Microparticles comprising tirzepatide or pharmaceutically acceptable salt thereof, and manufacturing method therefor

Abstract

The present invention relates to microparticles comprising tirzepatide or a pharmaceutically acceptable salt thereof and a manufacturing method therefor, wherein the content of tirzepatide or a pharmaceutically acceptable salt thereof is increased in the microparticles, thereby increasing the loading amount of a drug in the microparticles and exhibiting an effect of continuously releasing tirzepatide or a pharmaceutically acceptable salt thereof from the microparticles without initial over-release and lag time, thus preventing an excessive decrease in bioavailability. In addition, when the microparticles are used as a subcutaneous injection, the amount of microparticles included for one injection can be reduced, thereby reducing pain at the site of administration and causing no inflammatory response.

Description

Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof and a method for producing the same

[0001] The present invention relates to microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof and a method for producing the same.

[0002] Recent economic development and changes in eating habits have led to a sharp increase in the incidence of metabolic syndrome, a complex group of conditions that includes obesity, hyperlipidemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, and liver disease. While these conditions can occur independently, they are often closely interrelated and often present with multiple symptoms.

[0003] Overweight and obesity increase blood pressure and cholesterol levels, contributing to the development or worsening of various diseases such as heart disease, diabetes, and arthritis. Furthermore, overweight and obesity are major factors in increasing the incidence of arteriosclerosis, hypertension, hyperlipidemia, and heart disease not only in adults but also in children and adolescents.

[0004] Obesity is a complex disease involving the mechanisms of appetite control and energy metabolism. Therefore, methods to treat abnormal mechanisms related to appetite control and energy metabolism must be performed simultaneously. Therefore, efforts are ongoing to develop drugs that can treat the above abnormal mechanisms. As a result of the above efforts, obesity treatments such as rimonabant (Sanofi-Aventis), sibutramine (Abbott), Contrave (Takeda), and orlistat (Roche) have been developed. However, these drugs have the disadvantage of causing fatal side effects or having minimal effects in treating obesity. For example, rimonabant causes central nervous system disorders, sibutramine and Contrave cause cardiovascular side effects, and orlistat has been reported to only show an effect of about 4 kg of weight loss per year of use.

[0005] Meanwhile, metabolic syndrome, including obesity, increases the risk of developing liver diseases. Examples include metabolic liver disease, fatty liver disease, non-alcoholic fatty liver disease, steatohepatitis, and liver fibrosis. These liver diseases are on the rise alongside the rise in the obesity and diabetes populations, with an annual incidence rate of approximately 16% in Korea. Because liver disease often has no symptoms in its early stages and is often detected only at an advanced stage, it is a leading cause of death both domestically and internationally, highlighting the critical need for drug development.

[0006] For the treatment of obesity, glucagon-like peptide-1 (GLP-1) is a hormone secreted by the small intestine in response to food intake. It stimulates insulin secretion from the pancreas in a blood sugar concentration-dependent manner and suppresses glucagon secretion, thereby helping to lower blood sugar levels. It also acts as a satiety factor, slowing gastric digestion and delaying the passage of food through the stomach, thereby reducing food intake.

[0007] GIP, one of the gastrointestinal hormones secreted in response to food intake along with GLP-1, is a hormone composed of 42 amino acids secreted from K cells in the small intestine. It performs the function of promoting insulin secretion from the pancreas in a blood sugar concentration-dependent manner and helping to lower blood sugar levels. It has been reported to have effects such as increasing GLP-1 activity, anti-inflammatory effects, and improving lipid metabolism.

[0008] Accordingly, active research is underway to develop GLP-1 as a treatment for diabetes and obesity, leveraging its glycemic control and weight-loss effects. However, GLP-1 alone only reduces HbA1c by 0.5% to 1.8%, making it suitable for patients with HbA1c levels below 9% (Ther Adv Endocrinol Metab. 2015 Feb; 6(1): 3-18). In other words, the expected glycemic control achieved with GLP-1 monotherapy is limited.

[0009] Accordingly, research has been conducted on dual agonists capable of simultaneous activation of GLP-1 and GIP receptors. Tirzepatide, sold under the brand name Mounjaro, is a representative product of this dual agonist and is an antidiabetic drug used to treat type 2 diabetes. Tirzepatide is administered once a week via subcutaneous injection.

[0010] As described above, the above-mentioned terzepatide has the inconvenience of having to be administered once a week via subcutaneous injection. To solve this problem, it is necessary to develop an injection that can exert the pharmacological effect of terzepatide for more than one month with a single injection.

[0011] [Prior Art Literature]

[0012] [Patent Document]

[0013] (Patent Document 1) KR 10-2021-0110349 A1

[0014] The purpose of the present invention is to provide microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof and a method for producing the same.

[0015] Another object of the present invention is to provide microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof, which can increase the loading amount of the drug in the microparticles by increasing the content of terzepatide or a pharmaceutically acceptable salt thereof in the microparticles, and exhibit a continuous release effect of terzepatide or a pharmaceutically acceptable salt thereof from the microparticles without initial over-release and lag time, thereby preventing excessive decrease in bioavailability, and a method for preparing the same.

[0016] Another object of the present invention is to provide a microparticle comprising terzepatide or a pharmaceutically acceptable salt thereof, which is an injectable preparation for use as a subcutaneous injection, and which can reduce the amount of microparticles included in the injectable preparation for a single injection, thereby reducing pain at the site of administration and causing no inflammatory reaction, and a method for producing the same.

[0017] To achieve the above-described purpose, the present invention comprises terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, wherein the biodegradable polymer may be a microparticle comprising terzepatide or a pharmaceutically acceptable salt thereof, which comprises polylactide-co-glycolide (PLGA).

