Microparticles comprising orforglipron or pharmaceutically acceptable salt thereof, and method for preparing same

Abstract

The present invention relates to microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof, and a method for preparing same. The microparticles can continuously release orforglipron or a pharmaceutically acceptable salt thereof for one month or more after being injected into the body, and thus can exhibit an effect of preventing and / or treating obesity / diabetes by means of orforglipron or a pharmaceutically acceptable salt thereof continuously for a long time with a single injection. In addition, orforglipron or a pharmaceutically acceptable salt thereof is included in microparticles having a uniform size and shape and prepared using two or more different types of polymers, and thus, after being injected into the body, an initial burst release of orforglipron or a pharmaceutically acceptable salt thereof can be prevented, and the microparticles can be used as a long-acting formulation without side effects.

Description

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

[0001] The present invention relates to microparticles comprising orthoglypholone 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] However, since the existing prescribed GLP-1 series drugs are peptide drugs, they cannot be administered orally and must be administered once a week as an injection (pre-filled Pin). In addition, peptide drugs with a structure of 37 to 39 amino acids and long chain side branches to increase half-life are not easy to synthesize, so the supply worldwide cannot keep up with demand, resulting in a shortage and also high drug prices.

[0008] To overcome the shortcomings of these peptide drugs, there has been a constant need for the development of low-molecular-weight compound GLP-1R agonists that are easy to administer orally and inexpensive to synthesize (manufacture).

[0009] Recently, Eli Lilly developed orforglipron, a small-molecule GLP-1R agonist with high activity, and successfully completed phase 3 clinical trials. Orforglipron can be administered orally, and has demonstrated excellent obesity / diabetes treatment effects comparable to those of existing peptide drugs.

[0010] However, orforglipron, a low-molecular-weight GLP-1R agonist compound, was developed as an oral drug and must be taken once a day. Therefore, there is a need to develop an injectable drug that can provide long-term, sustained obesity / diabetes treatment effects through a single administration.

[0011] [Prior Art Literature]

[0012] [Patent Document]

[0013] KR 10-2021-0005843 A1

[0014] An object of the present invention is to provide microparticles comprising orthoglyphrolone 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 orforglyphoron or a pharmaceutically acceptable salt thereof, which can continuously release orforglyphoron or a pharmaceutically acceptable salt thereof for more than one month after being injected into the body, thereby exhibiting an effect of preventing and / or treating obesity / diabetes through orforglyphoron or a pharmaceutically acceptable salt thereof continuously for a long period of time with a single injection.

[0016] Another object of the present invention is to provide a method for producing microparticles comprising orforglyphoron or a pharmaceutically acceptable salt thereof, which can be used as a long-acting formulation without side effects, by preventing initial over-release of orforglyphoron or a pharmaceutically acceptable salt thereof after injection into the body, by including orforglyphoron or a pharmaceutically acceptable salt thereof in microparticles manufactured using two or more different polymers and having a uniform size and shape.

[0017] To achieve the above-described purpose, the present invention relates to microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof, and orforglipron or a pharmaceutically acceptable salt thereof, which comprises a biodegradable polymer.

[0018] Additionally, the microparticles may contain orthoglypholone or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:1 to 1:5.

[0019] Additionally, the biodegradable polymer may be selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and combinations thereof.

[0020] Additionally, the inherent viscosity of the biodegradable polymer may be 0.1 dl / g to 0.5 dl / g.

[0021] Additionally, the microparticles may contain two or more different types of biodegradable polymers.

[0022] Additionally, the microparticles may have a span value of 0.5 or less.

[0023] Additionally, the microparticles may have an average diameter of 20 to 60 μm.

[0024] Additionally, the micro particles may have a value of 0.1 to 3 according to the following formula 1:

[0025] [Formula 1]

[0026] AUC 0-7day / inf (%) = (AUC 0-7day / AUC inf ) * 100(%)

[0027] Here,

[0028] The above microparticles were administered as a single SC formulation to rats, and 17.36 mg / head of orforglipron or a pharmaceutically acceptable salt thereof was administered as a single injection, and the administered volume was 0.5 mL / head.

[0029] AUC inf is the value of AUC obtained by extrapolating the drug's plasma concentration to infinity based on the rate of elimination from the blood.

