A sustained-release microgranule preparation containing semaglutide or a pharmaceutically acceptable salt thereof, and a method for producing the same.

Abstract

The present invention provides a pharmaceutical composition comprising semaglutide or a salt thereof, a bioavailability improver, and sustained-release microspheres made of a biodegradable polymer, exhibiting high bioavailability and stable drug release characteristics over a long period of time, and a pharmaceutical composition comprising semaglutide or a salt thereof and sustained-release microspheres made of a biodegradable polymer, exhibiting safe drug release characteristics with high drug content and low initial release, and a method for producing the sustained-release microspheres. [Solution] A pharmaceutical composition for the prevention or treatment of diabetes, type 2 diabetes, preservation of beta-cell function, obesity, non-alcoholic steatohepatitis, and degenerative neurological diseases, comprising semaglutide or a salt thereof, a bioavailability improving agent, and a biodegradable polymer-based sustained-release microglobules, wherein the semaglutide or a salt thereof is present in an amount of 8% by weight or more of semaglutide relative to the total weight of the microglobules, and the bioavailability improving agent is present in an amount of 2.5% to 250% by weight relative to the weight of semaglutide, and a method for producing the same.

Description

Technical Field

[0001] The present invention relates to a sustained-release microparticle containing semaglutide with improved bioavailability or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing a sustained-release microparticle containing a high content of semaglutide, and a method for producing the sustained-release microparticle.

Background Art

[0002] Glucagon-like peptide-1 (GLP-1) is derived from pre-proglucagon, a 158-amino acid precursor polypeptide that is processed in different tissues, and forms numerous different proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and oxyntomodulin (OXM), which are involved in diverse physiological functions such as glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake. GLP-1 is produced as a 37-amino acid peptide corresponding to amino acids 72-108 of proglucagon (92-128 of preproglucagon). GLP-1(7-36) amide or GLP-1(7-37) acid is the biologically active form of GLP-1 that exhibits essentially equivalent activity at the GLP-1 receptor. GLP-1 and GLP-1 analogs that act as agonists at the GLP-1 receptor have been shown to provide effective glycemic control, for example, for treating patients with type 2 diabetes, and also provide other effects such as weight loss, preservation of beta-cell function, and reduction of hypertension, hypoglycemia, and / or hyperlipidemia. Certain GLP-1 analogs, including Byetta® Bydureon® & Bydurepn PEN® & Bydureon BCise® (exenatide), Ozempic® & Wegovy® (semaglutide), Victoza® & Saxenda® (liraglutide), Adlyxin® (lixisenatide); Tanzeum® (albiglutide), and Trulicity® (dulaglutide), are commercially available or in development.

[0003] GLP-1 agonists such as semaglutide are peptides, and their administration is often hampered by various barriers, including enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption from the intestinal mucosa, and first-pass metabolism in the liver. Therefore, they are primarily administered by injection. Although oral formulations have recently been commercialized, their bioavailability is very low compared to injectable formulations, and the required dosage is considerably higher. Furthermore, semaglutide-containing preparations are formulated for self-administration by patients for the continuous management of obesity and diabetes, making it extremely important to manage pain and inflammatory reactions that may occur at the injection site.

[0004] On the other hand, a technique for encapsulating semaglutide in microglobules made of biodegradable polymers for long-term release of semaglutide is known. However, in this case, the bioavailability of semaglutide encapsulated in microglobules is low, or the drug content within the microglobules is low, requiring the administration of a large number of microglobules to achieve a long-term effective pharmacological effect. However, administering a large number of microglobules into the body is difficult by subcutaneous injection, making it difficult for patients to administer them themselves (self-administration), and there are problems such as increased pain and inflammatory reactions at the injection site. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] The present invention was proposed to solve the above-mentioned problems, and aims to provide a pharmaceutical composition comprising semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and sustained-release microspheres made of a biodegradable polymer, exhibiting high bioavailability of semaglutide and stable drug release characteristics over a long period of time, and a pharmaceutical composition comprising semaglutide or a pharmaceutically acceptable salt thereof and sustained-release microspheres made of a biodegradable polymer, exhibiting safe drug release characteristics with high drug content and low initial release, and a method for producing said sustained-release microspheres. [Means for solving the problem]

[0006] The present invention will be described in detail below.

[0007] In this invention, the term "one or more" means one or more types. In the present invention, if there is one or more components, it is preferably one, two or more, three or more, one to three, or one to two components, but is not limited thereto.

[0008] In order to achieve the aforementioned objective, As one aspect of this invention, the present invention provides a pharmaceutical composition containing semaglutide-releasing microparticles that include a biodegradable polymer, have a semaglutide content of 8% by weight or more of semaglutide relative to the total weight of microparticles, and contain a bioavailability improving agent in an amount of 2.5% to 250% by weight relative to the weight of semaglutide.

[0009] In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of diabetes, type 2 diabetes, beta-cell function preservation, obesity, non-alcoholic steatohepatitis, or degenerative neurological disorders, comprising semaglutide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and a biodegradable polymer, wherein the semaglutide or a pharmaceutically acceptable salt thereof is present in an amount of 8% by weight or more of semaglutide based on the total weight of the microparticles, and the initial release inhibitor is present in an amount of 5 ppm to 2000 ppm.

[0010] Another aspect of the biodegradable polymers is that they include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyamino acid, polyalkyl cyanoacrylate (Polyalkyl Polymers selected from the group consisting of block copolymers of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); simple mixtures of two or more of these; copolymers of the polymer with polyethylene glycol (Polyethylenglycol, PEG);The following may be selected from the group consisting of a polymer-sugar complex in which the polymer or copolymer and sugar are bonded:

[0011] Another aspect is that the bioavailability improving agent includes sodium decanoate, disodium phosphate, choline, meglumine, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, ammonium phosphate, histidine, HEPES, HEPPS, spermine, spermidine, putrescine, methylene blue, proline, sugar, glycerol, surfactant, arginine, glycine, guanidine hydrochloride, urea, sodium chloride, and potassium chloride. Chloride, triethylamine, ethanolamine, triethanolamine, ethylenediamine, poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, rhizolutin, benzofuran, magnesium carbonate, magnesium hydroxide, magnesium oxide It may be one or more selected from the group consisting of oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, aluminum phosphate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxide, magaldrate, and benzofuran derivatives.

[0012] Another aspect is that the pharmaceutically acceptable salts of semaglutide may be the sodium salt, acetate salt, benzoate salt, hydroxynaphthoate salt, napadisylate salt, or pamoate salt of semaglutide.

[0013] Another aspect may be that the biodegradable polymer has an intrinsic viscosity of 0.16 to 1.7 dL / g of poly(lactide-co-glycolide), polyglycolide, or polylactide.

[0014] Another aspect is that the average particle size of the microparticles containing the semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent may be 5 μm to 100 μm.

[0015] Another aspect may be that the granulocyte span value containing the semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent is 1.5 or less.

[0016] Another aspect is that the weight of microglobules containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver is 20-1000 mg, 20-800 mg, 20-600 mg, 20-400 mg, 20-200 mg, 20-100 mg, 30-1000 mg, 30-800 mg, 30-600 mg, 30-400 mg, 30 It may also be 50mg-200mg, 30mg-100mg, 40mg-1000mg, 40mg-800mg, 40mg-600mg, 40mg-400mg, 40mg-200mg, 40mg-100mg, 50mg-1000mg, 50mg-800mg, 50mg-600mg, 50mg-400mg, 50mg-200mg, or 50mg-100mg.

[0017] Another aspect may be the inclusion of one or more release regulators selected from butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, napadisylic acid, naphthalenesulfonic acid, and pamoic acid.

[0018] Another aspect is that the granulocytes may contain 1 to 100 mg / kg of Na.

[0019] Another aspect is that the microglobules may contain 10 to 500 mg / kg of phosphorus.

[0020] Another aspect of the present invention is the provision of a method for producing sustained-release microglobules containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent.

[0021] Another aspect of the manufacturing method is that it may use a continuous phase containing an initial release inhibitor.

[0022] As another aspect, the initial release inhibitor may be a salt that is dissolved in the continuous phase during the production of the microspheres containing semaglutide to maintain the pH of the continuous phase at 7.0 or higher.

[0023] As another aspect, the initial release inhibitor can use a substance that forms one or more anions selected from phosphate salts, phosphide salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalate salts, silicate salts, sulfate salts, sulfide salts, sulfite salts, tartrate salts, tetraborate salts, thiosulfate salts, arsenate salts, arsenite salts, citrate salts, ferricyanide salts, and nitride salts of alkali metals, alkaline earth metals or ammonium. As another aspect, the initial release inhibitor may be one or more selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium phosphate.