[0018] In addition, the microparticles have pore sizes controlled on the surface and inside, so that when the microparticles are injected into the body, the initial over-release of terzepatide or a pharmaceutically acceptable salt thereof can be suppressed.

[0019] In addition, the internal pores of the cross-section of the above microparticles are distributed in a uniform size in the SEM image with a magnification of x2.0k, thereby forming a dense tissue structure.

[0020] Additionally, the surface of the microparticles can be smoothed by removing pores in an SEM image with a magnification of x2.0k.

[0021] Additionally, the polylactide-co-glycolide (PLGA) may have an intrinsic viscosity of 0.2 dl / g or less, and a molar ratio of lactide to glycolide of 50:50.

[0022] Additionally, the above-mentioned terzepatide or a pharmaceutically acceptable salt thereof may be included in an amount of 10 wt% or more based on the total weight of the microparticles.

[0023] Additionally, the microparticles may have an average diameter of 30 to 70 μm.

[0024] Another aspect of the present invention for achieving the above-described purpose may be a sustained-release injection composition comprising terzepatide or a pharmaceutically acceptable salt thereof including the microparticles.

[0025] In addition, the above injection composition can continuously release terzepatide or a pharmaceutically acceptable salt thereof in the body for more than one month with a single injection.

[0026] Another aspect of the present invention for achieving the above-described object may be a method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof, comprising the steps of: dissolving terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent to prepare an oily solution; mixing a surfactant and water to prepare an aqueous solution; forming an emulsion comprising terzepatide or a pharmaceutically acceptable salt thereof using the oily solution and the aqueous solution; and collecting and hardening the formed emulsion comprising terzepatide or a pharmaceutically acceptable salt thereof to prepare microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof, wherein the aqueous solution may further include a property-improving agent.

[0027] Additionally, the above-mentioned water solution may be mixed with a phase-improving agent to have a concentration of 0.1 to 10 (w / v)%.

[0028] In addition, the step of forming an emulsion containing terzepatide or a pharmaceutically acceptable salt thereof using the oily solution and the aqueous solution may be performed by injecting the oily solution and the aqueous solution into each channel using a microfluidic method, and forming an emulsion at an intersection where the flows of the oily solution and the aqueous solution come into contact with each other.

[0029] Additionally, the organic solvent may be selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, dimethyl sulfoxide, and mixtures thereof.

[0030] Additionally, the oily solution may contain terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:3 to 1:15.

[0031] The present invention increases the content of terzepatide or a pharmaceutically acceptable salt thereof in microparticles, thereby increasing the loading amount of the drug in the microparticles, and exhibits a continuous release effect of terzepatide or a pharmaceutically acceptable salt thereof from the microparticles without initial over-release and lag time, thereby preventing excessive decrease in bioavailability.

[0032] Additionally, when used as a subcutaneous injection, the amount of microparticles included in a single injection can be reduced, thereby reducing pain at the injection site and preventing inflammatory reactions.

[0033] Figure 1 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0034] Figure 2 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0035] Figure 3 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0036] Figure 4 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0037] Figure 5 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0038] Figure 6 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0039] Figure 7 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0040] FIG. 8 is a SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0041] FIG. 9 is a SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0042] FIG. 10 is a SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0043] FIG. 11 is a SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0044] FIG. 12 is an SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0045] FIG. 13 is an SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0046] FIG. 14 is an SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0047] FIG. 15 is an SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0048] FIG. 16 is a SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0049] FIG. 17 is an SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0050] FIG. 18 is a SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0051] FIG. 19 is an SEM image of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0052] Figure 20 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0053] Figure 21 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0054] Figure 22 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0055] Figure 23 shows the results of a pharmacokinetic experiment using microparticles containing terzepatide or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention.

[0056] The present invention relates to microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, wherein the biodegradable polymer comprises polylactide-co-glycolide (PLGA).

[0057] Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement them. However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein.

[0058] Obesity is one of the most common nutritional disorders worldwide. According to WHO statistics, approximately 250 million people are currently classified as obese, and it is predicted that approximately 300 million people will suffer from obesity in 20 years.

[0059] The above obesity refers to a state in which body fat is excessively accumulated due to an imbalance in calorie metabolism caused by excessive energy intake or decreased energy expenditure. Recently, the incidence of obesity has been rapidly increasing due to modern people's Western-style eating patterns and lack of exercise.

[0060] Additionally, in terms of numerical concepts, obesity is defined as a BMI (body mass index) of 25 or higher, and the BMI measurement method is an obesity measurement method that estimates the amount of body fat by dividing the weight (kg) by the square of the height (㎡).

[0061] Trizepatide, sold under the brand name Maunzaro, has shown in clinical trials that an average of 18% body weight loss was achieved at the highest dose. Terzepatide is a dual-action gastric inhibitory peptide (GIP) / glucagon-like peptide-1 (GLP-1) therapy. GLP-1 stimulates insulin secretion, reducing appetite and increasing satiety, while GIP can break down fat cells and reduce nausea.

[0062] Additionally, recent clinical trials have proven that it is effective in treating heart failure, reducing the risk of severe conditions such as cardiovascular death by 38%. It is effective not only in weight loss but also in improving symptoms such as heart disease, which can lead to serious health risks.

[0063] However, the side effects of terzepatide are similar to those of semaglutide. Patients may experience gastrointestinal symptoms such as nausea and diarrhea. Similar to semaglutide, terzepatide is administered by subcutaneous injection once a week.

[0064] To address the above issues, ongoing efforts are underway to achieve sustained efficacy for more than a month through a single subcutaneous injection of terzepatide or its pharmaceutically acceptable salt. Accordingly, development is underway to develop a sustained-release formulation using a biodegradable polymer.

[0065] The formulation for sustained release of terzepatide or a pharmaceutically acceptable salt thereof using the above biodegradable polymer may be a microparticle containing the above terzepatide or a pharmaceutically acceptable salt thereof.