[0030] AUC 0-7day AUC is the value obtained by extrapolating the drug's plasma concentration to 7 days based on the rate of elimination from the blood.

[0031] In addition, the above microparticles, when administered into the body as an injection, can continuously release orforglyphorone or a pharmaceutically acceptable salt thereof for more than one month.

[0032] Another aspect of the present invention for achieving the above-described object relates to a method for producing microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof, comprising the steps of: preparing an oily solution comprising orforglipron or a pharmaceutically acceptable salt thereof and a biodegradable polymer; preparing an aqueous solution by dissolving a surfactant in water; forming an emulsion by mixing the oily solution and the aqueous solution; obtaining the emulsion into an aqueous solution to remove residual solvent; and washing and freeze-drying the emulsion from which the residual solvent has been removed to produce microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof.

[0033] The present invention can continuously release orforglyphoron or a pharmaceutically acceptable salt thereof for more than one month after being injected into the body, and thus can exhibit an effect of preventing and / or treating obesity / diabetes through orforglyphoron or a pharmaceutically acceptable salt thereof for a long period of time with a single injection.

[0034] In addition, the microparticles containing orforglyphoron or a pharmaceutically acceptable salt thereof, which are manufactured using two or more different polymers and have a uniform size and shape, can prevent initial over-release of orforglyphoron or a pharmaceutically acceptable salt thereof after injection into the body, and thus can be used as a long-acting formulation without side effects.

[0035] Figure 1 is an SEM image of microparticles according to one embodiment of the present invention.

[0036] Figure 2 is an SEM image of microparticles according to one embodiment of the present invention.

[0037] Figure 3 is an SEM image of microparticles according to one embodiment of the present invention.

[0038] Figure 4 is an SEM image of microparticles according to one embodiment of the present invention.

[0039] Figure 5 is an SEM image of microparticles according to one embodiment of the present invention.

[0040] Figure 6 is an SEM image of microparticles according to one embodiment of the present invention.

[0041] Figure 7 is an SEM image of microparticles according to one embodiment of the present invention.

[0042] Figure 8 is an SEM image of microparticles according to one embodiment of the present invention.

[0043] Figure 9 is an SEM image of microparticles according to one embodiment of the present invention.

[0044] Figure 10 is an SEM image of microparticles according to one embodiment of the present invention.

[0045] Figure 11 shows the results of measuring the concentration of orphoglyphroglyphone in the blood after injecting microparticles according to one embodiment of the present invention into SD rats.

[0046] The present invention relates to microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof, and orforglipron or a pharmaceutically acceptable salt thereof comprising a biodegradable polymer, and a method for producing the same.

[0047] 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.

[0048] Obesity is a chronic disease that places a significant economic burden on more than one billion people worldwide. GLP-1 receptor agonists (GLP-RAs), similar to the incredin hormone GLP-1, reduce appetite and delay gastric emptying, thus enhancing blood sugar levels. Their use is also increasing as an obesity treatment.

[0049] Injectable GLP-RAs have already demonstrated long-term weight loss efficacy. Currently, only two injectable GLP-RAs are approved for weight management: liraglutide (3.0 mg once daily) and semaglutide (2.4 mg once weekly).

[0050] There has been a demand for an easy-to-use oral option that is similar in efficacy to injectable GLP-RAs, and oral semaglutide (Rybelsus®, Novo Nordisk), which uses an absorption enhancer to enable absorption from the stomach, has been approved for the treatment of type 2 diabetes.

[0051] Oral semaglutide must be taken 30 minutes before breakfast to be effective, and the approved oral formulation (14 mg) is less effective in weight loss than the injectable formulation (Wigobi, 2.4 mg). Higher-dose oral semaglutide (25 mg and 50 mg) is currently under development to overcome this limitation.

[0052] Orforglipron is an oral, non-peptide GLP-RA indicated for the treatment of obesity and type 2 diabetes. Its half-life is 29–49 hours, allowing for once-daily dosing. It is a potent partial agonist at the GLP-1 receptor, exerting a stronger effect on cAMP signaling than on β-arrestin recruitment. This pharmacological characteristic is lower receptor desensitization than that of fully acting GLP-1 RAs.

[0053] The main adverse effects of orforglyphorone are gastrointestinal, with diarrhea, nausea, dyspepsia, constipation, and vomiting being the most common. The safety profile of orforglyphorone is similar to that of existing GLP-1 receptor agonists (GLP-1 RAs), and the side effects are similar to those of injectable GLP-1 RAs.

