biodegradable polymer may be mixed in a weight ratio of 1:1 to 1:20, specifically, in a weight ratio of 1:1 to 1:10, and most specifically, in a weight ratio of 1:1 to 1:5, but is limited thereto. The weight ratio may be changed as needed within a range in which the formation of sustained-release microspheres and the release of ropivacaine are appropriately controlled.

[0062] In addition, in the step a), the non-steroidal anti-inflammatory agent and the biodegradable polymer may be mixed in a weight ratio of 1:1 to 1:20, specifically in a weight ratio of 1:1 to 1:10, and most specifically in a weight ratio of 1:1 to 1:5, but is limited thereto. The weight ratio may be changed as needed within a range in which the formation of sustained-release microspheres and the release of the non-steroidal anti-inflammatory agent are appropriately controlled.

[0063] Also, specifically, in step a), the biodegradable polymer may be mixed in an amount of 1 to 10% (w / v) of the mixed solution, but is not limited thereto. More specifically, it may be mixed in an amount of 2 to 7% (w / v), and most specifically, it may be mixed in an amount of 3 to 6% (w / v), but is not limited thereto. Any concentration of the mixed solution capable of forming sustained-release microspheres may be changed and applied as needed.

[0064] Another aspect of the present invention relates to a method for producing sustained-release microspheres, comprising the steps of: a) dissolving ropivacaine salt-free, an organic acid, and a biodegradable polymer in a solvent to produce a mixed solution; and b) spray-drying the mixed solution to obtain microspheres.

[0065] It may be, but is not limited to, lactic acid, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, carboxylic acid, propionic acid, glutaric acid, adipic acid, formic acid, toluic acid or naphthoic acid.

[0066] More specifically, the organic acid may be, but is not limited to, lactic acid or 1-hydroxy-2-naphthoic acid.

[0067] In addition, the above ropivacaine anhydride, its hydrate or its solvate; and the organic acid may be included in the sustained-release microspheres at a mass ratio of 10:1 to 1:1, specifically at a mass ratio of 8:1 to 1:1, and most specifically at a mass ratio of 6:1 to 1:1, but is not limited thereto. The mass ratio may be changed as needed within a range where the formation of sustained-release microspheres and the release of each drug are appropriately controlled.

[0068] Another aspect of the present invention provides a method for alleviating or treating pain, comprising administering to a subject sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent, and a biodegradable polymer.

[0069] The sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or a solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer, and a method for preparing the same are as described above.

[0070] The pain may be, but is not limited to, traumatic pain such as fractures, sprains, or contusions, osteoarthritis pain, burn or thermal pain, post-surgical pain, neuralgia, post-extraction pain, or inflammatory pain.

[0071] Another aspect of the present invention provides a use of sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer for pain relief or treatment.

[0072] The sustained-release microspheres comprising ropivacaine, a salt thereof, a hydrate or a solvate thereof; a non-steroidal anti-inflammatory agent and a biodegradable polymer, and a method for preparing the same are as described above.

[0073] The pain may be, but is not limited to, traumatic pain such as fractures, sprains, or contusions, osteoarthritis pain, burn or thermal pain, post-surgical pain, neuralgia, post-extraction pain, or inflammatory pain.

[0074] The present invention provides a pharmaceutical composition for providing a sustained and effective analgesic effect of ropivacaine and a non-steroidal anti-inflammatory agent. The composition can be applied to any disease that exhibits a pain-controlling effect. In particular, the formulation of the present invention features an improved sustained-release profile of ropivacaine and a non-steroidal anti-inflammatory agent, as well as simultaneous controlled release of both drugs, thereby providing a sustained and effective analgesic effect and significantly increasing medication compliance.

[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 is performed in a single step.

[0076] Figure 1 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 1-1.

[0077] Figure 2 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 1-2.

[0078] Figure 3 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 2-1.

[0079] Figure 4 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 2-2.

[0080] Figure 5 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-1.

[0081] Figure 6 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-2.

[0082] Figure 7 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-3.

[0083] Figure 8 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-4.

[0084] Figure 9 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-5.

[0085] Figure 10 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-6.

[0086] Figure 11 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-7.