[0066] The above microparticles include a biodegradable polymer and terzepatide or a pharmaceutically acceptable salt thereof, and when the microparticles are injected into the body, the microparticles are gradually decomposed in the body and can release terzepatide or a pharmaceutically acceptable salt thereof.

[0067] Typically, microparticles are broken down in the body over a period of one month or more, thereby releasing terzepatide or a pharmaceutically acceptable salt thereof, which may result in weight loss or improvement of symptoms such as heart disease.

[0068] However, these microparticles are difficult to produce with a uniform particle size when manufacturing the microparticles, so it may be difficult to continuously release them for one month.

[0069] Additionally, there may be a problem of over-release of terzepatide or its pharmaceutically acceptable salt during the initial injection.

[0070] In addition, since the encapsulation rate of terzepatide or its pharmaceutically acceptable salt in the microparticles is low or the weight ratio with the biodegradable polymer is small, a large amount of microparticles must be injected at a time, which causes pain during injection or causes inflammation at the injection site.

[0071] To prevent such problems, the present invention comprises terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, wherein the biodegradable polymer may be a microparticle comprising terzepatide or a pharmaceutically acceptable salt thereof, which comprises polylactide-co-glycolide (PLGA).

[0072] The microparticles of the present invention are intended to be provided as a sustained-release formulation comprising terzepatide or a pharmaceutically acceptable salt thereof, as described above.

[0073] Additionally, the microparticles include a biodegradable polymer, and the biodegradable polymer may include polylactide-co-glycolide (PLGA).

[0074] More specifically, the polylactide-co-glycolide (PLGA) may have an intrinsic viscosity of 0.2 dl / g or less, and a molar ratio of lactide to glycolide of 50:50.

[0075] Microparticles containing polylactide-co-glycolide (PLGA) as described above can exhibit a drug release effect of terzepatide or a pharmaceutically acceptable salt thereof continuously for more than one month by gradually increasing drug release from the beginning without a lag time.

[0076] Accordingly, the microparticles of the present invention may include polylactide-co-glycolide (PLGA), which is a biodegradable polymer and has an intrinsic viscosity of 0.2 dl / g or less and a molar ratio of lactide to glycolide of 50:50.

[0077] Additionally, the microparticles of the present invention may contain one or more types of biodegradable polymers.

[0078] When one type of the above biodegradable polymer is included, it means that only polylactide-co-glycolide (PLGA) having an intrinsic viscosity of 0.2 dl / g or less and a molar ratio of lactide to glycolide of 50:50 is included, and when two or more types are included, it may mean that polylactide-co-glycolide (PLGA) having an intrinsic viscosity of 0.2 dl / g or less and a molar ratio of lactide to glycolide of 50:50 is necessarily included.

[0079] Accordingly, when two or more biodegradable polymers are included, in addition to polylactide-co-glycolide (PLGA) having an inherent viscosity of 0.2 dl / g or less and a molar ratio of lactide to glycolide of 50:50, polylactide-co-glycolide (PLGA) having a molar ratio of lactide to glycolide of 75:25, polylactide-co-glycolide (PLGA) having a molar ratio of lactide to glycolide of 65:35, etc., may be additionally included, and in addition to the polylactide-co-glycolide (PLGA), a biodegradable polymer selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and mixtures thereof may be additionally included.

[0080] However, when producing microparticles including polylactide-co-glycolide (PLGA) having an intrinsic viscosity of 0.2 dl / g or less and a molar ratio of lactide to glycolide of 50:50, the microparticles exhibit drug release from the beginning without a lag time as described above, but initial over-release may be a problem.

[0081] In addition, the microparticles of the present invention may contain terzepatide or a pharmaceutically acceptable salt thereof in an amount of 10 wt% or more, 11 wt% or more, 12 wt% or more, 13 wt% or more, 14 wt% or more, 15 wt% or more, or 16 wt% or more, based on the total weight of the microparticles. As described above, by including terzepatide or a pharmaceutically acceptable salt thereof in the microparticles within the above-described range, the content of the drug can be increased, thereby reducing the amount of microparticles administered through a single injection. Increasing the content of terzepatide or a pharmaceutically acceptable salt thereof in the microparticles as described above can exhibit the above-described effects, but, as with the biodegradable polymer, can become a factor inducing initial over-release.

[0082] That is, as described above, the conventional sustained-release formulation containing terzepatide or a pharmaceutically acceptable salt thereof has a problem in that the initial effect of injection is not achieved due to a delay time when a biodegradable polymer is selected to prevent initial over-release, and even if another biodegradable polymer is used to prevent this problem, even if the content of terzepatide or a pharmaceutically acceptable salt thereof in the particle is increased to reduce the amount of microparticles administered at one time, the problem of initial over-release occurs.

[0083] When manufacturing a sustained-release formulation using a biodegradable polymer, the type of biodegradable polymer and the content of terzepatide or its pharmaceutically acceptable salt in the microparticles are likely to be factors highly related to the initial over-release.

[0084] In order to solve the above problems and to exhibit drug release from the beginning of injection without delay time, the present invention attempted to solve the above problems by controlling the properties of microparticles.

[0085] That is, when the microparticles of the present invention are used as an injection composition, drug release occurs from the beginning without a lag time, initial over-release does not become a problem, and the release effect of terzepatide or a pharmaceutically acceptable salt thereof can be exhibited for more than one month.

[0086] Specifically, the microparticles of the present invention have pore sizes controlled on the surface and inside, so that when the microparticles are injected into the body, the initial over-release of terzepatide or a pharmaceutically acceptable salt thereof can be suppressed.