[0054] The reason for these side effects is thought to be that the starting dose of orforglyphoron was high (3 mg), followed by rapid weekly dose increases until the maintenance dose was reached.

[0055] In the case of the above-mentioned orthoglyphlic acid, it has a great advantage in that it can show the same level of obesity / diabetes treatment effect as existing injectable drugs as an oral GLP-1 RA. However, in order to treat obesity / diabetes, the dosage must be increased until the maintenance dose is reached, and the side effects that occur as a result are a problem.

[0056] To avoid these problems, there is a need for the development of long-acting formulations that can maintain the effects of orforglyphorone or a pharmaceutically acceptable salt thereof for more than one month, one to six months, or one to five months through a single injection rather than daily dosing.

[0057] The present invention relates to microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof, and orforglipron or a pharmaceutically acceptable salt thereof, which comprise a biodegradable polymer, in order to utilize the above-described long-acting formulation capable of maintaining the effect of orforglipron or a pharmaceutically acceptable salt thereof.

[0058] The above microparticles of the present invention, having a uniform spherical shape, can be used as an injection, and as described above, when injected into the body, they can continuously release orthoglyphroglyphone for more than 1 month, 1 month to 6 months, or 1 month to 5 months by decomposition of the biodegradable polymer.

[0059] In addition, unlike orthoglyphrolone or a pharmaceutically acceptable salt thereof currently under development as an oral dosage form, the microparticles of the present invention can reach a maintenance dose without initial over-release, thereby exhibiting excellent weight loss effects and preventing and treating diabetes, while minimizing side effects.

[0060] Specifically, the microparticles may have a value of 0.1 to 3, 0.2 to 2.5, 0.3 to 2.0, 0.3 to 1.9, 0.3 to 1.8, 0.4 to 1.7, 0.5 to 1.6, 0.5 to 1.5, 0.5 to 1.4, 0.5 to 1.3, 0.5 to 1.2, and 0.5 to 1.1 according to the following formula 1:

[0061] [Formula 1]

[0062] AUC 0-7day / inf (%) = (AUC 0-7day / AUC inf ) * 100(%)

[0063] Here,

[0064] The above microparticles were administered as a single SC formulation to rats, and 17.36 mg / head of orforglipron or a pharmaceutically acceptable salt thereof was administered as a single injection, and the administered volume was 0.5 mL / head.

[0065] AUC inf is the value of AUC obtained by extrapolating the drug's plasma concentration to infinity based on the rate of elimination from the blood.

[0066] AUC 0-7day AUC is the value obtained by extrapolating the drug's plasma concentration to 7 days based on the rate of elimination from the blood.

[0067] The above AUC is a value for the bioavailability of a drug based on the blood concentration curve after drug administration, according to the pharmacokinetic evaluation. Accordingly, AUC inf After administering the injection of the present invention, the value for the bioavailability of orthoglyphrolone by the injection is referred to as AUC. 0-7day refers to the value for the bioavailability of orforglyphoron up to 7 days. Consequently, the value derived by Equation 1 is the ratio of the bioavailability of the total orforglyphoron upon administration of the microparticles of the present invention as an injection to the bioavailability up to 7 days after administration as an injection, and a lower value means that there is no initial over-release.

[0068] That is, as described above, in the case of oral dosage forms of orforglyphorone, side effects may occur during the initial administration and during the process of rapidly increasing the dosage until reaching the maintenance dose, which is caused by excessive exposure to orforglyphorone or a pharmaceutically acceptable salt thereof.

[0069] In the present invention, in order to prevent the above-described problem, the release of excessive orphoglypholone or a pharmaceutically acceptable salt thereof is controlled at the initial stage of injection, thereby minimizing the side effect problem until the maintenance dose is reached.

[0070] To achieve the above release effect, the microparticles may contain orforglyphoron or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:1 to 1:5, a weight ratio of 1:1.5 to 1:4, or a weight ratio of 1:1.5 to 1:3. Within the above range, the dosage of the microparticles may not be excessive in order to maintain a continuous efficacy of orforglyphoron or a pharmaceutically acceptable salt thereof for more than one month with a single injection.