[0087] Figure 12 is a scanning electron microscope photograph showing the properties of microspheres manufactured in Example 3-8.

[0088] Figure 13 is data comparing the in vitro drug release profiles of ropivacaine of microspheres manufactured in Manufacturing Example 1 (Examples 1-1 and 1-2) and microspheres manufactured in Manufacturing Example 2 (Examples 2-1 and 2-2).

[0089] Figure 14 is data comparing the in vitro release drug profiles of ropivacaine of microspheres manufactured in Manufacturing Example 1 (Examples 1-1 and 1-2) and microspheres manufactured in Manufacturing Example 3 (Examples 3-1 to 3-4).

[0090] Figure 15 is data comparing the in vitro release drug profiles of ropivacaine of microspheres manufactured in Manufacturing Example 1 (Examples 1-1 and 1-2) and microspheres manufactured in Manufacturing Example 3 (Examples 3-5 to 3-8).

[0091] Figure 16 is data comparing the in vitro drug release profiles of ropivacaine and ketorolac of microspheres manufactured in Examples 3-5 and 3-6, respectively.

[0092] Figure 17 is data comparing the drug profiles of the in vitro release of ropivacaine and diclofenac from microspheres manufactured in Examples 3-7 and 3-8, respectively.

[0093] Figure 18 is data comparing the mechanical withdrawal response threshold for up to 168 hours after administration of microspheres (Examples 4-1 to 4-3) manufactured in Manufacturing Example 4 to an animal model of post-surgical pain.

[0094] Figure 19 is data showing the mechanical withdrawal response threshold for up to 48 hours after administration of microspheres (Examples 4-1 to 4-3) manufactured in Manufacturing Example 4 to an animal model of post-surgical pain.

[0095] Figure 20 is data comparing the change in the mechanical avoidance response threshold according to the administered dose of microspheres manufactured in Example 4-1.

[0096] Figure 21 is data comparing the change in the mechanical withdrawal response threshold according to the synergistic effect of the analgesic and anti-inflammatory action of microparticles manufactured in Examples 4-1 to 4-3.

[0097] Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are only illustrative of the present invention, and the present invention is not limited to the following examples.

[0098] Manufacturing Example 1. Manufacturing of microspheres containing ropivacaine

[0099] Ropivacaine base (Apothecon, India) and biodegradable polymer (Poly(D,L-lactide-co-glycolide), PLGA) were mixed according to the composition shown in Table 1 below, and dichloromethane was added as a solvent to completely dissolve them. As an example of a biodegradable polymer, poly(lactide-co-glycolide) was used as Resomer from Evonik, and low viscosity (intrinsic viscosity 0.16-0.24 dL / g) PLGA was used as Resomer. ® RG 502H, high viscosity (intrinsic viscosity 0.32-0.44 dL / g) PLGA is Resomer ® RG 503H was purchased and used, and the product information is as shown in Table 2 below.

[0100] Ingredients Example 1-1 Example 1-2 Ropivacaine base (g) 33 Low viscosity PLGA (g) 7 High viscosity PLGA (g) 7 Dichloromethane (mL) 140 140

[0101] IngredientsProduct NameComponentsIntrinsic Viscosity (dL / g)Low Viscosity PLGAResomer ® RG 502HPoly(D,L-lactide-co-glycolide) lactide : glycolide 50:500.16-0.24High viscosity PLGAResomer ® RG 503HPoly(D,L-lactide-co-glycolide) lactide : glycolide 50:500.32-0.44

[0102] The mixed solution shown in Table 1 above was spray-dried using a spray dryer (Mini Spray Dryer B-290, Buchi, Switzerland) according to the spray drying conditions shown in Table 3 below to produce sustained-release microspheres.

[0103] Nozzle type: Two-fluid nozzle, Ψ0.7 mm Atomization gas: High purity nitrogen gas Inlet temperature (℃) 50 Outlet temperature (℃) 37 Aspirator (%) 100 Flowmeter (L / h) 357 Feed flow (mL / min) 6

[0104] Manufacturing Example 2. Manufacturing of microspheres containing ropivacaine and organic acid

[0105] Ropivacaine was mixed with ropivacaine base (Apothecon, India), organic acid, and biodegradable polymer (Poly(D,L-lactide-co-glycolide), PLGA) according to the composition shown in Table 4 below, and then dichloromethane was added as a solvent and completely dissolved.