[0087] The micro particles with the above surface and internal pore sizes controlled can be characterized in that the internal pores for the cross-section cut more specifically are distributed in a uniform size in an SEM image with a magnification of x2.0k to form a dense tissue structure, and the surface is characterized in that a large number of pores of uniform size are formed to form a smooth surface in an SEM image with a magnification of x2.0k.

[0088] When spherical microparticles are manufactured using a biodegradable polymer, it can be confirmed through SEM images that the biodegradable polymer has numerous pores formed on its interior and surface. The presence or absence of pores on the surface of the microparticles can be easily confirmed through SEM images, and the internal pores of the microparticles can be confirmed through SEM images of the cross-sections of the microparticles.

[0089] In particular, when the magnification is adjusted to x2.0k to confirm the microparticles, it can be confirmed that multiple pores are formed on the surface and inside, and that the pores also exist in various sizes. Due to the surface and inside pores as described above, the microparticles injected into the body can be gradually decomposed as moisture penetrates the pores.

[0090] That is, when the above microparticles are manufactured using a biodegradable polymer, a large number of pores with various diameters can be formed on the interior and surface. However, the occurrence of the aforementioned initial over-release and delay time can be determined by these various pores.

[0091]

[0092] *Therefore, in the present invention, in order to solve the above-described problem, the pores on the inside and the surface are adjusted to be small by using a property improvement agent, so that the surface has a smooth shape and the inside forms a dense tissue structure.

[0093] The above-mentioned property improving agent is selected from the group consisting of sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl2), magnesium sulfate (MgSO4), sodium sulfate (Na2SO4), mannitol, ammonium, potassium sulfate, disodium phosphate, dipotassium phosphate, trisodium phosphate, disodium citrate, trisodium citrate, and sodium succinate, and may preferably be sodium chloride (NaCl), but is not limited to the above examples, and any property improving agent that can be adjusted to have the property of the present invention described above may be used without limitation.

[0094] The above microparticles may have an average diameter of 30 to 70 μm, 30 to 60 μm, or 30 to 50 μm. In addition, the standard deviation for the average diameter may be 1 to 30 μm, 1 to 20 μm, 1 to 10 μm, or 1 to 7 μm. It can be confirmed that uniform particles can be manufactured within the above diameter range, and when used as a sustained-release injection using the uniform particles, the foreign body sensation can be reduced, the convenience of administration can be improved, and the initial over-release can be prevented when injected into the body and the effect of continuous release of terzepatide or a pharmaceutically acceptable salt thereof can be exhibited.

[0095] The microparticles of the present invention may have a span value of 1.2 or less, 0.7 or less, 0.5 or less, or 0.4 or less. More specifically, the microparticles of the present invention may have a span value of 0.2 to 0.4. Microparticles exhibiting a span value within the above range mean that the diameter of the particles is very uniform, and when uniform particles such as the above are injected into the body, initial over-release of terzepatide or a pharmaceutically acceptable salt thereof can be prevented and a continuous release effect can be exhibited for more than one month.

[0096] According to another embodiment of the present invention, a sustained-release injectable composition comprising terzepatide or a pharmaceutically acceptable salt thereof may include the microparticles.

[0097] The above-described injectable composition can continuously release terzepatide or a pharmaceutically acceptable salt thereof in the body for more than one month with a single injection. In addition, as described above, it can exhibit sustained release of terzepatide or a pharmaceutically acceptable salt thereof at the beginning of injection without initial over-release and without delay, so that when used as an injectable composition, the effect of terzepatide or a pharmaceutically acceptable salt thereof can be exhibited from the beginning of injection, and the effect can be sustained for more than one month.

[0098] The above-mentioned injectable composition can be prepared by mixing the microparticles of the present invention with a suspending agent. The suspending agent includes a tonicity agent, a suspending agent, and a solvent.

[0099] More specifically, the isotonic agent may be selected from the group consisting of D-Mannitol, Maltitol, Sorbitol, Lactitol, Xylitol, Sodium chloride and mixtures thereof, preferably D-Mannitol, but is not limited to the above examples.

[0100] The above suspending agent is composed of sodium carboxymethylcellulose, polysorbate 80, starch, starch derivatives, polyhydric alcohols, chitosan, chitosan derivatives, cellulose, cellulose derivatives, collagen, gelatin, hyaluronic acid (HA), alginic acid, algin, pectin, carrageenan, chondroitin, chondroitin sulfate, dextran, dextran sulfate, polylysine, titin, fibrin, agarose, fluran, xanthan gum, and mixtures thereof. Selected from the group, preferably sodium carboxymethylcellulose and polysorbate 80, but not limited to the above examples.

[0101] The above solvent can be used as injection water, and any solvent that can be used as injection water can be used without limitation.

[0102] According to another embodiment of the present invention, a method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof comprises the steps of: dissolving terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent to produce an oily solution; mixing a surfactant and water to produce an aqueous solution; forming an emulsion comprising terzepatide or a pharmaceutically acceptable salt thereof using the oily solution and the aqueous solution; and collecting and hardening the formed emulsion comprising terzepatide or a pharmaceutically acceptable salt thereof to produce microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof, wherein the aqueous solution may further comprise a property improving agent.

[0103] The above oily solution can be prepared by dissolving terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent.

[0104] The biodegradable polymer is as described above.

[0105] The organic solvent is selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, dimethyl sulfoxide, and mixtures thereof. Preferably, a mixed solvent in which methanol and dimethyl sulfoxide are mixed as cosolvents and dichloromethane is mixed as a solvent is used as an organic solvent to dissolve terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, thereby preparing an oily solution.