[0071] In addition, for continuous decomposition in the body and continuous release of orthoglycolone or a pharmaceutically acceptable salt thereof, the biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate and combinations thereof, preferably polylactide-co-glycolide (PLGA), and the polylactide-co-glycolide has a monomer ratio of lactide:glycolide of 50:50 to 85:15, 50:50 to 25:75, and may be 50:50 or 25:75.

[0072] In addition, the inherent viscosity of the biodegradable polymer may be 0.1 dl / g to 0.5 dl / g. The inherent viscosity of the biodegradable polymer is a factor that affects the rate of decomposition in the body, and by using a biodegradable polymer that satisfies the above range, the effect of releasing orthoglyphroglyphone or a pharmaceutically acceptable salt thereof can be exhibited continuously for more than one month.

[0073] The above microparticles may include two or more different biodegradable polymers. Specifically, when the biodegradable polymer includes polylactide-co-glycolide, two or more polylactide-co-glycolides having different intrinsic viscosities may be selected and used. When polylactide-co-glycolide and polylactic acid are used as the biodegradable polymers, the polylactide-co-glycolide and polylactic acid may each have different intrinsic viscosities. When only polylactic acid is used as the biodegradable polymer, polylactic acids having different intrinsic viscosities may be used. However, the present invention is not limited to the above examples, and any polymer that can exhibit a sustained-release effect of orforglyphoron or a pharmaceutically acceptable salt thereof for more than one month may be used without limitation.

[0074] More specifically, when polylactide-co-glycolide is used as the biodegradable polymer, the intrinsic viscosity of the first polylactide-co-glycolide may be 0.15 dl / g to 0.25 dl / g, and the intrinsic viscosity of the second polylactide-co-glycolide may be 0.35 dl / g to 0.45 dl / g. At this time, the first polylactide-co-glycolide may have an intrinsic viscosity of 0.15 dl / g to 0.25 dl / g and may include a plurality of polylactide-co-glycolides having different monomer ratios of lactide:glycolide. In addition, at this time, the second polylactide-co-glycolide may have an intrinsic viscosity of 0.35 dl / g to 0.45 dl / g and may include a plurality of polylactide-co-glycolides having different monomer ratios of lactide:glycolide.

[0075] In addition to the weight ratio range of the above-described orforglyphron or its pharmaceutically acceptable salt and the biodegradable polymer, the type of the biodegradable polymer, and the intrinsic viscosity range, in order to control the release of excessive orforglyphron or its pharmaceutically acceptable salt at the beginning of injection and to release orforglyphron or its pharmaceutically acceptable salt at a constant level, the microparticles of the present invention may have a span value of 0.5 or less, and may be 0.3 or less.

[0076] The above span value may be a value calculated by the following equation 2.

[0077] Span value = (D90-D10) / D50

[0078] The above span value represents the width of the particle size distribution in particle size distribution and the entire measurement range in equipment accuracy. A larger span value means a wider particle size distribution, and conversely, a smaller span value means a narrower particle size distribution.

[0079] That is, as shown in the above figure, the micro particles of the present invention are characterized by a very narrow particle size distribution.

[0080] While various technologies exist for manufacturing microparticles using existing biodegradable polymers, conventional manufacturing methods suffer from a lack of uniform control over the size of the microparticles. While particles larger than a certain size are removed through a sieving process, the manufacturing process often results in particles of uneven size, making it nearly impossible to achieve the span value achieved in the present invention.

[0081] In addition, the microparticles may have an average diameter (D50) of 20 µm to 60 µm, 25 µm to 55 µm, 30 µm to 50 µm, or 30 µm to 45 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 it is possible to manufacture uniform particles within the above diameter range, and when using the uniform particles as a sustained-release injection, 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 continuously releasing orthoglyphroglyphone or a pharmaceutically acceptable salt thereof can be exhibited.

[0082] By utilizing microparticles having the above-described span value and average diameter, the microparticles administered as an injection are composed of very uniform particles without a large difference in diameter, and when the microparticles are decomposed in the body, the decomposition of the microparticles occurs at a similar rate, so that the release rate of orforglipron or a pharmaceutically acceptable salt thereof can be controlled through the decomposition of the microparticles.