[0024] As another aspect, provided are a pharmaceutical composition containing sustained-release microspheres containing a biodegradable polymer and having a semaglutide content of 8% by weight or more as semaglutide based on the total weight of the microspheres and an initial drug release of 10% or less, and a method for producing the same. [Effect of the Invention]

[0025] The sustained-release pharmaceutical composition containing semaglutide, its pharmaceutically acceptable salt, and a bioavailability improver according to one production example of the present invention can contain a high content of drug compared to the particle size, has a high bioavailability when administered in vivo, shows a long-term sustained effect, and can reduce the dose, so it has the effect of minimizing the pain and inflammatory reactions of patients that may occur during administration. [Brief Description of the Drawings]

[0026] [Figure 1] It is a graph showing the change in blood drug concentration over time after administering microspheres containing semaglutide produced in Production Example 12 to rats. [Figure 2]This bar graph shows the initial release of semaglutide-containing granules produced in manufacturing examples 5, 6, 10, and 15. [Figure 3a] This is a scanning electron microscope (SEM) image showing a cross-section of microspheres manufactured using only 0.1(w / v)% PVA in the continuous phase. [Figure 3b] This is a scanning electron microscope image showing a cross-section of microspheres prepared using 0.1(w / v)% PVA and 2(w / v)% Na2HPO4 as the continuous phase. [Modes for carrying out the invention]

[0027] The present invention will be described in detail below.

[0028] The present invention comprises semaglutide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029] Semaglutide is a GLP-1 receptor agonist. 6.26 This is -{18-[N-(17-carboxyheptadecanoyl)-L-γ-glutamyl]-10-oxo3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1(7-37), and is also sometimes called N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37). The structure of semaglutide is as shown in Chemical Formula 1 below.

[0030] [ka]

[0031] Such semaglutides can be manufactured as described in Manufacturing Example 4 of International Patent Publication WO2006 / 097537, or commercially available semaglutides can be used.

[0032] Semaglutide may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Any salt commonly used in the industry may be used without limitation. The term “pharmaceutically acceptable salt” in this invention means any organic or inorganic addition salt of the compound in which, at concentrations that are relatively non-toxic and harmless to the patient, the side effects resulting from the salt do not diminish the beneficial efficacy of the active ingredient. Specific examples include, but are not limited to, sodium, acetate, benzoate, hydroxynaphthoate, napadisylate, or pamoate of semaglutide.

[0033] The active ingredient of the present invention, semaglutide or a pharmaceutically acceptable salt thereof, may be in various forms, such as amorphous or crystalline.

[0034] In this invention, "bioavailability improving agent" refers to a substance that improves bioavailability when encapsulated within microglobulins together with the active ingredient semaglutide or a pharmaceutically acceptable salt thereof. Specifically, it refers to a substance that, when contained within sustained-release microglobulins containing semaglutide or a pharmaceutically acceptable salt thereof and administered into the body, increases the area under the blood concentration-time curve (AUC) of semaglutide compared to microglobulins that do not contain the "bioavailability improving agent." More specifically, when sustained-release microglobulins are administered to rats, when 1 mg / kg of semaglutide is administered, the area under the blood concentration-time curve (AUC) of semaglutide increases. total This refers to a substance whose (mg / kg) is expressed as 600 ng*day / mL or more, preferably 1,000 ng*day / mL or more, and more preferably 1,300 ng*day / mL or more.

[0035] In one specific example, the bioavailability improving agent is sodium decanoate. decanoate), disodium hydrogen phosphate, choline, meglumine, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, ammonium phosphate, histidine, HEPES (Hydroxyethyl piperazine Ethane Sulfonic Acid), HEPPS (4-(2-Hydroxyethyl)piperazine-1-propanesulfonic acid), spermine, spermidine, putrescine, methylene blue, proline, sugars, glycerol, surfactant, arginine, glycine, guanidine hydrochloride Hydrochloride, urea, sodium chloride, potassium chloride, triethylamine, ethanolamine, triethanolamine, ethylenediamine, poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, rhizolutin, benzofuran, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate It may be one or more selected from the group consisting of carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, aluminum phosphate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxide, magaldrate, and benzofuran derivatives.

[0036] More specifically, the bioavailability improving agent may be one or more selected from the group consisting of sodium decanoate, disodium hydrogen phosphate, choline, histidine, HEPES, glycerol, surfactants such as Twin 80 and Span 80, arginine, poloxamer, benzathine, and bupivacaine, but is not limited thereto.

[0037] More specifically, the bioavailability improving agent may be one or more selected from the group consisting of sodium decanoate, disodium hydrogen phosphate, poloxamer F127, and benzathine, but is not limited thereto.

[0038] In specific forms, the bioavailability improving agent may be included in amounts of 2.5% to 250% by weight, 2.5% to 200% by weight, 2.7% to 150% by weight, or 2.7% to 100% by weight relative to the weight of semaglutide, but is not limited to these amounts.

[0039] The pharmaceutical composition according to the present invention provides the area under the blood concentration-time curve (AUC) of semaglutide up to 24 hours after administration. 0-24hr ) is the area under the total blood concentration-time curve (AUC). total ) may be 20% or less, 10% or less, 5% or less, 0.1-20%, 1-10%, or 1-5%.

[0040] The pharmaceutical composition according to the present invention has an area under the blood concentration-time curve (AUC) of semaglutide from administration to the dosing interval day. 0-QXM ) is the area under the total blood concentration-time curve (AUC). total ) may be 95% or less, 90% or less, 85% or less, 0.1-95%, 1-95%, 10-95%, 1-90%, 10-90%, 20-95%, 30-95%, 40-95%, 50-95%, 60-95%, 70-95%, 80-95%, or 70-85%.

[0041] Furthermore, the pharmaceutical composition according to the present invention may also be a pharmaceutical composition containing sustained-release microglobules in which the semaglutide content is 12% by weight or more of semaglutide relative to the total microglobule weight, while the initial release of the drug is less than 10% within 24 hours.

[0042] The biodegradable polymers contained in the semaglutide-releasing microspheres of the pharmaceutical composition according to the present invention include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), which is a copolymer of lactide and glycoside, polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyamino acid, polyalkyl cyanoacrylate (PolyalkylThe polymer is selected from the group consisting of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA), two or more simple mixtures, copolymers of the polymer and polyethylene glycol (Polyethylenglycol, PEG), and polymer-sugar complexes in which the polymer or copolymer is bonded to a sugar.

[0043] In one specific embodiment, the pharmaceutical composition according to the present invention may include microparticles containing two or more of the biodegradable polymers. In another specific embodiment, the pharmaceutical composition according to the present invention may contain two or more microparticles, each containing one or more polymers selected from the biodegradable polymers.

[0044] Two or more polymers selected from the group consisting of poly-lactide-co-glycolide and polylactide polymers may have intrinsic viscosities of 0.16 dL / g to 1.7 dL / g, 0.2 dL / g to 1.3 dL / g, or 0.24 dL / g to 1.2 dL / g, although these are not limited to the above.

[0045] The intrinsic viscosity of the polylactide-coglycolide or polylactide used in this invention refers to the viscosity measured at 25°C in chloroform at a concentration of 0.1% (w / v) using an Ubbelohde viscometer. If the intrinsic viscosity of the polylactide-coglycolide or polylactide is less than 0.16 dL / g, the molecular weight of the polymer is insufficient, making it difficult to exhibit a sustained-release effect of semaglutide or its pharmaceutically acceptable salt. If the intrinsic viscosity exceeds 1.7 dL / g, an effect of excessively delayed release of semaglutide or its pharmaceutically acceptable salt may be observed. Furthermore, when producing microspheres using polymers with high intrinsic viscosity, there is a problem that an excessive amount of the production solvent must be used due to the high viscosity of the polymer, making it difficult to produce reproducible microspheres. Examples of commercially available polymers having the aforementioned properties include Evonik's Resomer® series, such as RG502H, RG503H, RG504H, RG502, RG503, RG504, RG653H, RG752H, RG752S, RG755S, RG750S, RG757S, RG858S, R202H, R203H, R205H, R202S, R203S, R205S, R206S, and R207S, as well as Corbion's PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG7502, PDLG7507, PDLG 5002A, PDLG 5002, PDLG 5004A, and PDLG 5004.

[0046] The biodegradable polymer content in sustained-release microglobulins containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention may be 60% to 95% by weight, 65% to 93% by weight, or 70% to 90% by weight relative to the total weight of microglobulins, but is not limited thereto.

[0047] The content of semaglutide or its pharmaceutically acceptable salt in sustained-release microglobulins containing semaglutide or its pharmaceutically acceptable salt and a bioavailability improving agent according to the present invention is preferably 8% or more by weight, 12% or more by weight, 14% or more by weight, 37% or less by weight, 35% or less by weight, or 33% or less by weight as semaglutide relative to the total weight of microglobulins. If the content of semaglutide or its pharmaceutically acceptable salt in microglobulins is less than 8% by weight based on semaglutide, the amount of high molecular weight used may be excessively large compared to the drug, which may lower the bioavailability of semaglutide or its pharmaceutically acceptable salt. If the content is excessively high, there is a problem of increased initial release of semaglutide or its pharmaceutically acceptable salt, which is undesirable.