[0106] The above oily solution may contain terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:3 to 1:15, a weight ratio of 1:4 to 1:14, a weight ratio of 1:5 to 1:13, a weight ratio of 1:5 to 1:12, a weight ratio of 1:5 to 1:11, a weight ratio of 1:5 to 1:10, a weight ratio of 1:5 to 1:9, a weight ratio of 1:5 to 1:8, or a weight ratio of 1:5 to 1:7. Within the above range, the oily solution may contain terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, and exhibit a sustained-release effect of terzepatide or a pharmaceutically acceptable salt thereof for more than 1 month without initial over-release. In addition, by including terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer within the above range, pain during injection can be alleviated and inflammation at the injection site can be suppressed.

[0107] The surfactant included in the above-mentioned aqueous solution is at least one selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate (e.g., Span™ 80), polyoxyethylene sorbitan fatty acid ester (e.g., Tween™ 80), polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, ester amines, linear diamines, patty amines, and mixtures thereof, and may preferably be polyvinyl alcohol, but is not limited to the above examples, and any surfactant that can be prepared into a completely spherical emulsion may be used.

[0108] In addition, the aqueous solution may further include a phase improver in addition to the surfactant. The phase improver may be included in an amount of 0.1 wt% to 10 wt%, 0.2 wt% to 9 wt%, 0.3 wt% to 8 wt%, 0.4 wt% to 7 wt%, 0.5 wt% to 6 wt%, or 0.5 wt% to 5 wt%, based on the total weight of the aqueous solution. When the phase improver is included in an amount less than the above range, the phase improvement effect is insufficient, and initial over-release may become a problem. When the phase improver is included in an amount exceeding 5 wt%, there is no difference in the effect of improving the initial over-release due to the phase improvement.

[0109] The final concentration of the aqueous solution containing the above-mentioned property improving agent may be 0.1 to 10 (w / v)%, 0.1 to 9 (w / v)%, 0.1 to 8 (w / v)%, 0.1 to 7 (w / v)%, 0.1 to 6 (w / v)%, 0.1 to 5 (w / v)%, or 0.5 to 5 (w / v)%. When the concentration of the aqueous solution is below the above range, the property improving effect is insignificant, and when it exceeds the above range, there is no difference in the effect of improving the initial over-release due to the property improving effect.

[0110] As described above, there is no limitation on the method of preparing an emulsion using the oily solution and the aqueous solution after preparing them respectively.

[0111] In the present invention, a method for manufacturing microparticles using a microfluidic method is described.

[0112] A microchip for utilizing the above microfluidic method can be formed on a wafer or a glass substrate. A microchannel is formed in the microchip, and more specifically, the microchannel includes a channel through which an oily solution flows, a channel through which an aqueous solution flows, and a transport channel. The channel through which the oily solution flows and the channel through which the aqueous solution flows are formed to meet each other at one point, and one end of the transport channel can be connected to a portion where the two channels are joined.

[0113] The channel through which the oily solution flows and the channel through which the aqueous solution flows are respectively coupled with an injection unit for injecting the oily solution and the aqueous solution, and one end of the moving channel may be coupled with a recovery unit for recovering a solution containing an emulsion.

[0114] The above microchannel can be formed in a material selected from the group consisting of a glass substrate, a silicon wafer, or a polymer film, but examples of the above materials are not limited to the above examples, and any material capable of forming a microchannel can be used.

[0115] The polymer film may be selected from the group consisting of polyimide, polyethylene, fluorinated ethylene propylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polysulfone, and mixtures thereof, but is not limited to the above examples.

[0116] As an example, aluminum is deposited on a silicon wafer using an e-beam evaporator, and photoresist is patterned on the aluminum using photolithography. The aluminum is then etched using the photoresist as a mask, the photoresist is removed, and the silicon is etched using DRIE (deep ion reactive etching) using the aluminum as a mask. After the aluminum is removed, glass is anodic bonded to the wafer to seal it, thereby fabricating the microchannels described above.

[0117] The microchannel for manufacturing the microparticles of the present invention can use a 144-channel chip. In the case of the microchip, the average diameter of the microchannel for injecting the oil phase solution and the aqueous solution is 300 μm to 500 μm, and the oil phase solution and the aqueous solution can pass through the resistance channel after moving through each channel. The average diameter of the resistance channel is 10 μm to 50 μm. After passing through the resistance channel, the oil phase solution and the aqueous solution pass through a junction channel where they intersect, and the diameter of the junction channel can be 100 μm to 400 μm. After the oil phase solution and the aqueous solution intersect within the junction channel to form an emulsion, they pass through a microchannel having a diameter of 150 μm to 200 μm, and then pass through a microchannel having a diameter of 200 μm to 300 μm.

[0118] However, the average diameter of the microchannel may vary depending on the range of injection pressure and flow rate conditions. Furthermore, the average diameter of the microchannel is closely related to the average diameter of the particles, but is also closely related to the injection pressure and flow rate conditions of the oily and aqueous solutions.

[0119] The oily solution and the aqueous solution prepared as described above can be allowed to flow under the flow rate conditions described below through the first microchannel and the second microchannel in which an intersection is formed.

[0120] That is, the oily solution flows along the first microchannel, and the aqueous solution flows along the second microchannel shaped to form an intersection with the first microchannel, where it meets the flow of the oily solution.

[0121] More specifically, when the oil solution is injected into the first microchannel, the flow rate condition is 100 μL / min to 300 μL / min, and may be 150 μL / min to 270 μL / min.

[0122] In addition, when the above-mentioned water solution is injected into the second microchannel, the flow rate condition may be 10,000 μL / min to 30,000 μL / min, and 15,000 μL / min to 27,000 μL / min.