[0106] Lactic acid (Sigma Aldrich, USA) or 1-hydroxy-2-naphthoic acid (Sigma Aldrich, USA) were used as examples of organic acids.

[0107] As an example of a biodegradable polymer, poly(lactide-co-glycolide) was used as Resomer from Evonik, and low viscosity (intrinsic viscosity 0.16-0.24 dL / g) PLGA was used as Resomer. ® RG 502H, high viscosity (intrinsic viscosity 0.32-0.44 dL / g) PLGA is Resomer ® RG 503H was purchased and used, and the product information is as shown in Table 2 above.

[0108] Ingredients Example 2-1 Example 2-2 Ropivacaine salt-free (g) 33 Lactic acid (g) 0.98 5 1-hydroxy-2-naphthoic acid (g) -2.17 8 Low viscosity PLGA (g) 77 Dichloromethane (mL) 140 140

[0109] The mixed solution shown in Table 4 above was spray-dried using a spray dryer (Mini Spray Dryer B-290, Buchi, Switzerland) according to the spray drying conditions shown in Table 3 above to produce sustained-release microspheres.

[0110] Manufacturing Example 3. Manufacturing of microspheres containing ropivacaine and non-steroidal anti-inflammatory drugs (NSAIDs)

[0111] Ropivacaine base (Apothecon, India), non-steroidal anti-inflammatory drugs (NSAIDs), and biodegradable polymer (Poly(D,L-lactide-co-glycolide), PLGA) were mixed according to the composition shown in Table 5 below, and dichloromethane was added as a solvent and completely dissolved.

[0112] As examples of non-steroidal anti-inflammatory drugs, ibuprofen base (Ibuprofen base, Baden Aniline and Soda Factory, Germany), naproxen base (Naproxen base, Zhejiang Charioteer Pharmaceutical, China), Ketorolac Tromethamine (Tokyo Chemical Industry, Japan), and Diclofenac sodium (Diclofenac sodium, Amoli Organics, India) were used. Ketorolac Tromethamine and Diclofenac sodium were converted into Ketorolac base and Diclofenac base, respectively, through a salt conversion process.

[0113] As an example of a biodegradable polymer, poly(lactide-co-glycolide) was used as Resomer from Evonik, and low viscosity (intrinsic viscosity 0.16-0.24 dL / g) PLGA was used as Resomer. ® RG 502H, high viscosity (intrinsic viscosity 0.32-0.44 dL / g) PLGA is Resomer ® RG 503H was purchased and used, and the product information is as shown in Table 2 above.

[0114] IngredientsExample 3-1Example 3-2Example 3-3Example 3-4Example 3-5Example 3-6Example 3-7Example 3-8Ropivacaine salt-free (g)33333333Ibuprofen salt-free (g)2.255Naproxen salt-free (g)2.5172.5171.259Ketorolac salt-free (g)2.7912.791Diclofenac salt-free (g)3.2383.238Low viscosity PLGA (g)7777High viscosity PLGA (g)7777Dichloromethane (mL)140140140140140140140140140

[0115] The mixed solution shown in Table 5 above was spray-dried using a spray dryer (Mini Spray Dryer B-290, Buchi, Switzerland) according to the spray drying conditions shown in Table 3 above to produce sustained-release microspheres.

[0116] Manufacturing Example 4. Manufacturing of a freeze-dried composition for parenteral administration

[0117] The microspheres manufactured in Examples 1-1, 3-7 and 3-8 were prepared as suspensions according to the composition shown in Table 6 below, and then placed in vials for freeze-drying. The suspensions were freeze-dried using freeze-drying equipment (25L Genesis SQ EL-85°, SP Scientific, USA) according to the conditions shown in Table 7 below to prepare freeze-dried compositions for parenteral administration.