[0048] Microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent according to the present invention have average particle sizes of 5 μm to 100 μm, 5 to 90 μm, 5 μm to 80 μm, 10 μm to 90 μm, 10 μm to 80 μm, 15 μm to 100 μm, 15 μm to 90 μm, 15 μm to 80 μm, 70 μm to 100 μm, 70 μm to 90 μm, 70 μm to 80 μm, and 60 μm to 100 μm. Preferably, the particles have a uniform particle distribution of 60μm~80μm, 60μm~70μm, 20μm~90μm, 20μm~70μm, 20μm~60μm, 30μm~80μm, 30μm~60μm, 40μm~70μm, 40μm~50μm, 30μm~40μm, 20μm~30μm, 5μm~30μm, 5μm~20μm, 10μm~20μm, or 5μm~10μm. The term "average particle size" used in this invention refers to the particle size that corresponds to 50% of the volume % in the particle size distribution curve, and means the median diameter, expressed as D50 or D(v, 0.5).

[0049] If the average particle size of microglobules containing semaglutide or a pharmaceutically acceptable salt and a bioavailability enhancer is less than 5 μm, it is undesirable because the release of semaglutide or a pharmaceutically acceptable salt from the microglobules will be excessively rapid. If the average particle size exceeds 100 μm, it is undesirable because the injection needle will become excessively thick during administration to the human body, which may induce pain during injection or cause leakage of the drug from the injection site after injection.

[0050] Microparticles containing semaglutide or a pharmaceutically acceptable salt and bioavailability improving agent of the present invention preferably have a uniform particle distribution. Microparticles containing semaglutide or a pharmaceutically acceptable salt and bioavailability improving agent having a uniform particle distribution have a smaller injection deviation compared to non-uniform microparticles, allowing for more accurate dosage administration. The span value of the microparticles containing semaglutide or a pharmaceutically acceptable salt and bioavailability improving agent of the present invention is preferably 1.5 or less. More preferably, the span value is 1.2 or less. More specifically, the span value may be 1.5 or less, 1.2 or less, 0.1 to 1.5, 0.3 to 1.5, 0.5 to 1.5, 0.1 to 1.0, 0.4 to 1.0, 0.6 to 1.0, 0.2 to 0.8, or 0.4 to 0.8. The term "span value" used in this invention is an index indicating the uniformity of particle size of microspheres, and refers to the value obtained by the formula Span value = (Dv0.9 - Dv0.1) / Dv0.5. Here, Dv0.1 refers to the particle size corresponding to 10% of the volume % on the particle size distribution curve of the microspheres, Dv0.5 refers to the particle size corresponding to 50% of the volume % on the particle size distribution curve of the microspheres, and Dv0.9 refers to the particle size corresponding to 90% of the volume % on the particle size distribution curve of the microspheres.

[0051] The sustained-release microglobulins of the present invention, containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, are administered via an injection route, such as subcutaneous injection, and are particularly self-administerable, so it is preferable that semaglutide is released over a relatively long period of time. Preferably, the sustained-release microglobulins in the pharmaceutical composition of the present invention, although not limited thereto, can release semaglutide or a pharmaceutically acceptable salt thereof for 1 month or more, 2 months or more, 3 months or more, 1 to 2 months, 1 to 3 months, 1 to 4 months, 1 to 5 months, 1 to 6 months, 2 to 6 months, 2 to 5 months, 2 to 4 months, 2 to 3 months, 3 to 5 months, or 3 to 4 months. Furthermore, while the release pattern of the sustained-release microglobulins containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent of the present invention is not particularly limited, it is preferable that when administered into the body, semaglutide or a pharmaceutically acceptable salt thereof is released at a rate of less than 10%, less than 15%, or less than 20% within 24 hours.

[0052] Furthermore, the total amount of sustained-release microgranulocyte preparations containing the semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent in the pharmaceutical composition of the present invention is 20-1000 mg, 20-800 mg, 20-600 mg, 20-400 mg, 20-200 mg, 20-100 mg, 30-1000 mg, 30-800 mg, 30-600 mg, and 30 mg The dosage may be ~400mg, 30mg~200mg, 30mg~100mg, 40mg~1000mg, 40mg~800mg, 40mg~600mg, 40mg~400mg, 40mg~200mg, 40mg~100mg, 50mg~1000mg, 50mg~800mg, 50mg~600mg, 50mg~400mg, 50mg~200mg, or 50mg~100mg. The composition contains sustained-release microglobulins containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer within the above ranges, and the composition according to the present invention has the advantage of not only minimizing inflammatory responses at the administration site but also enabling patient self-administration.

[0053] Microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer may further contain a release regulator. Examples of substances used as release regulators include, but are not limited to, one or more selected from butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, napadisylic acid, naphthalenesulfonic acid, and pamoic acid. Preferably, the release regulator may be, but is not limited to, hydroxynaphthoic acid, napadisylic acid, or pamoic acid.

[0054] The pharmaceutical composition comprising semaglutide or a pharmaceutically acceptable salt thereof and microparticles containing a bioavailability enhancer according to the present invention can be formulated into various dosage forms, for example, known parenteral formulations. Thus, the pharmaceutical composition according to the present invention may further contain, in addition to the semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer, a viscosity enhancer, a stabilizer, an isotonic agent, an initial release inhibitor, a surfactant, an excipient, and / or a carrier. Examples of usable isotonic agents include water-soluble excipients or sugars such as mannitol, sucrose, sorbitol, trehalose, lactose, and sodium chloride, and examples of viscosity enhancers include carmellose sodium, carboxymethylcellulose sodium, and povidone. In addition, buffering agents such as monohydrogen phosphate, anhydrous citric acid, sodium hydroxide, and sodium chloride can be used.

[0055] The pharmaceutical composition containing sustained-release microglobulins according to the present invention may contain a microglobulin initial release inhibitor in an amount less than a certain level.

[0056] In the present invention, the initial release inhibitor is a substance included in the continuous phase to suppress the rapid release of the active ingredient in the microparticle manufacturing process, and is characterized by being present in less than a certain amount in the microparticles according to the present invention.

[0057] Specifically, the initial release inhibitor may be present in an amount of 5 to 2000 ppm, preferably 10 to 1500 ppm, more preferably 20 to 1000 ppm, and most preferably 20 to 500 ppm, relative to the total weight of microspheres.

[0058] Specifically, the initial release inhibitor is a substance that, when dissolved in the continuous phase, can maintain the pH of the continuous phase at 7 or higher, more specifically, 7 or higher, 7.2 or higher, 7.4 or higher, 8.0 or higher, 8.5 or higher, 9.0 or higher, 7.0 to 9.0, or 7.0 to 8.5, and any substance that can form divalent or higher anions in the continuous phase can be used. The initial release inhibitor may be one or more selected from alkali metals, alkaline earth metals, or ammonium phosphate salts, phosphide salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalate salts, silicate salts, sulfate salts, sulfide salts, sulfite salts, tartrate salts, tetraborate salts, thiosulfate salts, arsenate salts, arsenite salts, citrates, felicyanide salts, and nitride salts, but is not limited thereto.

[0059] Specifically, the initial release inhibitor may be one or more substances selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium phosphate, but is not limited thereto.

[0060] The pharmaceutical compositions according to the present invention can be administered in therapeutically effective doses of semaglutide, for example, to treat diabetes, specifically type 2 diabetes, beta-cell function preservation, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, or degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease. The therapeutically effective dose of semaglutide can be evaluated by a physician. The pharmaceutical compositions according to the present invention, which contain semaglutide, can also be administered once a month to once a quarter. In some specific examples, the monthly dose of the compositions according to the present invention, based on semaglutide, is 1 mg to 100 mg, 1 mg to 80 mg, 1 mg to 60 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 6 mg, 2 mg to 100 mg, 2 mg to 80 mg, 2 mg to 60 mg, 2 mg to 30 mg, 2 mg to 20 mg, 2 mg to 10 mg, 2 mg to 8 mg, and 2 mg The dosage may be ~6 mg, 4 mg~100 mg, 4 mg~80 mg, 4 mg~60 mg, 4 mg~30 mg, 4 mg~20 mg, 8 mg~100 mg, 8 mg~80 mg, 8 mg~60 mg, 8 mg~30 mg, 10 mg~100 mg, 10 mg~80 mg, 10 mg~60 mg, 10 mg~30 mg, 20 mg~100 mg, 20 mg~80 mg, 20 mg~60 mg, or 20 mg~30 mg. The pharmaceutical composition according to the present invention, comprising semaglutide or a pharmaceutically acceptable salt thereof and microparticles containing a bioavailability enhancer, can also be administered parenterally, for example, by subcutaneous injection. The pharmaceutical composition according to the present invention may consist of a drug portion containing microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver, and a solvent portion used to suspend the microspheres. It may also be in the form of a double-chamber syringe with the drug portion in one chamber and the solvent portion in the other, or a pre-filled syringe in which the drug portion is suspended in the solvent portion. When configured in this pre-filled syringe form in which the drug portion is suspended in the solvent portion, the solvent portion used may be an injectable oil containing medium-chain oil, mineral oil, etc.