[0083] According to another embodiment of the present invention, a method for producing microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof may include the steps of: preparing an oily solution comprising orforglipron or a pharmaceutically acceptable salt thereof and a biodegradable polymer; preparing an aqueous solution by dissolving a surfactant in water; forming an emulsion by mixing the oily solution and the aqueous solution; obtaining the emulsion into an aqueous solution to remove a residual solvent; and washing and freeze-drying the emulsion from which the residual solvent has been removed to produce microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof.

[0084] The above-mentioned oily solution may be prepared by dissolving orthoglyphrolone or a pharmaceutically acceptable salt thereof and a biodegradable polymer in an organic solvent. The organic solvent may be selected from the group consisting of ethyl acetate, chloroform, chloroethane, dichloroethane, dichloromethane, trichloroethane, and mixtures thereof, and preferably may be selected from the group consisting of ethyl acetate, dichloromethane, and mixtures thereof.

[0085] In the above oily solution, the weight ratio of orforglyphoron or a pharmaceutically acceptable salt thereof and the biodegradable polymer may be included in a weight ratio of 1:1 to 1:5, may be included in a weight ratio of 1:1.5 to 1:4, and may be included in a weight ratio of 1:1.5 to 1:3. Within the above range, in order to maintain a continuous efficacy of orforglyphoron or a pharmaceutically acceptable salt thereof for more than one month with a single injection, the dosage of microparticles may not be excessive.

[0086] The above-mentioned aqueous solution may be prepared by dissolving a surfactant in water.

[0087] The surfactant may be at least one selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and mixtures thereof. The surfactant may be at least one selected from the group consisting of methylcellulose, polyvinylpyrrolidone, lecithin, gelatin, polyvinyl alcohol, sorbitan monooleate (e.g., Span™ 80, etc.), polyoxyethylene sorbitan fatty acid ester (e.g., Tween™ 80, etc.), polyoxyethylene castor oil derivatives, sodium lauryl sulfate, sodium stearate, ester amines, linear diamines, patty amines, and mixtures thereof, and preferably 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.

[0088] As described above, after preparing the oily solution and the aqueous solution, respectively, an emulsion containing orthoglyphrolone or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:1 to 1:5 can be prepared using these.

[0089] The method for preparing an emulsion using the above-described oily solution and aqueous solution is not limited.

[0090] However, the present invention aims to describe a method for manufacturing microparticles using a microfluidic method.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] The above microchannels have an average diameter of 60 to 150 μm, preferably 80 to 100 μm, but are not limited thereto. When microchannels having an average diameter less than the above range are used, an emulsion having an excessively small diameter may be produced, which may affect the release and in vivo absorption of the effective drug.

[0097] In addition, when the average diameter of the microchannel exceeds the above range value, the average size of the manufactured microparticles exceeds 60㎛, and foreign body sensation and pain may increase when administered as an injection, and as the diameter of the microchannel increases, the particle size distribution of the manufactured particles increases, making it difficult to manufacture microparticles with a uniform particle size.

[0098] Additionally, the average diameter of the microchannel is closely related to the average diameter of the particles, but is also closely related to the flow rate ratio (μl / min) of the oily solution and the aqueous solution.

[0099] In addition, the cross-sectional width (w) and the cross-sectional height (d) of the microchannel are closely related to the average diameter (d') of the microparticles being manufactured. The width (w) of the cross-sectional microchannel is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles, and the height (d) of the cross-sectional microchannel is in the ratio range of 0.7 to 1.3 with respect to the average diameter (d') of the microparticles.

[0100] That is, once the average diameter (d') of the microparticles to be manufactured is determined, the width (w) and height (d) of the microchannel cross-section must be set to a ratio range of 0.7 to 1.3 of d' to enable manufacturing of microparticles of the desired size.

[0101] In order to manufacture microparticles using the above microchip, an oily solution may be injected into the channel through which the oily solution flows, and an aqueous solution may be injected into the channel through which the aqueous solution flows, so that an emulsion may be formed at the portion where the two channels are joined.

[0102] When the oily solution and the aqueous solution are each injected into the microchannel, the flow rate ratio of the oily solution and the aqueous solution may be 1:50 to 1:100, 1:60 to 1:90, 1:70 to 1:90, or 1:80 to 1:90. By controlling the flow rate ratio of the oily solution and the aqueous solution as described above, an emulsion having a uniform diameter can be produced.