[0118] Ingredients Example 4-1 Example 4-2 Example 4-3 Example 1-1 (mg) 500 Example 3-7 (mg) 500 Example 3-8 (mg) 500 Mannitol (mg) 224 224 224 Sodium carboxymethyl cellulose (Sodium carboxymethyl cellulose) 454 545 Polysorbate 80 (polysorbate 80) 222 Water for injection (mg) 430 9430 94309

[0119] Freezing shelf temperature (℃) -45 Holding time (min) 180 Freezing / decompression shelf temperature (℃) -45 Holding time (min) 30 Condenser temperature (℃) -55 Initial shelf pressure (mTorr) 800 Drying stage 12345 Shelf temperature (℃) -45 -40 -100 20 Arrival time (min) 0 30 60 60 60 Holding time (min) 30 360 1440 360 360 Shelf pressure (mTorr) 200 100 100 100 100 Storage shelf temperature (℃) 20 Shelf pressure (mTorr) 200

[0120] Experimental Example 1. Evaluation of particle size of manufactured microspheres

[0121] To evaluate the particle size of the microspheres manufactured in Manufacturing Examples 1, 2, and 3, the average particle size was measured using a particle size analyzer (Mastersizer 3000, Malvern panalytical, UK) according to the conditions in Table 8 below.

[0122] Dispersion solvent water stirring RPM2800 shielding degree (%)20 particles refractive index1.52 measurement time (sec)10 number of measurements (times)3

[0123] The results of particle size evaluation of the microspheres are shown in Table 9 below. As a result of particle size evaluation, it was confirmed that the particle size of the microspheres varied depending on the type of organic acid added, the type of non-steroidal anti-inflammatory drug added, the amount of non-steroidal anti-inflammatory drug added, and the type of biodegradable polymer.

[0124] Example 1-1 Example 1-2 Example 2-1 Example 2-2 Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 3-5 Example 3-6 Example 3-7 Example 3-8 D [4,3] 20.0 2 2 8 2 1 0 1 3 6 2 7 3 0 4 2 5 4 3 7 4 1 9 1 1 6 5 9 9 5 6 Span 2 4 6 2 9 2 1 2 5 2 3 6 5 1 9 2 2 0 6 2 4 0 1 9 0 2 1 1 9 8 2 0 4 D 1 0 2 1 6 1 6 4 3 6 9 1 4 6 8 7 7 7.654.904.814.043.031.651.35D5016.516.518.49.1038.626.421.931.01 7.114.28.948.63D9042.850.942.724.415058.250.079.436.432.919.419.0

[0125] Experimental Example 2. Characteristic Evaluation

[0126] To evaluate the properties of the microspheres manufactured in Manufacturing Examples 1, 2, and 3, a scanning electron microscope (TM4000Plus, Hitachi, Japan) was used to evaluate the properties according to the conditions in Table 10 below.

[0127] Accelerating voltage (kV) 10 Magnification 2000

[0128] The results of the property evaluation of the microspheres are shown in Figures 1 to 12. The property evaluation results confirmed that all of the microspheres exhibited a spherical shape with a smooth surface regardless of the type of organic acid added, the type of non-steroidal anti-inflammatory drug added, the amount of non-steroidal anti-inflammatory drug added, and the type of biodegradable polymer.

[0129] Experimental Example 3. In vitro drug release evaluation

[0130] To evaluate the drug release of the microspheres manufactured in Manufacturing Examples 1, 2, and 3, an in vitro drug release evaluation was conducted under bio-like conditions. Microspheres corresponding to 3 mg of ropivacaine were placed in 120 mL glass vials, and the drug release evaluation was performed in a shaking water bath according to the conditions in Table 11. The concentrations of ropivacaine, ketorolac, and diclofenac in the released solution were analyzed by HPLC-UV.

[0131] Apparatusshaking water bath with 120mL Glass vialMedium 100mL, pH 7.4PBS with 0.02% polysorbate 20Temperature (℃)37Shaking RPM100

[0132] The results of the in vitro drug release evaluation of the microspheres are shown in Figures 13 to 17. The results of the in vitro drug release evaluation confirmed that the drug release rate of ropivacaine varied depending on the type of added organic acid, the type of added non-steroidal anti-inflammatory drug, the amount of the non-steroidal anti-inflammatory drug, and the type of biodegradable polymer.