[0061] In one specific embodiment, sustained-release microglobulins containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, as contained in the pharmaceutical composition according to the present invention, have a higher drug content compared to the microglobulin content, while suppressing the initial excessive release of the drug which may cause fatal side effects, resulting in high bioavailability and sufficient efficacy as a GLP-1 inhibitor for the desired period. This makes them useful for the prevention or treatment of diabetes, specifically type 2 diabetes, beta-cell function preservation, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, or degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease.

[0062] In another embodiment, the present invention provides a method for producing sustained-release microglobules containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent.

[0063] In another embodiment, the present invention provides a method for producing sustained-release microglobules in which initial release is significantly suppressed despite containing a high content of semaglutide or a pharmaceutically acceptable salt thereof.

[0064] The following describes in detail a method for producing a sustained-release microglobulin injection containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent of the present invention.

[0065] The sustained-release microglobulin injection formulation containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer according to the present invention can be manufactured, for example, by the "solvent extraction and evaporation method," but the manufacturing method is not limited thereto.

[0066] As one specific example of a manufacturing method, the present invention provides a method for producing sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, comprising the following steps: (a) a step of dissolving semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improving agent, and one or more biodegradable polymers in one or more organic solvents to produce a solution (dispersed phase) containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improving agent, and a polymer; (b) the semaglutide produced in step (a); (c) A step of adding a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer-containing solution to an aqueous solution (continuous phase) containing a surfactant to produce an emulsion; (b) A step of extracting and evaporating an organic solvent from the dispersed emulsion phase produced in step (b) as a continuous phase to form microspheres; and (d) A step of recovering the microspheres from the continuous phase in step (c) to produce microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver with improved bioavailability.

[0067] Another aspect is that the bioavailability improving agent in step (a) above may be one or more selected from the group consisting of poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, lysoltin, and benzofuran.

[0068] In another aspect, the present invention provides a method for producing sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, comprising the following steps: (a') Dissolving semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent in an aqueous solution to create a primary aqueous solution phase, dissolving one or more biodegradable polymers in an organic solvent to create an oil phase, and then mixing the primary aqueous solution and the oil phase to produce a W / O emulsion (primary emulsion) containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improving agent, and a polymer; (b') The product produced in step (a') (c') A step of producing a W / O / W emulsion (secondary emulsion) by adding a primary emulsion containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer to an aqueous phase (continuous phase) containing a surfactant; (c') A step of extracting and evaporating an organic solvent from the oil phase of the secondary emulsion produced in step (b') as a continuous phase to form microspheres; (d') A step of recovering the microspheres from the continuous phase in step (c') to produce microspheres containing semaglutide or a pharmaceutically acceptable salt thereof with improved bioavailability, and a bioavailability improver.

[0069] Another aspect is that in step (a') above, the bioavailability improving agent may be one or more selected from the group consisting of sodium decanoate, disodium hydrogen phosphate, choline, meglumine, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, ammonium phosphate, histidine, HEPES, HEPPS, spermine, spermidine, putrescine, methylene blue, proline, sugars, glycerol, surfactants, arginine, glycine, guanidine hydrochloride, urea, sodium chloride, potassium chloride, triethyleneamine, ethanolamine, triethanolamine, and ethylenediamine.

[0070] Another aspect of the present invention provides a method for producing sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, comprising the following steps: (a) A step of dissolving semaglutide or a pharmaceutically acceptable salt thereof and one or more biodegradable polymers in an organic solvent and suspending a bioavailability improving agent in this solution to produce a suspension (dispersed phase) containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improving agent, and a polymer; (b) The semaglutide produced in step (a) above (c) A step of producing an emulsion by adding a pharmaceutically acceptable salt, a bioavailability improving agent, and a polymer-containing suspension to an aqueous solution phase (continuous phase) containing a surfactant; (c) A step of extracting and evaporating an organic solvent from the dispersed emulsion phase produced in step (b) as a continuous phase to form microspheres; and (d) A step of recovering the microspheres from the continuous phase in step (c) to produce microspheres containing semaglutide or a pharmaceutically acceptable salt thereof with improved bioavailability, and a bioavailability improving agent.

[0071] Another aspect is that in step (a) above, the bioavailability improving agent may be one or more selected from the group consisting of magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, aluminum phosphate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxydolamaldrate, and benzofuran derivatives.

[0072] Another aspect is that the pH of the continuous phase used in the above manufacturing method may be 7 or higher.

[0073] In the production of sustained-release microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent according to the present invention, a biodegradable polymer can be used, but is not limited thereto, to suppress the excessive release of initial semaglutide or a pharmaceutically acceptable salt thereof while containing a high amount of semaglutide or a pharmaceutically acceptable salt thereof relative to the weight of the microparticles, thereby achieving high bioavailability and releasing at a constant concentration for a desired long period, such as 1 month or more, 3 months or more, 1 to 2 months, 1 to 3 months, 1 to 4 months, 1 to 5 months, 1 to 6 months, 2 to 6 months, 2 to 5 months, 2 to 4 months, 2 to 3 months, 3 to 5 months, or 3 to 4 months. Specifically, these include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), a copolymer of lactide and glycoside, polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarateIt is preferable to use polymers selected from the group consisting of fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate lactide) (PBSLA), two or more simple mixtures, copolymers of the polymer and polyethylene glycol (Polyethylenglycol, PEG), and polymer-sugar complexes in which the polymer or copolymer is bonded to a sugar, preferably two or more polymers. In one specific embodiment, the production method according to the present invention can use poly(lactide-co-glycolide) and / or polylactide polymers as biodegradable polymers.

[0074] In the present invention, two or more different biodegradable polymers may include two or more polymers with different repeating units and two or more repeating units, or two or more polymers with different molar ratios of repeating units. For example, the microspheres may be a mixture of microspheres containing poly-lactide-co-glycolide and microspheres containing polylactide polymer, or microspheres containing both poly-lactide-co-glycolide and polylactide polymer.

[0075] Furthermore, as a specific example, if there are two different biodegradable polymers, the content ratio of these biodegradable polymers by weight may be 0.5:10~10:0.5, 0.5:8~8:0.5, 1:10~10:1, 1:4~4:1, 1:3~3:1, or 1:2~2:1, but is not limited to these.

[0076] More specifically, when polylactide-co-glycolides are used as two or more biodegradable polymers to produce sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent according to the present invention, at least one or more biodegradable polymers having an intrinsic viscosity of 0.16 dL / g to 0.45 dL / g may be included.

[0077] The organic solvent used to dissolve one or more biodegradable polymers in step (a), (a'), or (a) of the specific manufacturing method described above is one or more organic solvents. Alternatively, a mixed organic solvent, which is a mixture of two or more organic solvents, may be used. Specifically, the mixed solvent may be a mixture of an organic solvent that is miscible with water and an organic solvent that is not miscible with water. In this case, it is preferable to use the organic solvent that is not miscible with water in an amount of at least 50% (v / v), 60% (v / v), 50-99.9% (v / v), 50-90% (v / v), 50-80% (v / v), 50-70% (v / v), 60-90% (v / v), or 60-80% (v / v). By utilizing the water-immiscible nature of the organic solvent, the dispersed phase can be homogeneously mixed in a continuous phase containing a surfactant in step (b), (b'), or (b) described later to form an emulsion. The type of organic solvent used to dissolve one or more such biodegradable polymers is not particularly limited, but preferably, a mixed solvent of one or more solvents selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol can be used. More preferably, one solvent selected from dichloromethane and ethyl acetate and one or more organic solvents selected from dimethyl sulfoxide, enmethylpyrrolidone, methyl alcohol, and acetic acid can be used.

[0078] The method for homogeneously mixing the dispersed phase and the continuous phase containing the surfactant in step (b), (b'), or (b") is not particularly limited, but can be carried out using a high-speed stirrer, an in-line mixer, a membrane emulsion method, a microfluidic emulsion method, an ultrasonic mixer, or a static mixer. When forming an emulsion using a high-speed stirrer, an in-line mixer, an ultrasonic mixer, or a static mixer, it is difficult to obtain a uniform emulsion, so it is preferable to perform an additional sieving step or the like between step (c) and step (d), between step (c') and step (d'), or between step (c") and step (d") described below.

[0079] The type of surfactant used in step (b), (b'), or (b") is not particularly limited, and any surfactant that can help the dispersed phase form a stable droplet dispersion phase within the continuous phase can be used. The surfactant may be polyvinyl alcohol.

[0080] In step (b), (b'), or (b") above, the surfactant content in the continuous phase containing the surfactant may be 0.01 w / v% to 20 w / v%, preferably 0.03 w / v% to 18 w / v%, 0.05 w / v% to 15 w / v%, 0.07 w / v% to 10 w / v%, or 0.1 w / v% to 5 w / v%, based on the total volume of the continuous phase containing the surfactant. If the surfactant content is less than 0.01 w / v%, droplet-shaped dispersed phases or emulsions may not form in the continuous phase, and if the surfactant content exceeds 20 w / v%, fine particles may form in the continuous phase due to the excess surfactant, and it may be difficult to remove the surfactant afterward.