[0103] More specifically, when the oily solution is injected into the first microchannel, the flow rate conditions may be 0.1 ml / min to 0.5 ml / min, 0.1 ml / min to 0.4 ml / min, 0.1 ml / min to 0.3 ml / min, or 0.1 ml / min to 0.2 ml / min.

[0104] In addition, when the above-mentioned water solution is injected into the second microchannel, the flow rate conditions may be 10 ml / min to 30 ml / min, 10 ml / min to 25 ml / min, 10 ml / min to 20 ml / min, or 10 ml / min to 15 ml / min.

[0105] 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 orthoglyphroleporone or a pharmaceutically acceptable salt thereof in the oil phase solution is formed, and more specifically, an emulsion is formed in the form of orthoglyphroleporone or a pharmaceutically acceptable salt thereof being evenly distributed in the spherical biodegradable polymer.

[0106] 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.

[0107] The emulsion thus manufactured can be collected in a tank containing the aqueous solution, thereby preventing aggregation between the initially manufactured emulsions.

[0108] 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.

[0109] Thereafter, the organic solvent present in the emulsion collected in the tank may be removed by stirring under constant temperature conditions and stirring speed, thereby evaporating and removing the organic solvent remaining in the emulsion. At this time, the stirring conditions may be stirring at a speed of 300 to 500 rpm for 2 to 8 hours at 38°C to 48°C, and specifically stirring at a speed of 350 to 450 rpm for 2.5 to 7 hours at 40°C to 45°C.

[0110] As described above, under stirring conditions, the formation of pores on the surface of the emulsion can be prevented and the residual organic solvent can be minimized by removing the residual organic solvent.

[0111] 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.

[0112] The microparticles finally produced are in the form of microparticles made of a spherical biodegradable polymer in which orthoglyphroleporone or a pharmaceutically acceptable salt thereof is evenly distributed, and may contain orthoglyphroleporone or a pharmaceutically acceptable salt thereof and the biodegradable polymer in a weight ratio of 1:1 to 1:5.

[0113] The weight ratio of orthoglycollopone or a pharmaceutically acceptable salt thereof and a biodegradable polymer contained in the above microparticles is the same as the weight ratio of orthoglycollopone or a pharmaceutically acceptable salt thereof and a biodegradable polymer dissolved in an organic solvent when preparing an oily solution, which means that by preparing the microparticles and evaporating and removing all of the organic solvent, microparticles containing orthoglycollopone or a pharmaceutically acceptable salt thereof and a biodegradable polymer in the same weight ratio as in the oily solution can be prepared.

[0114] The above-mentioned manufactured microparticles can be prepared into an injectable composition by mixing with a suspending agent. The suspending agent includes a tonicity agent, a suspending agent, and a solvent.

[0115] 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.

[0116] 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.

[0117] The above solvent can be used as injection water, and any solvent that can be used as injection water can be used without limitation.

[0118] Manufacturing example

[0119] An oily solution was prepared by dissolving orthoglycol and a biodegradable polymer in dichloromethane. A water solution containing 0.5 wt% polyvinyl alcohol, a surfactant, was prepared by mixing it with water. The oily solution and the water 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 water solution was 1:83.3. The temperature condition was maintained at 17°C, and the stirring speed was 200 rpm. Microparticles generated at the intersection where the flow of the oily solution and the flow of the water solution met were collected in a tank containing the water solution. The microparticles collected in the tank were first stirred at 17°C for 30 minutes at a speed of 200 rpm, and then the temperature was raised to 40°C to 45°C, and stirred at a speed of 400 rpm for 3 or 6 hours. The microparticles that had completed stirring were washed several times with sterilized, filtered purified water and freeze-dried to produce microparticles.