[0133] Specifically, as shown in Fig. 13, in the case of Examples 2-1 and 2-2 containing organic acids, the release rate (%) of ropivacaine was higher than in Examples 1-1 and 1-2 not containing organic acids, and in the case of containing organic acids, the release rate of ropivacaine was found to reach approximately 100% after 72 hours. In particular, in terms of drug release after 72 hours, it was confirmed that in the case of containing organic acids, both low-viscosity and high-viscosity biodegradable polymers exhibited high release rates.

[0134] In addition, as shown in FIGS. 14 and 15, it was confirmed that in the presence of a biodegradable polymer of the same viscosity, even if a non-steroidal anti-inflammatory drug is included, the release rate of ropivacaine is not reduced compared to Example 1-1 or Example 1-2, which contains only ropivacaine. Through this, it was confirmed that the sustained-release microspheres of the present invention can be applied as a composite form of ropivacaine and a non-steroidal anti-inflammatory drug, since the release rate of ropivacaine itself is not inhibited even if the release rate of ropivacaine is somewhat changed depending on the type and content of the non-steroidal anti-inflammatory drug.

[0135] In addition, as shown in FIGS. 16 and 17, although the release rate differs somewhat depending on whether low-viscosity and high-viscosity biodegradable polymers are mixed, it was confirmed that the release rates of ropivacaine and non-steroidal anti-inflammatory drugs were each maintained excellently.

[0136] In addition, it was confirmed that the drug release of non-steroidal anti-inflammatory drugs (ketorolac, diclofenac) from the microspheres of Examples 3-5 to 3-8 showed the same drug release profile as that of ropivacaine, and the same drug release rate as that of ropivacaine.

[0137] Experimental Example 4. Evaluation of analgesic effects in an animal model of postoperative pain.

[0138] To evaluate the analgesic effect of the lyophilized composition for parenteral administration manufactured in Manufacturing Example 4, an analgesic effect evaluation was conducted in an animal model of post-surgical pain.

[0139] Nine-week-old male SD rats weighing approximately 300 g that had been acclimated for 7 days were used as test animals. After the test animals were anesthetized, the left hind foot pad was disinfected. Using a scalpel blade No. 11, a longitudinal incision of approximately 1 cm was made approximately 0.5 cm from the tarsal joint on the heel side. The plantaris muscle was elevated and a longitudinal incision of approximately 0.7 cm was made to control bleeding. The wound tissue was closed horizontally twice using Nylon 5-0, and a single dose of the drug was administered near the sciatic nerve.

[0140] For the administered drug, the lyophilized composition for parenteral administration prepared in Manufacturing Example 4 was reconstituted in water for injection and used as a test group. Physiological saline was used as a negative control, and Naropin was used as a positive control. ® (Ropivacaine HCl solution) and Exparel ® (Bupivacaine liposome suspension) were used respectively. The composition of the test groups and administration conditions are shown in Table 12 below.

[0141] Test group, sex, number of animals (animals), test substance, injection site, ropivacaine or bupivacaine, dose (mg / kg), G1M6, physiological saline, near the sciatic nerve - G2M6, Naropin ® Ropivacaine, 5 mg / kg near the sciatic nerve G3M6Exparel ®Bupivacaine, 8.87 mg / kg G4M6, Example 4-1, near the sciatic nerve, Ropivacaine, 20 mg / kg G5M6, Example 4-1, near the sciatic nerve, Ropivacaine, 40 mg / kg G6M6, Example 4-1, near the sciatic nerve, Ropivacaine, 60 mg / kg G7M6, Example 4-2, near the sciatic nerve, Ropivacaine, 20 mg / kg G8M6, Example 4-3, near the sciatic nerve, Ropivacaine, 20 mg / kg

[0142] The analgesic effect was evaluated by measuring the mechanical withdrawal threshold of the central area of ​​the sole where the surgery was performed using a dynamic plantar aesthesiometer (Ugo basile, Italy). The mechanical withdrawal threshold was measured before surgery (Baseline) and 1, 3, 5, 8, 24, 48, 72, 96, 120, and 168 hours after drug administration. Repeated measures analysis of variance and multivariate analysis were performed to evaluate the analgesic effect according to the type and time of the administered drug. The results of the measurement of the mechanical withdrawal threshold in the postoperative pain animal model are shown in Figures 18 to 21 and Table 13 below.