[0081] The continuous phase used in step (b), (b'), or (b") above may be water and may additionally contain an initial release inhibitor, which is a substance that forms a polyvalent anion when dissolved in water to control the initial release of microspheres containing a high concentration of drug.

[0082] In steps (b), (b'), or (b") above, the type of initial release inhibitor is not particularly limited, and any basic salt that can be dissolved in the continuous phase and maintained at a pH of 7.0 or higher can be used. The initial release inhibitor can be one or more substances selected from alkali metals, alkaline earth metals, or ammonium phosphate salts, phosphine salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalate salts, silicate salts, sulfate salts, sulfide salts, sulfite salts, tartrate salts, tetraborate salts, thiosulfate salts, arsenate salts, arsenite salts, citrates, felicyanide salts, and nitride salts.

[0083] Specifically, the initial release inhibitor may be one or more substances selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium phosphate, but is not limited thereto.

[0084] In step (b), (b'), or (b") above, the content of the initial release inhibitor in the continuous phase used may be 0.05 w / v% to 20 w / v%, preferably 0.1 w / v% to 15 w / v%, more preferably 0.2 w / v% to 12.5 w / v%, and most preferably 0.3 w / v% to 10 w / v%, based on the total volume of the continuous phase containing the initial release inhibitor. If the content of the initial release inhibitor exceeds 20 w / v%, the emulsion droplets may burst during granule production. Conversely, if it is lower than 0.05 w / v%, the initial release of granules containing high levels of semaglutide may not be sufficiently suppressed.

[0085] When the initial release inhibitor is included in the continuous phase during microbulb production, the initial release in microbulbs containing 12(w / w) or more semaglutide can be preferably reduced to 10% or less, more preferably to 8% or less, and most preferably to 5% or less.

[0086] The continuous phase used in step (b), (b'), or (b") above may be water, and water partially containing one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate may be used to adjust the extraction rate of the organic solvent from the dispersed phase in emulsion state.

[0087] Furthermore, the pH of the continuous phase may be, but is not limited to, 7.0 or higher, 7.2 or higher, 7.4 or higher, 8.0 or higher, 8.5 or higher, 9.0 or higher, 7.0 to 9.0, or 7.0 to 8.5. When the pH of the continuous phase is adjusted within the above range, the bioavailability of microparticles containing semaglutide or a pharmaceutically acceptable salt thereof may be further increased.

[0088] In step (c), (c'), or (c"), if the emulsion containing the droplet-form dispersed phase and the continuous phase containing the surfactant is maintained or stirred at a temperature below the boiling point of the organic solvent for a certain period of time, for example, 2 to 48 hours, the organic solvent is extracted from the dispersed phase, which consists of droplet-form semaglutide or its pharmaceutically acceptable salt, a bioavailability enhancer, and a polymer solution, as the continuous phase. Some of the organic solvent extracted as the continuous phase may evaporate from the surface. While the organic solvent is extracted and evaporated from the droplet-form semaglutide or its pharmaceutically acceptable salt, the bioavailability enhancer, and the polymer solution, the droplet-form dispersed phase can solidify to form microspheres.

[0089] In step (c), (c'), or (c") above, the temperature of the continuous phase may be heated for a certain period of time to further efficiently remove the organic solvent. The heating temperature is not limited and can be appropriately adjusted by a typical technician of the industry depending on the organic solvent used. For example, when using dichloromethane as the organic solvent, the heating may be applied to maintain a temperature of 30°C or higher, 40°C or higher, 45°C or higher, 30-50°C, 40-50°C, or 45°C.

[0090] In step (d), (d'), or (d"), the method for recovering the microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer can be carried out using various known techniques, such as filtration or centrifugation.

[0091] Between steps (c) and (d), between steps (c') and (d'), or between steps (c") and (d"), residual surfactants can be removed by filtration and washing, and the fine particles can be recovered by filtration again.

[0092] The washing step to remove any remaining surfactant can usually be performed using water, and this washing step can be repeated several times.

[0093] Furthermore, as mentioned above, uniform microspheres can be obtained by additionally using a sieving process between steps (c) and (d), between steps (c') and (d'), or between steps (c") and (d)). The sieving process can be performed using known techniques, and microspheres of small and large particles can be filtered using sieves of different sizes to obtain microspheres of uniform size.

[0094] In the manufacturing method of the present invention, after step (d), step (d'), or step (d") or after the filtration and washing step, the obtained microspheres can be dried using a conventional drying method to finally obtain dried microspheres.

[0095] Other than the matters described above, the provisions defined in the above-mentioned pharmaceutical composition shall apply to all matters not separately defined, including semaglutide, bioavailability enhancers, biodegradable polymers, and their content.

[0096] The present invention provides a method for producing sustained-release microglobulin injections containing semaglutide or a pharmaceutically acceptable salt of the drug, which maintains an effective concentration for a desired period without abrupt, transient release, thus offering high bioavailability. Furthermore, it is possible to produce sustained-release microglobulin injections containing uniformly sized semaglutide or a pharmaceutically acceptable salt of the drug, along with a bioavailability enhancer, resulting in a drug with good administration capabilities. [Examples]

[0097] [Examples] The present invention will be described in more detail below with reference to the following manufacturing examples. However, the following manufacturing examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following manufacturing examples.

[0098] Manufacturing example Production of biodegradable polymer microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer.

[0099] Manufacturing Example 1 (w / o / w method): Production of biodegradable polymer microspheres containing semaglutide and a bioavailability enhancer dissolved in the internal aqueous phase. A primary aqueous phase was prepared by dissolving 0.15 g of sodium semaglutide salt (manufacturer: Chengdu, China) as the drug and 0.33 g of poloxamer F127 as a bioavailability improver in 1.66 g of tertiary distilled water. The organic phase was prepared by mixing RG653H and RG753H (manufacturer: Evonik, Germany) as biodegradable polymers in a 1:1 weight ratio to a total of 1.52 g and dissolving them in 20.8 g of dichloromethane (manufacturer: JT Baker, USA). A primary emulsion (dispersed phase) was prepared by dispersing the aqueous phase in the organic phase using a homogenizer. 2,000 mL of 0.1% polyvinyl alcohol (viscosity: 4.8~5.8 mPa·s) aqueous solution was used as the continuous phase. The continuous phase was connected to an emulsifier equipped with a 40 μm diameter porous membrane. The prepared dispersed phase was then injected into the porous membrane along with the continuous phase to produce an emulsion containing dispersed microdroplets of biodegradable polymer containing semaglutide. The suspension was placed in a preparation container and stirred at a speed of 200 rpm. The temperature of the preparation container was maintained at 25°C, and after the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After cooling the temperature to 25°C, the mixture was filtered, and residual polyvinyl alcohol was removed with tertiary distilled water before freeze-drying.

[0100] Manufacturing Example 2 (w / o / w method): Production of biodegradable polymer microspheres containing semaglutide and a bioavailability enhancer dissolved in the internal aqueous phase and an initial release inhibitor contained in the continuous phase. A primary aqueous phase was prepared by dissolving 0.2 g of sodium semaglutide salt as the drug and 0.02 g of disodium phosphate as a bioavailability enhancer in 1.0 g of tertiary distilled water. The organic phase was prepared by dissolving 0.8 g of PDL 04A (manufacturer: Corbion, Netherlands) as a biodegradable polymer in 6.65 g of dichloromethane. A primary emulsion (dispersed phase) was prepared by dispersing the aqueous phase in the organic phase using a homogenizer. For the continuous phase, 2,000 mL of a 0.1% polyvinyl alcohol aqueous solution containing 2% (w / w) disodium phosphate as an initial release inhibitor was used. After connecting the continuous phase to an emulsifier equipped with a porous membrane with a diameter of 40 μm, the prepared dispersed phase was injected into the porous membrane together with the continuous phase to produce an emulsion in which fine droplets of biodegradable polymer containing semaglutide were dispersed. The suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0101] The preparation vessel temperature was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After cooling to 25°C, the mixture was filtered, and residual polyvinyl alcohol was removed with tertiary distilled water before freeze-drying.

[0102] Manufacturing Example 3 (w / o / w method): Production of biodegradable polymer microspheres containing semaglutide, a release regulator, and a bioavailability enhancer dissolved in the internal aqueous phase, and an initial release inhibitor contained in the continuous phase. A primary aqueous phase was prepared by dissolving 0.2 g of semaglutide-free base (manufacturer: Chengdu, China) as the drug, and 0.02 g each of sodium decanoate and disodium phosphate as release regulators and bioavailability improvers in 1.8 g of tertiary distilled water. The organic phase was prepared by dissolving 0.76 g of PDLG 7504A (manufacturer: Corbion, Netherlands) as the biodegradable polymer in 14.4 g of dichloromethane. A primary emulsion (dispersed phase) was prepared by dispersing the aqueous phase in the organic phase using a homogenizer. For the continuous phase, 2,000 mL of a 0.1% polyvinyl alcohol aqueous solution containing 2% (w / w) disodium phosphate as an initial release inhibitor was used. The continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm. The prepared dispersed phase was then injected into the porous membrane together with the continuous phase to produce an emulsion in which biodegradable polymer microdroplets containing semaglutide were dispersed. The suspension was then placed in a preparation container and stirred at a speed of 200 rpm.