[0123] As described above, by making the flow rates of the oil phase solution and the aqueous solution different and maintaining the condition that the flow rate of the aqueous solution is greater than the flow rate of the oil phase solution, the aqueous solution having a relatively greater flow rate compresses the oil phase solution at the point where the flow of the oil phase solution and the flow of the aqueous solution meet, and at this time, due to the repulsive force of the oil phase solution and the aqueous solution, a spherical emulsion including the biodegradable polymer and terzepatide or a pharmaceutically acceptable salt thereof in the oil phase solution is formed, and more specifically, an emulsion is formed in the form of terzepatide or a pharmaceutically acceptable salt thereof being evenly distributed in the spherical biodegradable polymer.

[0124] The temperature at which the above-mentioned oily solution and aqueous solution flow through the microchannel is also 15 to 20°C, and preferably 17°C. That is, after flowing through the microchannel and forming an intersection to generate microparticles, the temperature is maintained at a constant low temperature of 15 to 20°C until the collected emulsion is stirred. Only when a low temperature is maintained during the process of producing microparticles can spherical particles be produced and maintained. In other words, if the temperature is not low, it is difficult to produce particles with a consistent spherical shape.

[0125] The emulsion prepared above can be collected in a tank containing the aqueous solution and stirred at 200 to 300 rpm.

[0126] The above-mentioned aqueous solution is a mixed solution of a surfactant and purified water prepared for the preparation of the above-mentioned emulsion. A portion of the prepared aqueous solution is injected into a microchannel, and another portion is moved to a water tank, which can be used to prevent the collected emulsions from clumping together.

[0127] Afterwards, the temperature can be increased to 20°C to 30°C or 25°C, and stirred for 0.5 to 1.5 hours or 1 hour to harden and produce microparticles.

[0128] The above microparticles can be stirred at a constant temperature condition and stirring speed to remove the remaining organic solvent, thereby evaporating and removing the organic solvent remaining in the emulsion. At this time, the stirring conditions are stirring at a speed of 200 to 400 rpm for 2 to 4 hours at 35°C to 45°C, specifically stirring at a speed of 200 to 300 rpm for 2.5 to 3.5 hours at 35°C to 40°C, and more specifically stirring at a speed of 200 to 300 rpm for 3 hours at 40°C.

[0129] As described above, under stirring conditions, very small pores are formed on the surface of the emulsion as the residual organic solvent is removed, so that spherical particles with smooth surfaces can be manufactured, and the residual organic solvent can be minimized.

[0130] Finally, the emulsion is stirred to remove all residual organic solvent, washed several times with sterile filtered purified water to remove any remaining surfactant, and then freeze-dried to produce microparticles.

[0131]

[0132] Manufacturing example

[0133] Preparation of microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof

[0134] Tirzepatide (manufacturer: polypeptide) and PLGA were weighed and homogeneously dissolved in a mixed solvent prepared by mixing co-solvents MeOH and DMSO in DCM solvent. The mixed solvent was prepared by mixing MeOH, DMSO, and DCM in a weight ratio of 1:2:6. An aqueous solution was prepared by adding NaCl as a phase improver to a 0.5% polyvinyl alcohol aqueous solution to have a final concentration of 0.5 (w / v)%. The oily solution and the aqueous solution were injected into a microchannel formed on a silicon wafer and allowed to flow. At this time, the flow rate ratio of the oily solution and the aqueous solution was 1:100. The temperature condition was maintained at 17℃. Microparticles generated at the intersection where the flow of the oily solution and the flow of the aqueous solution meet were collected in a tank containing the aqueous solution. The microparticles collected in the above tank were stirred at a speed of 200 to 300 rpm for 1 hour at 25°C to harden the emulsion. Thereafter, the remaining organic solvent was removed by stirring at a speed of 200 to 300 rpm for 3 hours at 40°C, washed several times with sterile filtered purified water, and freeze-dried to produce microparticles.

[0135] Experimental Example 1

[0136] Confirmation of the initial burst pattern according to the AP ratio

[0137] When producing the microparticles of the above manufacturing example, the weight ratio of terzepatide and the biodegradable polymer was adjusted as shown in Table 1 below to produce an oily solution. The aqueous solution did not contain a phase-improving agent, and the microparticles were produced using this. The microparticles were suspended in water for injection to produce an injectable composition, and a pharmacokinetic evaluation was performed. The test conditions were as follows:

[0138] - Male SD Rat, 6 weeks old

[0139] - 10 SD rats per group (40 rats in total) were used, and the average blood concentration of terzepatide was calculated for each measurement time.

[0140] - Subcutaneous administration (1.24 mg / head)

[0141] Terzepatide biodegradable polymer drug loading amount 1109.1% 1712.5% ​​1516.7%

[0142] Figures 1 to 3 show that PDLG7502A (molar ratio of lactide to glycolide of 75:25) was used as a biodegradable polymer. Figure 1 shows that the weight ratio of Tirzepatide (manufacturer: polypeptide) and the biodegradable polymer was 1:10 (drug loading amount 9.1%), Figure 2 shows that the weight ratio of Tirzepatide (manufacturer: polypeptide) and the biodegradable polymer was 1:7 (drug loading amount 12.5%), and Figure 3 shows that the weight ratio of Tirzepatide (manufacturer: polypeptide) and the biodegradable polymer was 1:5 (drug loading amount 16.7%). According to Figures 1 to 3, it was confirmed that as the drug content increased, an initial over-release occurred.

[0143]

[0144] Additionally, biodegradable polymers PDLG5002A (lactide to glycolide molar ratio of 50:50) and PDLG7502A (lactide to glycolide molar ratio of 75:25) were used in a weight ratio of 1:3, and an oily solution was prepared so that the weight ratio of Tirzepatide (manufacturer: polypeptide) and PLGA was 1:7 (Fig. 4) or 1:5 (Fig. 5), and the aqueous solution did not contain a phase-improving agent, and microparticles were prepared.

[0145] According to FIGS. 4 and 5, it was confirmed that when PDLG5002A was included, a greater initial over-release was observed in the case where the weight ratio of Tirzepatide and the biodegradable polymer was 1:5 than in the case of PDLG7502A alone (FIG. 3).