[0143] Mean±SDG1G2G3G4G5G6G7G80 h(before surgery)40.3±6.939.7±5.937.9±8.138.2±7.640.1±4.340.9±6.537.8±6.837.5±4.11 h16.6±4.824.4±8.627.9±4.221.3±3.722.7±5.130.7±4.8 ** 26.2±3.624±2.73 h20±1.525.6±6.630.5±3.324.8±5.426.3±7.133.4±9.1 *32.9±4.328.5±3.95 h19.7±2.126.4±4.928.7±6.626.5±5.828.7±4.436.6±6.7 ** 39.6±4.3 ** 43.1±3.8 ** 8 h22.1±1.630.5±7.130.9±3.429.4±3.834.2±2.9 ** 37.8±5.9 ** 39.3±6.4 ** 45.6±1.5 ** 24 h30.8±5.330.5±5.831.2±3.932.1±6.535.5±2.337.6±7.337.8±4.440.8±2.848 h30.1±2.433.5±431.2±2.931.2±3.234.1±2.635.3±636.8±3.239.7±3.2 * 72 h30.8±4.234.7±3.634.7±2.431.8±4.230.7±2.133.4±536.8±2.139.2±3.4 * 96 h30±5.433.2±3.933±431.7±4.931.4±2.433.9±3.836.3±1.738.7±2.2120 h30.4±5.335.2±2.932.3±2.931.6±4.932.5±334.4±2.836.9±0.837.6±2.1168 h30.1±3.532.1±1.130.8±2.630.3±4.633.7±333.5±3.635.8±1.135.2±2.2*p < 0.05 vs G1 **p < 0.01 vs G1

[0144] As a result, the mechanical avoidance threshold significantly decreased before and after surgery (0 h vs 1 h), and as the surgical site recovered over the following week, the mechanical avoidance threshold gradually increased. Both the positive control group (G2 and G3) and the test groups (G4 to G8) showed higher mechanical avoidance thresholds than the negative control group (G1). In addition, in the test groups G4, G5, and G6, the mechanical avoidance threshold showed a dose dependence in which the drug dose of ropivacaine increased (20 mg / kg to 60 mg / kg). In particular, in the test groups G7 and G8, higher mechanical avoidance thresholds were shown compared to the test group G4 even though the dose of ropivacaine was the same (20 mg / kg). This is likely due to the synergistic effect of the analgesic and anti-inflammatory effect of diclofenac contained in the microspheres.

[0145] The Scheffe method for post-hoc comparison showed that the test groups G6, G7, and G8 had a significant analgesic effect compared to the negative control group (G1).

[0146] These results demonstrate that the sustained-release microspheres of the present invention can maintain the analgesic and anti-inflammatory effects for a long period of time because the release of ropivacaine and non-steroidal anti-inflammatory drugs is stably maintained for a long period of time. Conventional sustained-release microspheres, when multiple active ingredients are combined or complexed inside, can cause problems such as an inconsistent drug release rate or an inability to maintain the drug release for a long period of time due to interference between drugs, which affects the properties of the microspheres. However, the sustained-release microspheres of the present invention overcome the limitations of the past, and can improve medication compliance when utilizing sustained-release microspheres in the form of drug combinations or complexes.

[0147] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics 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 entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0148] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. Ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; Extended-release microspheres comprising nonsteroidal antiinflammatory drugs (NSAIDs) and biodegradable polymers.

2. In the first paragraph, the ropivacaine is a ropivacaine base, a sustained-release microsphere.

3. In the first paragraph, the sustained-release microspheres, wherein the non-steroidal anti-inflammatory agent is at least one selected from the group consisting of ibuprofen, naproxen, ketorolac, and diclofenac.

4. In the first paragraph, the biodegradable polymer is at least one selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof, a sustained-release microsphere.

5. In the first paragraph, the intrinsic viscosity of the biodegradable polymer is 0.1-1.0 dL / g, the western-type microspheres.

6. In the first paragraph, the biodegradable polymer comprises a low viscosity biodegradable polymer having an intrinsic viscosity of 0.1-0.25 dL / g, a high viscosity biodegradable polymer having an intrinsic viscosity of 0.30-0.5 dL / g, or a mixture thereof, a sustained-release microsphere.