[0103] The preparation vessel temperature was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After cooling to 25°C, the mixture was filtered, and residual polyvinyl alcohol was removed with tertiary distilled water before freeze-drying.

[0104] Manufacturing Example 4 (o / w method): Production of biodegradable polymer microspheres containing semaglutide and a bioavailability enhancer dissolved in an organic phase and an initial release inhibitor contained in a continuous phase. The dispersed phase was prepared by thoroughly stirring for at least 30 minutes using 19.9 g of a mixed solvent (approximately 16:4:1 by weight) of dichloromethane, glacial acetic acid (manufacturer: Daejeong, South Korea), and methanol (manufacturer: Daejeong, South Korea) with 0.79 g of PDLG 7504A as a biodegradable polymer, 0.2 g of semaglutide free base as a drug, and 0.006 g of benzathine as a bioavailability improver. For the continuous phase, 2,000 mL of a 0.1% aqueous polyvinyl alcohol solution containing 2% (w / w) disodium phosphate as an initial release inhibitor was used. After connecting the continuous phase to an emulsifier equipped with a porous membrane with a diameter of 40 μm, the prepared dispersed phase was injected into the porous membrane together with the continuous phase to produce an emulsion in which fine droplets of the biodegradable polymer containing semaglutide were dispersed. The suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0105] The preparation vessel temperature was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After cooling to 25°C, the mixture was filtered, and residual polyvinyl alcohol was removed with tertiary distilled water before freeze-drying.

[0106] Manufacturing Examples 5-32: Production of biodegradable polymer microspheres containing semaglutide or a pharmaceutically acceptable salt thereof. Semaglutide (manufacturer: Chengdu, China) was used as the drug in amounts of 0.125 to 0.450 g, and a bioavailability enhancer (see Table 1) was used in amounts of 0 to 1.2 g. Finally, at least one of the biodegradable polymers R203H, RG203H, RG503H, RG653H, RG753H, PDL04A, and PDLG7504A was used as the biodegradable polymer in amounts of 0.75 to 2.55 g, and weighed to achieve batch sizes of 1.0 to 3.0 g (for production examples 1 to 32, production examples 16, 19, and 30 had a batch size of 3.0 g, production examples 1, 13, 14, 15, 29, and 30 had a batch size of 2.0 g, and the rest had a batch size of 1.0 g). Dichloromethane was used as the solvent for preparing the dispersed phase, and production examples 4 to 29 and production examples 31 and 32 were homogeneously dissolved using at least one of glacial acetic acid and methanol as a cosolvent. A primary emulsion was prepared by dispersing the aqueous phase in the organic phase using a 40 μm porous emulsion membrane. For the continuous phase, 0.1% polyvinyl alcohol (viscosity: 4.8-5.8 mPa.s) and 2,000 ml of 2.0% Na2HPO4 (Disodium phosphate) aqueous solution were used in Preparation Examples 2-32, while 2,000 ml of polyvinyl alcohol (viscosity: 4.8-5.8 mPa.s) and 1.0% NaCl aqueous solution were used in Preparation Example 1. After connecting the continuous phase to an emulsifier equipped with a 40 μm diameter porous membrane, the prepared dispersed phase was injected into the porous membrane together with the continuous phase to produce an emulsion in which biodegradable polymer microdroplets containing semaglutide were dispersed. The suspension was placed in a preparation container and stirred at a speed of 200-300 rpm.

[0107] The preparation vessel temperature was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After cooling to 25°C, the mixture was filtered, and residual polyvinyl alcohol was removed with tertiary distilled water before freeze-drying.

[0108] Manufacturing examples 5 and 10 did not include an initial release inhibitor in the continuous phase.

[0109] [Table 1-1] [Table 1-2] [Table 1-3]

[0110] Production Examples 1-4 show the production of microgranules due to differences in bioavailability improvers, using poloxamer F127, disodium phosphate, sodium decanoate + disodium phosphate, and benzathine, respectively. Production Examples 4-9 show the production of microgranules due to the benzathine content, Production Examples 11-15 show the production of microgranules due to the semaglutide content, and Production Examples 16-29 show the production of microgranules due to polymers.

[0111] Manufacturing Examples 33-37 (O / W Manufacturing Method): Production of biodegradable polymer microspheres containing dexamethasone acetate or a pharmaceutically acceptable salt thereof. For the production of dexamethasone granules, the dispersed phase contained at least one of the biocompatible polymers Purasorb PDLG 7502A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands), RG 752H (iv 0.14-0.22 dl / g; manufacturer: Evonik, Germany), and RG 753H (iv 0.32-0.44 dl / g; manufacturer: Evonik, Germany), PDL04A, PDL02, and PDLG 7504A (manufacturer: Corbion, Netherlands). Dexamethasone acetate (manufacturer: Pfizer, USA) was mixed with dichloromethane (manufacturer: JT Baker, USA), dimethyl sulfoxide (manufacturer: JT Baker, USA), and benzyl alcohol (manufacturer: Junsei, Japan). In production examples 33-37, the continuous phase was prepared using 0.5% polyvinyl alcohol (viscosity: 4.8-5.8 mPa.s) and 2,000 ml of a 2.5% NaCl aqueous solution.

[0112] [Table 2]

[0113] Production examples 33-37 illustrate the production of microparticles depending on the type of polymer and the amount of dexamethasone acetate used.

[0114] Manufacturing examples 38-51 Combination administration of semaglutide microglobulins and dexamethasone acetate microglobulins is shown in manufacturing examples 38-51 (see Table 3).

[0115] [Table 3]

[0116] Experimental Example 1: Measurement of semaglutide inclusion amount within microspheres To measure the semaglutide encapsulation amount in microparticles produced in Production Examples 1-32 and the dexamethasone encapsulation amount in microparticles produced in Production Examples 33-37, 10 mg of microparticles were completely dissolved in DMSO and then diluted with the mobile phase. 20 μL of the diluted solution was injected into an HPLC and measured at a detection wavelength of 214 nm. The column used in this experiment was a ZORBAX 300SB-C18, 5 μm, 4.6 × 150 mm, and the mobile phase was 45% 0.1% TFA acetonitrile, 55% 0.1% TFA aqueous solution. The experiment was conducted in isocratic mode. The measured encapsulation amounts are shown in Table 4 below.

[0117] [Table 4]

[0118] Experimental Example 2: In-vivo pharmacokinetic study using rats

[0119] Experimental Example 2-1: Changes in semaglutide blood concentration due to bioavailability enhancers and release regulators To evaluate the drug release mechanism of semaglutide-releasing microglobules according to the present invention, semaglutide concentrations in the blood were measured after administering the drug to rats.

[0120] Microparticles were measured to obtain semaglutide concentrations of 1.2 mg (4.0 mg / kg) or 3.6 mg (12.0 mg / kg), dispersed in 0.5 mL suspension, and injected into SD rats (Sprague-Dawley rats, 300 g). 0.5 mL of blood was collected at pre-planned time intervals, and the blood semaglutide concentration was measured using HPLC. The measured AUC and Cmax are shown in Table 5.

[0121] [Table 5]

[0122] As can be seen in Table 5 above, in the case of microgranules containing semaglutide produced in Production Examples 1 to 4 of the present invention, it was confirmed that the ratio of cumulative AUC up to 24 hours after administration, in which the initial release phase at administration can be observed, was less than 10%, while showing a high AUC.

[0123] Experimental Example 2-2. Improvement of semaglutide bioavailability by benzathine content To evaluate the drug release mechanism of semaglutide sustained-release microglobulins according to the present invention, bioavailability (%) was measured after administration to rats. Specifically, semaglutide sustained-release microglobulins with benzathine content of 0.6(w / w)%, 1.2(w / w)%, 2.3(w / w)%, and 5(w / w)% relative to the total batch weight, and semaglutide sustained-release microglobulins without benzathine, were dispersed in 0.5 mL suspensions at a dose of 1.2 mg (4.0 mg / kg) or 3.6 mg (12.0 mg / kg) of semaglutide contained in the sustained-release microglobulins, respectively, and then injected into SD rats (Sprague-Dawley Rat, 300 g). Subsequently, pharmacokinetic parameters were analyzed to compare the improvement in bioavailability in rats. The results showed that the AUC increased by approximately twofold or more in production examples 4, 7, 8, and 9 compared to production example 6. Overall, the AUC was similar, and we observed a bioavailability that was more than 40% higher.

[0124] [Table 6]

[0125] Experimental Example 2-3. Improvement of AUC due to semaglutide content To evaluate the drug release mechanism of semaglutide-releasing microglobules according to the present invention, AUC was measured after administration to rats.