[0146]

[0147] Additionally, we examined whether the initial over-release was affected by the type of biodegradable polymer by using different biodegradable polymers. The biodegradable polymers used were PDLG7504A (lactide:glycolide molar ratio of 75:25) or PDL02A (PLA polymer), and an oily solution was prepared with a weight ratio of 1:5 of tirzepatide and biodegradable polymer. The aqueous solution did not contain a phase-improving agent, and microparticles were prepared.

[0148] The test results are as shown in Figs. 6 and 7.

[0149] According to the test results, when PDLG7504A or PDL02A was used as a biodegradable polymer, no initial over-release occurred, but it was confirmed that almost no release of terzepatide occurred after the initial release.

[0150]

[0151] In light of the above experiments, it was confirmed that when PLGA with a molar ratio of lactide to glycolide of 50:50 was used as a biodegradable polymer, or when the weight ratio of terzepatide and PLGA was 1:5 and the drug loading amount was 16.7%, the problem of initial over-release occurred.

[0152]

[0153] Experimental Example 2

[0154] Examination of the properties of microparticles according to the presence or absence of a property improvement agent

[0155] Microparticles were manufactured using the same method as in the above manufacturing example. Biodegradable polymers PDLG5002A (lactide to glycolide molar ratio of 50:50) and PDLG7502 A (lactide to glycolide molar ratio of 75:25) were mixed in a weight ratio of 1:3 and used, and the weight ratio of Tirzepatide (manufacturer: polypeptide) and PLGA was manufactured to be 1:5. Then, only the application of NaCl was changed to prepare an aqueous solution, which was used to manufacture microparticles.

[0156] Fig. 8 is an SEM photograph of microparticles including a phase-improving agent as in a manufacturing example of the present invention, and Fig. 9 is a SEM photograph of microparticles manufactured without applying a phase-improving agent to the aqueous solution, and the results thereof.

[0157] According to Fig. 8, the surface of the particle is formed very uniformly, pores on the surface are hardly observed, and the formation of the cut cross-section also confirms that the structure is very densely structured.

[0158] On the other hand, according to Figure 9, it can be confirmed that large pores are formed on the surface of the particle and that the cross-section has a loose texture. Furthermore, it can be confirmed that during the process of cutting the microparticles to form the cross-section, the particles are not cut uniformly and are easily broken.

[0159]

[0160] Experimental Example 3

[0161] Examination of the properties of microparticles according to the content of the property improving agent

[0162] Microparticles were manufactured using the same method as in the above manufacturing example. Biodegradable polymers PDLG5002 (lactide to glycolide molar ratio of 50:50) and PDLG7502 (lactide to glycolide molar ratio of 75:25) were used in a weight ratio of 1:3, and an oily solution was prepared so that the weight ratio of Tirzepatide (manufacturer: polypeptide) and PLGA was 1:5, and then NaCl was mixed to prepare an aqueous solution so that the final concentration was 5 (w / v)%, 0.5 (w / v)%, or 0.1 (w / v)%, and microparticles were manufactured.

[0163] The results are as shown in Figs. 10 to 15.

[0164] Figures 10 and 13 show that the final concentration of the aqueous solution is 5 (w / v)%, Figures 11 and 14 show that the final concentration of the aqueous solution is 0.5 (w / v)%, and Figures 12 and 15 show that the final concentration of the aqueous solution is 0.1 (w / v)%. Figures 10 to 15 are SEM photographs at a magnification of x2.0k.

[0165] The above FIGS. 10 to 12 are photographs of the particle surfaces. Referring to FIGS. 10 and 11 , the surfaces of the microparticles can be confirmed to be smooth, spherical in shape, while FIG. 12 shows that the particle surfaces are irregularly formed. The irregular, uneven appearance of the surface is due to the presence of pores, a sunken shape, or an uneven surface formation.

[0166] The above Figures 13 to 15 are photographs of cross-sections of particles, and it can be confirmed that as the content of the property improving agent increases, the internal pores are formed smaller and more densely. On the other hand, when the final concentration of the aqueous solution is 0.1 (w / v)%, it can be confirmed that the pores are formed large, and when the particle is cut, it is not cut, but rather broken.

[0167]

[0168] Additionally, the types of polymers were RG502H (lactide to glycolide molar ratio of 50:50) / RG504H (lactide to glycolide molar ratio of 50:50) / RG653H (lactide to glycolide molar ratio of 65:35) in a weight ratio of 1:1:1, and an oily solution was prepared so that the weight ratio of Tirzepatide (manufacturer: polypeptide) and PLGA was 1:5. Then, NaCl was mixed into the aqueous solution to produce microparticles with different final concentrations of 5 (w / v)%, 0.5 (w / v)%, 0.1 (w / v)%, and no NaCl.

[0169] The results of comparing the properties of the interior and surface of microparticles according to the difference in concentration of the aqueous solution are as shown in Figs. 16 to 19.

[0170] Figure 16 shows a case where the final concentration of the aqueous solution is 5 (w / v)%, Figure 17 shows a case where the final concentration of the aqueous solution is 0.5 (w / v)%, Figure 18 shows a case where the final concentration of the aqueous solution is 0.1 (w / v)%, and Figure 19 shows a case where an aqueous solution that does not contain NaCl is used.

[0171] Even if the type of biodegradable polymer is kept the same, it can be confirmed that the surface properties and cross-section properties of the particles differ depending on whether NaCl is included in the aqueous solution and the concentration difference when included.