[0120]

[0121] The types and ratios of biodegradable polymers for producing the above microparticles are specifically as shown in Table 1 below:

[0122] Classification API: Polymer ratio Oil solution Water solution PVA (%) API (g) Polymer (Polymer composition ratio_%) DCM (g) Orforglipron (g) PDLG5002A (g) PDLG5002 (g) PDLG5004A (g) PDLG5004 (g) PDLG7502A (g) PDLG7504A (g) PDL02A (g) Manufacturing example 11: 50.15----0.75 (100%)--4.20.5 Manufacturing example 21: 20.3----0.6 (100%)--3.40.5 Manufacturing example 31: 1.50.3----0.45 (100%)--3.00.5 Manufacturing example 41: 20.3----0.6 (100%)--3.40.5 Manufacturing example 51: 20.3----0.45 (66.7%)0.15 (33.3%)-4.00.5 Manufacturing Example 61: 20.3----0.3 (50%)0.3 (50%)-4.20.5 Manufacturing Example 71: 20.30.06 (10%)0.12 (20%)-0.12 (20%)0.3 (50%)--3.70.5 Manufacturing Example 81: 20.30.12 (20%)--0.12 (20%)0.36 (60%)--3.70.5 Manufacturing Example 91: 20.30.06 (10%)-0.12 (20%)-0.42 (70%)--3.70.5 Manufacturing Example 101: 20.3----0.3 (50%)-0.3 (50%)3.70.5

[0123] Here, API stands for Orphoglyphron,

[0124] PDLG5002A or PDLG5002 is PLGA with an intrinsic viscosity of 0.2 dl / g and a monomer ratio of lactide:glycolide of 50:50.

[0125] PDLG5004A or PDLG5004 is PLGA with an intrinsic viscosity of 0.4 dl / g and a monomer ratio of lactide:glycolide of 50:50.

[0126] PDLG7502A is PLGA with an intrinsic viscosity of 0.2 dl / g and a monomer ratio of lactide:glycolide of 75:25.

[0127] PDLG7504A is PLGA with an intrinsic viscosity of 0.4 dl / g and a monomer ratio of lactide:glycolide of 75:25.

[0128] PDL02A is a PLA with an intrinsic viscosity of 0.2 dl / g.

[0129]

[0130] Experimental Example 1

[0131] Review of the character

[0132] The SEM images of the microparticles manufactured by Manufacturing Examples 1 to 10 are as shown in FIGS. 1 to 10, and the particle size analysis results are as shown in Table 2 below:

[0133] Manufacturing Example 1 Manufacturing Example 2 Manufacturing Example 3 Manufacturing Example 4 Manufacturing Example 5 Manufacturing Example 6 Manufacturing Example 7 Manufacturing Example 8 Manufacturing Example 9 Manufacturing Example 10D1031.9433.4933.1832.6832.6632.4636.3934.4236.9831.33D2032.8535.1234.7533.9633.9033.5537.6436.1937.89 32.28D3033.6336.4636.0935.0935.0034.5738.5437.4338.7733.08D4034.4137.613 7.2936.2036.0835.5639.3038.3939.5133.84D5035.1738.6438.3737.3237.1736.584 0.0439.2740.2534.60D6036.0439.6439.4438.4538.3037.7040.8140.1441.0235.36 D7036.9440.6840.5339.6739.4938.9341.6041.0641.7936.28D8038.3741.8141.754 1.0140.8140.3042.4842.0142.7237.42D9040.3543.2543.2942.6442.3842.0343.55 43.2743.7639.49D9541.9744.1244.4243.6943.4643.2644.4043.9245..0541.30Span value0.240.250.260.270.260.260.180.230.170.24

[0134] As shown in the above-described Figures 1 to 10 and Table 2, it was confirmed that the microparticles manufactured by Manufacturing Examples 1 to 10 exhibited a narrow particle size distribution characteristic with Span values ​​of 0.24, 0.25, 0.26, 0.27, 0.26, 0.26, 0.18, 0.23, 0.17, and 0.24.

[0135]

[0136] Experimental Example 2

[0137] Pharmacokinetic evaluation results

[0138] Pharmacokinetic evaluation was conducted using the microparticles of Manufacturing Examples 4 to 9 above.

[0139] The composition of the test group is as shown in Table 3 below:

[0140] Military prescription number, species / age / sex, number of times administered, route of administration, dosage, API, dosage (mg / head), (mL / head) Manufacturing example 4G1 Rat / 8 weeks old / male 10 SC single dose 17.360.5 Manufacturing example 5G210 Manufacturing example 6G310 Manufacturing example 7G410 Manufacturing example 8G510 Manufacturing example 9G610

[0141] For the above pharmacokinetic experiment, the supplementary solvents for preparation of injections are as shown in Table 4 below:

[0142] Dosage, Mixing Purpose, Ingredient Name, Dosage Unit, 0.5 mL, Tonicity Agent, D-Mannitol 25.00 mg, Suspending Agent, Sodium Carboxymethylcellulose 1.25 mg, Suspending Agent, Polysorbate 80 (Tween 80) 0.50 mg, Solvent, Water for Injection (WFI), Appropriate Amount mL

[0143] The test results are as shown in Fig. 11. According to Fig. 11, when the microparticles of the present invention are administered as an injection, the initial release is at a maximum of 38.963 ng / mL based on the blood concentration, but it decreases slightly thereafter, and then continuously increases again starting from 2 weeks, and the maximum blood concentration is shown between 7 and 16 weeks, after which the blood concentration decreases. Afterwards, it was confirmed that the release of orforglyphorone is shown for up to 20 weeks, confirming that the release is continuous for 1 to 5 months.

[0144] Based on the above pharmacokinetic results, the results of confirming AUC, Cmax, etc. are as shown in Table 5 below:

[0145] ParametersG1G2G3G4G5G6AUC last (ng·hr / mL)257114.992246329.567257418.471204913.219240303.534228233.961AUC inf (ng·hr / mL)261154.986259467.102268526.474205961.384241512.503229202.697C max (ng·hr / mL)256.162233.243245.002217.02263.763285.292T max (hr)184820162520117611761512AUC 0-7day (ng·hr / mL)3899.3422363.0311363.7012224.4941897.5321633.985AUC 0-7day / inf (%)1.490.910.511.080.790.71

[0146] Based on the pharmacokinetic evaluation results, AUC 0-7day (%) was derived in the same manner as Equation 1 below, and the results are as shown in Table 5 above. [Equation 1]

[0147] AUC 0-7day (%) = (AUC 0-7day / AUC inf ) * 100(%)

[0148]

[0149] According to the above experimental results, it was confirmed that by using the microparticles of the present invention, not only can bioavailability be increased, but also a sustained release effect of orthoglyphroleporone can be exhibited without initial release.

[0150] 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.

[0151] The present invention relates to microparticles comprising orthoglypholone or a pharmaceutically acceptable salt thereof and a method for producing the same.

Claims

Orforglipron or a pharmaceutically acceptable salt thereof; and a biodegradable polymer; Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The above microparticles contain orthoglyphrolone or a pharmaceutically acceptable salt thereof and a biodegradable polymer in a weight ratio of 1:1 to 1:

5. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The above biodegradable polymer is selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, and combinations thereof. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The inherent viscosity of the above biodegradable polymer is 0.1 dl / g to 0.5 dl / g. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The above microparticles contain two or more different types of biodegradable polymers. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The above micro particles have a span value of 0.5 or less. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The above microparticles have an average diameter of 20 to 60 μm. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. In the first paragraph, The above micro particles have a value of 0.1 to 3 according to the following formula 1. Microparticles comprising orphoglypholone or a pharmaceutically acceptable salt thereof: [Formula 1] AUC 0-7day / inf (%) = (AUC 0-7day / AUC inf ) * 100(%) Here, The above microparticles were administered as a single SC formulation to rats, and 17.36 mg / head of orforglipron or a pharmaceutically acceptable salt thereof was administered as a single injection, and the administered volume was 0.5 mL / head. AUC inf is the value of AUC obtained by extrapolating the drug's plasma concentration to infinity based on the rate of elimination from the blood. AUC 0-7day AUC is the value obtained by extrapolating the drug's plasma concentration to 7 days based on the rate of elimination from the blood. In the first paragraph, The above microparticles, when administered as an injection, continuously release orforglyphorone or a pharmaceutically acceptable salt thereof for more than one month. Microparticles comprising orthoglyphlorone or a pharmaceutically acceptable salt thereof. A step of preparing an oily solution comprising orthoglyphlogoporone or a pharmaceutically acceptable salt thereof and a biodegradable polymer; A step of preparing an aqueous solution by dissolving a surfactant in water; A step of forming an emulsion by mixing the oily solution and the aqueous solution; A step of obtaining the above emulsion into an aqueous solution and removing the residual solvent; and A step of washing and freeze-drying the emulsion from which the residual solvent has been removed to produce microparticles containing orthoglyphrolone or a pharmaceutically acceptable salt thereof. A method for producing microparticles comprising orforglipron or a pharmaceutically acceptable salt thereof.

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