[0126] In the experiment, rats were injected with two types of semaglutide sustained-release microglobulins: one containing 0.125g, 0.150g, 0.350g, and 0.400g of semaglutide, and the other containing 1.2g of benzathine as a bioavailability enhancer; and the other containing 0.400g of semaglutide, without the bioavailability enhancer. For the injection of the semaglutide microglobulins, 3.6mg (12.0mg / kg) of semaglutide contained in the sustained-release microglobulins was dispersed in 0.5mL of suspension and then injected into SD rats (Sprague-Dawley Rat, 300g).

[0127] [Table 7]

[0128] We confirmed that the AUC increases as the drug content increases. In particular, by administering microglobulins from Production Example 12 to experimental animals and examining the changes in blood drug levels (Figure 1), and by analyzing pharmacokinetic parameters, we were able to confirm that the cumulative drug release rate up to 28 days after administration was 62.28% of the total drug release. This confirms that the drug release rate up to the administration period of the formulation is 80% or less of the total drug release, indicating a favorable drug release pattern.

[0129] Experimental Example 2-4. Initial release with and without the use of an initial release inhibitor. Table 8 below shows the initial release depending on whether or not the continuous phase contains an initial release inhibitor.

[0130] [Table 8]

[0131] The experimental results described above confirmed that including an initial release inhibitor in the continuous phase during microgranule production significantly reduces the initial release of the drug in microgranules containing high levels of semaglutide.

[0132] Experimental Example 3-1. Comparison of microparticle characteristics with the addition of disodium hydrogen phosphate and the use of similar salts. This experiment was conducted to compare the properties of microparticle production when using disodium phosphate-like salts as the initial release inhibitor.

[0133] Table 1 shows the control dosage form without the initial release inhibitor (production example 55), and production examples 56-58 show the dosage forms produced with the addition of Na2HPO4, K2HPO4, and NaH2PO4, respectively, as initial release inhibitors. Table 9 shows the main characteristics and initial release of production examples 55-58.

[0134] [Table 9]

[0135] Referring to production examples 55-58 in Tables 1 and 9, it was confirmed that when Na2HPO4 and K2HPO4 were added as initial release inhibitors compared to the control formulation, the initial release was reduced to less than 1%. However, when NaH2PO4 was added to the continuous phase as an initial release inhibitor, the initial release was 17%, which was significantly higher than the control formulation, confirming that not all disodium phosphate-like salts exhibit an effect of suppressing initial release. The pH of production example 55 was approximately 3, production examples 56 and 57 were approximately 7, and production example 58 was approximately 5. Although linear data is not shown, it was determined that the high initial release in production examples 55 and 58 may be due to pH, and when cross-sectional images were examined using SEM, it was confirmed that multiple internal pores were distributed in the acidic formulation, while the number of internal pores decreased when the pH was neutral or basic. This result was determined to be the reason for the suppression of initial release.

[0136] Experimental Example 3-2. Comparison of microparticle characteristics depending on the type of initial release inhibitor added. This experiment was conducted to compare the characteristics of microparticle production using initial release inhibitors Na2CO3, NaHCO3, (NH4)2SO4, and (NH4)2HPO4.

[0137] Table 1 shows the control dosage form without the initial release inhibitor (production example 66) and the dosage forms produced with the addition of Na2CO3, NaHCO3, (NH4)2SO4, and (NH4)2HPO4 as initial release inhibitors, respectively, in production examples 68-71. Table 10 shows the main characteristics and initial release of production examples 66 and 68-71.

[0138] [Table 10]

[0139] Referring to Tables 1 and 10, and production examples 66, 68-71, it can be seen that production examples 66 and 70 show slightly higher initial release. Production examples 66 and 70, which showed high initial release, were acidic with pH values ​​of approximately 3 and 5, respectively, while production examples 68, 69, and 71, which were neutral and basic, showed initial release of less than 3%. Based on these results, it was confirmed that among initial release inhibitors, when added to the continuous phase, if the continuous phase exhibits an acidic pH, a very high initial release of semaglutide is observed. On the other hand, when using an initial release inhibitor that makes the basic pH appear above pH 7 (neutral or basic), the initial release of semaglutide is clearly suppressed. Looking at the initial release of production examples 68, 69, and 71, it was confirmed that initial release is suppressed more when the pH is basic than when it is neutral, but the suppression of initial release does not increase linearly with the degree of basicity.

[0140] Experimental Example 3-3. Comparison of microparticle characteristics after pH adjustment following the addition of disodium hydrogen phosphate. After adding 2(w / v)% disodium hydrogen phosphate as an initial release inhibitor, the pH was intentionally adjusted to confirm whether the initial release inhibitory effect on microparticles was maintained even when the pH changed after the use of the initial release inhibitor, by observing changes in initial release.

[0141] Specifically, Table 1 shows the control formulation without the initial release inhibitor (Production Example 66), the formulation with 2(w / v)% disodium hydrogen phosphate added as an initial release inhibitor and without intentionally adjusting the pH (Production Example 63), the formulation with the pH adjusted to 2 (acidic) using HCl (Production Example 64), and the formulation with the pH adjusted to 12 using NaOH (Production Example 65).

[0142] Table 11 shows the main characteristics and initial release of manufacturing examples 63-66.

[0143] [Table 11]

[0144] As can be seen from Table 11, when microspheres are produced using a continuous phase containing 2(w / v)% Na2HPO4 as an initial release inhibitor, it was confirmed that the initial release inhibitory effect of semaglutide is maintained even if the pH of the continuous phase is intentionally adjusted to be acidic thereafter.

[0145] Experimental Example 4. Comparison of microparticle characteristics depending on the amount of disodium hydrogen phosphate added. This experiment was conducted to compare the properties of microparticles depending on the amount of disodium hydrogen phosphate added as an initial release inhibitor.

[0146] Table 1 shows the control dosage form without added Na2HPO4 (production example 55) and the dosage forms with added Na2HPO4 at 0.5(w / v)%, 1(w / v)%, 2(w / v)%, 3(w / v)%, and 4(w / v)%, respectively, as shown in production examples 59, 60, 56, 61, and 62. Table 12 shows the main characteristics and initial release of production examples 55, 56, and 59-62.

[0147] [Table 12]

[0148] Referring to production examples 55, 56, and 59-62 in Tables 1 and 12, it was confirmed that the initial release of the dosage form with 0.5(w / v)% Na2HPO4 added decreased to 0.64% compared to the initial release of 4.6% for the control dosage form. The initial release rates for Na2HPO4 concentrations of 1(w / v)% and 2(w / v)% were 0.56% and 0.4%, respectively. However, when 3(w / v)% and 4(w / v)% Na2HPO4 were added, the initial release was 0.77% and 0.86%, respectively, showing a tendency to increase compared to when 2% Na2HPO4 was added. It was determined that when Na2HPO4 was used at concentrations of 4(w / v)% or higher, a large amount of polymer aggregation occurred during granule production, and the tendency for the initial release to increase as the Na2HPO4 content increased starting from 2(w / v)% was due to the polymer aggregation phenomenon described above.

[0149] Experimental Example 5. Method for Measuring Residual Amounts of Sodium and Phosphorus To measure the sodium and phosphorus content in the microspheres used in the above examples and comparative examples, 300 mg of microspheres were mixed with 6 mL of nitric acid aqueous solution (a 1:1 mixture of ultrapure water and nitric acid) and 3 mL of hydrogen peroxide. The mixture was then heated to over 100°C, and acid was added until the gas generated during the dissolution process changed from yellow to white. The resulting sample was weighed, dissolved in ultrapure water, and then injected into an inductively coupled plasma emission spectrometer (ICP-OES) (Thermo Scientific Co., iCAP 6300 Duo, UK) and measured at a detection wavelength of 598.5 nm. The results are shown in Experimental Examples 5-1 and 5-2 below.

[0150] Experimental Example 5-1. Comparison of residual sodium and phosphorus in microparticles depending on the amount of disodium hydrogen phosphate added. The residual amounts of sodium and phosphorus in the microspheres produced by manufacturing examples 59-61 and 63 were confirmed and are shown in Table 13.

[0151] [Table 13]

[0152] Referring to Table 13, it was confirmed that the amount of sodium and phosphorus residues increased significantly as the amount of Na2HPO4 added increased, and that the content of the initial release inhibitor remaining in the microgranules was 10 ppm to 200 ppm based on sodium and 5 ppm to 100 ppm based on phosphorus.

[0153] Experimental Example 5-2. Comparison of residual sodium and phosphorus in microparticles after changes in biodegradable polymers and the addition of benzathine. The residual amounts of Na and P in production examples 16, 63, and 67 were examined and are shown in Table 14.

[0154] [Table 14]

[0155] Referring to Table 14, it was confirmed that the residual sodium and phosphorus content due to the initial release inhibitor contained in the continuous phase differed depending on the manufacturing conditions of the semaglutide-containing granules. The residual initial release inhibitor content in the granules ranged from 50 ppm to 500 ppm based on sodium, and from 10 ppm to 100 ppm based on phosphorus.