[0172]

[0173] Experimental Example 4

[0174] Review of whether the inclusion of a saturation enhancer suppresses initial over-release

[0175] An oily solution was prepared by containing biodegradable polymers RG502H (lactide to glycolide molar ratio of 50:50) / RG504H (lactide to glycolide molar ratio of 50:50) / RG653H (lactide to glycolide molar ratio of 65:35) in a weight ratio of 1:1:1, and a weight ratio of 1:5 of Tirzepatide (manufacturer: polypeptide) and PLGA. Then, NaCl was mixed to prepare an aqueous solution to a final concentration of 5 (w / v)% or 0.1 (w / v)%, thereby preparing microparticles. The microparticles were suspended in water for injection to prepare an injection composition, and a pharmacokinetic evaluation was performed. The test conditions were as follows:

[0176] - Male SD Rat, 7 weeks old

[0177] - 10 SD rats per group (40 rats in total) were used, and the average blood concentration of terzepatide was calculated for each measurement time.

[0178] - Subcutaneous administration (1.24 mg / head)

[0179] The test results are shown in Table 2, Figures 20 and 21 below:

[0180] GroupFormulationAP ratioNaCl concentrationCmax (ng / ml)AUC 0~28day (hr*ng / ml)Tmax (day)3rd PK G8502H / 504H / 653H=1 / 1 / 11:55%377.14107554.8921.04th PK G2502H / 504H / 653H=1 / 1 / 11:50.1%392.54129576.7421.0

[0181] According to the above test results, it was confirmed that the occurrence of initial over-release differed due to the difference in the concentration of the aqueous solution according to the addition of NaCl. However, when using an aqueous solution containing 5% NaCl, a slight decrease in the bio-efficiency rate was observed compared to when containing 0.1% NaCl, but the difference was not significant.

[0182] Additionally, the results of pK release for cases where 5(w / v)% or 0.5(w / v)% NaCl aqueous solutions were used are as shown in Table 3, Figures 22 and 23 below.

[0183] GroupFormulationAP ratioNaCl concentrationCmax (ng / ml)AUC 0~28day (hr*ng / ml)Tmax (day)3rd PK G45002 / 7502=1 / 31:55%212.57102104.25104th PK G55002 / 7502=1 / 31:50.5%356.35244950.0514

[0184] The experimental results in Table 3 above were conducted under the same experimental conditions as in Table 2 above, and although there are differences in Cmax, AUC, and Tmax values ​​due to differences in biodegradable polymers, it was confirmed that when a 0.5% NaCl aqueous solution was used, the initial over-release inhibition effect was similar to that of a 5% NaCl aqueous solution. However, as shown in Table 3 above, it was confirmed that AUC decreased as the concentration of NaCl increased, so that the properties can be controlled by NaCl, and the initial over-release can be controlled according to the above-described property control, but the degree of decomposition of the biodegradable polymer in the body can be affected by controlling the size of the pores, whether they are created, etc. For this reason, when an aqueous solution exceeding the 5% NaCl concentration range is used, the bioavailability may be too low, which may cause a problem in that the effect of the release of terzepatide or a pharmaceutically acceptable salt thereof may be insufficient.

[0185] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

[0186] The present invention relates to microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof and a method for producing the same.

Claims

1. Containing terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer; The above biodegradable polymer comprises polylactide-co-glycolide (PLGA). Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

2. In paragraph 1, The above micro particles have controlled surface and internal pore sizes, so that when the micro particles are injected into the body, the initial over-release of terzepatide or a pharmaceutically acceptable salt thereof is suppressed. Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

3. In paragraph 2, The internal pores of the cross-section of the above micro particles are distributed in a uniform size in the SEM image with a magnification of x2.0k, forming a dense tissue structure. Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

4. In paragraph 2, The surface of the above micro particles is smooth with the pores removed in the SEM image at a magnification of x2.0k. Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, The above polylactide-co-glycolide (PLGA) has an inherent viscosity of 0.2 dl / g or less and a molar ratio of lactide to glycolide of 50:

50. Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, The above terzepatide or a pharmaceutically acceptable salt thereof is contained in an amount of 10 wt% or more based on the total weight of the microparticles. Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, The above micro particles have an average diameter of 30 to 70 μm. Microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

8. Containing micro particles according to any one of clauses 1 to 7. A sustained-release injectable composition comprising terzepatide or a pharmaceutically acceptable salt thereof.

9. In paragraph 8, The above injection composition continuously releases terzepatide or a pharmaceutically acceptable salt thereof in the body for more than one month with a single injection. A sustained-release injectable composition comprising terzepatide or a pharmaceutically acceptable salt thereof.

10. A step of preparing an oily solution by dissolving terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent; A step of preparing an aqueous solution by mixing a surfactant and water; A step of forming an emulsion containing terzepatide or a pharmaceutically acceptable salt thereof using the above oily solution and aqueous solution; and A step of collecting and hardening an emulsion containing the above-formed terzepatide or a pharmaceutically acceptable salt thereof to produce microparticles containing terzepatide or a pharmaceutically acceptable salt thereof, The above-mentioned water-soluble solution additionally contains a property-improving agent. A method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

11. In paragraph 10, The above-mentioned water-soluble solution contains a water-soluble improver at a concentration of 0.1 to 10 (w / v)%. A method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

12. In paragraph 10, The step of forming an emulsion containing terzepatide or a pharmaceutically acceptable salt thereof using the above oily solution and aqueous solution is as follows: The oil phase solution and the water phase solution are injected into each channel by microfluidic method, and an emulsion is formed at the intersection where the flows of the oil phase solution and the water phase solution come into contact with each other. A method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

13. In paragraph 10, The above organic solvent is selected from the group consisting of methanol, chloroform, chloromethane, dichloromethane, trichloroethane, ethanol, dimethyl sulfoxide and mixtures thereof. A method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

14. In paragraph 10, The above oily solution contains terzepatide or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:3 to 1:

15. A method for producing microparticles comprising terzepatide or a pharmaceutically acceptable salt thereof.

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