7. In the first paragraph, the sustained-release microspheres, wherein the ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof is contained in an amount of 10 to 40% (w / w) of the sustained-release microspheres.

8. In the first paragraph, the non-steroidal anti-inflammatory agent is contained in 10 to 40% (w / w) of the sustained-release microspheres.

9. A sustained-release microsphere in accordance with claim 1, wherein the ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and the non-steroidal anti-inflammatory agent are contained in a molar ratio of 1:0.5 to 1:

2.

10. A sustained-release microsphere according to claim 1, wherein the ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and the biodegradable polymer are included in a weight ratio of 1:1 to 1:

20.

11. In the first paragraph, the non-steroidal anti-inflammatory agent and the biodegradable polymer are included in a weight ratio of 1:1 to 1:20, wherein the sustained-release microspheres.

12. In paragraph 1, The above-mentioned western-type microspheres comprise ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; A sustained-release microsphere prepared by dissolving a non-steroidal anti-inflammatory drug and a biodegradable polymer in a solvent and then spray-drying the same.

13. In paragraph 1, Sustained-release microspheres, wherein the biodegradable polymer is included in an amount of 1 to 10% (w / v) of the mixed solution in the manufacturing step of sustained-release microspheres through spray drying.

14. Sustained-release microspheres comprising ropivacaine base, a hydrate thereof or a solvate thereof; an organic acid; and a biodegradable polymer.

15. In the 14th paragraph, the organic acid is lactic acid or 1-hydroxy-2-naphthoic acid, a sustained-release microsphere.

16. In claim 14, sustained-release microspheres comprising the ropivacaine salt, a hydrate thereof, or a solvate thereof; and the organic acid in a mass ratio of 10:1 to 1:

1.

17. A sustained-release preparation comprising the sustained-release microspheres of paragraph 1.

18. A pharmaceutical composition for suppressing, preventing or treating pain, comprising the sustained-release formulation of Article 17.

19. A pharmaceutical composition according to claim 18, further comprising an anti-inflammatory agent. 20.a) A step of preparing a mixed solution by dissolving ropivacaine or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; a non-steroidal anti-inflammatory agent; and a biodegradable polymer in a solvent; and b) A method for producing western-type microspheres, comprising the step of spray-drying the above mixed solution to obtain microspheres.

21. A method for manufacturing sustained-release microspheres in claim 20, wherein the non-steroidal anti-inflammatory agent is at least one selected from the group consisting of ibuprofen, naproxen, ketorolac, and diclofenac.

22. A method for producing sustained-release microspheres in claim 20, wherein the biodegradable polymer is at least one selected from the group consisting of poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polylactide, polyglycolide, polycaprolactone, and mixtures thereof.

23. A method for producing a sustained-release microsphere in claim 20, wherein the intrinsic viscosity of the biodegradable polymer is 0.1-0.5 dL / g.

24. A method for producing sustained-release microspheres in claim 20, wherein the biodegradable polymer comprises a low-viscosity biodegradable polymer having an intrinsic viscosity of 0.1-0.25 dL / g, a high-viscosity biodegradable polymer having an intrinsic viscosity of 0.30-0.5 dL / g, or a mixture thereof. 25.a) Ropivacaine base, its hydrate or its solvate; A step of preparing a mixed solution by dissolving an organic acid and a biodegradable polymer in a solvent; and b) A method for producing western-type microspheres, comprising the step of spray-drying the above mixed solution to obtain microspheres.

26. A method for producing sustained-release microspheres in claim 25, wherein the organic acid is lactic acid or 1-hydroxy-2-naphthoic acid.

27. A method for producing sustained-release microspheres, wherein the ropivacaine salt, a hydrate thereof, or a solvate thereof in claim 25, and the organic acid are included in a mass ratio of 10:1 to 1:

1.

28. A method for alleviating or treating pain, comprising administering to a subject a composition comprising the western-type microspheres of any one of claims 1 to 16.

29. Pain relief or therapeutic use of a composition comprising the western-type microspheres of any one of claims 1 to 16.

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