[0156] Experimental Example 6. Comparison of SEM observation results of microspheres with and without the use of disodium hydrogen phosphate in the continuous phase. Figure 3a shows microspheres produced using only 0.1(w / v)% PVA in the continuous phase, and Figure 3b shows microspheres produced using 0.1(w / v)% PVA and 2(w / v)% Na2HPO4 in the continuous phase.

[0157] Referring to Figures 3a and 3b, it was confirmed that in the case of microparticles produced using only 0.1% PVA in the continuous phase, multiple pores were present in the cross-section of the microparticles. In the case of microparticles produced using 0.1(w / v)% PVA and 2(w / v)% Na2HPO4 in the continuous phase, it was confirmed that most of the pores were absent or, if pores were present, the number and size of the pores were significantly reduced. This is judged to indicate an effect of reducing channels that may affect the initial release of the drug.

Claims

1. It contains sustained-release microspheres consisting of semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability enhancer, and a biodegradable polymer. A pharmaceutical composition for the prevention or treatment of diabetes, type 2 diabetes, preservation of beta-cell function, obesity, non-alcoholic steatohepatitis, or degenerative neurological disease, wherein the semaglutide or a pharmaceutically acceptable salt thereof is contained in an amount of 8% by weight or more of semaglutide based on the total weight of microglobulins, and the bioavailability improving agent is contained in an amount of 2.5% to 250% by weight based on the weight of semaglutide.

2. It comprises semaglutide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and sustained-release microspheres consisting of a biodegradable polymer. A pharmaceutical composition for the prevention or treatment of diabetes, type 2 diabetes, preservation of beta-cell function, obesity, non-alcoholic steatohepatitis, or degenerative neurological disease, wherein the semaglutide or a pharmaceutically acceptable salt thereof is contained in an amount of 8% by weight or more of semaglutide based on the total weight of microglobulins, and the initial release inhibitor is contained in an amount of 5 ppm to 2000 ppm.

3. The pharmaceutical composition according to claim 1 or 2, wherein the sustained-release microglobulins, when administered into the body, release less than 20% of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours.

4. The pharmaceutical composition according to claim 1 or 2, wherein the sustained-release microglobulins, when administered into the body, release less than 15% of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours.

5. The pharmaceutical composition according to claim 1 or 2, wherein the sustained-release microglobulins, when administered into the body, release less than 10% of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours.

6. The biodegradable polymers include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide, PLGA) which is a copolymer of lactide and glycoside, polydioxanone (Polydioxanone), polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyaminoacid, polyalkylcyanoacrylate (Polyalkyl Polymers selected from the group consisting of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); copolymers or simple mixtures thereof of two or more of these; copolymers of the polymer with polyethylene glycol (PEG);The pharmaceutical composition according to claim 1 or claim 2, comprising one or more selected from the group consisting of the polymer or copolymer and a polymer-sugar complex in which the polymer or copolymer is bonded to a sugar.

7. The pharmaceutically acceptable salt of semaglutide is a sodium salt, acetate, benzoate, hydroxynaphthoate, napadisylate, or pamoate of semaglutide, according to claim 1 or 2.

8. The bioavailability improving agents include sodium decanoate, disodium hydrogen phosphate, choline, meglumine, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, ammonium phosphate, histidine, HEPES, HEPPS, spermine, spermidine, putrescine, and methylene blue. blue), proline, sugar, glycerol, surfactant, arginine, glycine, guanidine hydrochloride, urea, sodium chloride, potassium chloride Chloride, triethylamine, ethanolamine, triethanolamine, ethylenediamine, poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, rhizolutin, benzofuran, magnesium carbonate, magnesium hydroxide Hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxideThe pharmaceutical composition according to claim 1, comprising one or more selected from the group consisting of hydroxide, zinc phosphate, aluminum hydroxide, aluminum phosphate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxide, magaldrate, and benzofuran derivatives.

9. The pharmaceutical composition according to claim 1, further comprising 5 ppm to 2000 ppm of an initial release inhibitor.

10. The pharmaceutical composition according to claim 2 or 9, wherein the initial release inhibitor is one or more substances selected from alkali metals, alkaline earth metals, or ammonium phosphate salts, phosphine salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalate salts, silicate salts, sulfate salts, sulfide salts, sulfite salts, tartrate salts, tetraborate salts, thiosulfate salts, arsenate salts, arsenite salts, citrate salts, felicyanide salts, and nitride salts.

11. The pharmaceutical composition according to claim 1 or claim 2, wherein the average particle size of the sustained-release microspheres is 5 μm to 100 μm.

12. The pharmaceutical composition according to claim 1 or claim 2, wherein the weight of the sustained-release microglobules is 20 to 1000 mg.

13. The pharmaceutical composition according to claim 1 or claim 2, wherein the intrinsic viscosity of the biodegradable polymer is 0.16 dL / g to 1.7 dL / g.

14. A pharmaceutical composition according to claim 1 or claim 2, comprising one or more release regulators selected from the group consisting of butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, napadisylic acid, naphthalenesulfonic acid, and pamoic acid.

15. A method for producing microspheres comprising: (a) dissolving semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and one or more biodegradable polymers in an organic solvent to produce a solution (dispersed phase) containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer; (b) adding the solution containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer produced in step (a) to an aqueous solution (continuous phase) containing a surfactant to produce an emulsion; (c) extracting and evaporating an organic solvent from the dispersed phase in emulsion produced in step (b) as a continuous phase to form microspheres; and (d) recovering the microspheres from the continuous phase in step (c).

16. The method for producing bioavailability according to claim 15, wherein the bioavailability improving agent was one or more selected from the group consisting of poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, resolutin, and benzofuran.

17. (a') A step to produce a W / O emulsion (primary emulsion) containing semaglutide or a pharmaceutically acceptable salt and a bioavailability improver by dissolving them in an aqueous solution to create a primary aqueous phase, and then dissolving one or more biodegradable polymers in an organic solvent to create an oil phase, and then mixing the primary aqueous solution and the oil phase; (b') The semaglutide or a pharmaceutically acceptable salt, a bioavailability improver, and a polymer produced in step (a'); A method for producing microspheres made of semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer, comprising the steps of: (c') adding a primary emulsion containing to an aqueous solution phase (continuous phase) containing a surfactant to produce a W / O / W emulsion (secondary emulsion); (c') extracting and evaporating an organic solvent from the oil phase in the secondary emulsion state produced in step (b') as a continuous phase to form microspheres; and (d') recovering the microspheres from the continuous phase in step (c').

18. The method for producing bioavailability according to claim 17, wherein the bioavailability improving agent is one or more selected from the group consisting of sodium decanoate, disodium hydrogen phosphate, choline, meglumine, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, ammonium phosphate, histidine, HEPES, HEPPS, spermine, spermidine, putrescine, methylene blue, proline, sugar, glycerol, surfactant, arginine, glycine, guanidine hydrochloride, urea, sodium chloride, potassium chloride, triethyleneamine, ethanolamine, triethanolamine, and ethylenediamine.

19. A method for producing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer, comprising the steps of: (a) dissolving semaglutide or a pharmaceutically acceptable salt thereof and one or more biodegradable polymers in an organic solvent and suspending a bioavailability improver in this solution to produce a suspension (dispersed phase) containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer; (b) adding the suspension containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer produced in step (a) to an aqueous solution (continuous phase) containing a surfactant to produce an emulsion; (c) extracting and evaporating the organic solvent from the dispersed phase in emulsion produced in step (b) as a continuous phase to form microspheres; and (d) recovering the microspheres from the continuous phase in step (c).

20. The method for producing bioavailability according to claim 19, wherein the bioavailability improving agent is one or more selected from the group consisting of magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, aluminum phosphate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxide magaldrate, and benzofuran derivatives.

21. The biodegradable polymers include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide, PLGA) which is a copolymer of lactide and glycoside, polydioxanone (Polydioxanone), polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyaminoacid, polyalkylcyanoacrylate (Polyalkyl Polymers selected from the group consisting of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); copolymers or simple mixtures thereof of two or more of these; copolymers of the polymer with polyethylene glycol (PEG);A manufacturing method according to any one of claims 15 to 20, wherein the material is one or more selected from the group consisting of the polymer or copolymer and a polymer-sugar complex in which the polymer or copolymer is bonded to a sugar.

22. A method for producing microspheres according to any one of claims 15 to 20, further comprising one or more release regulators selected from the group consisting of butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, hydroxynaphthoic acid, napadisylic acid, and pamoic acid.

23. The method for producing a product according to any one of claims 15 to 20, wherein the organic solvent in step (a), (a'), or (a'') is one or more organic solvents selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol.

24. The manufacturing method according to any one of claims 15 to 20, wherein the surfactant in step (b), (b'), or (b'') is polyvinyl alcohol.

25. The production method according to any one of claims 15 to 20, wherein the continuous phase in step (b), (b'), or (b'') is water, or a mixed solvent of water and one or more solvents selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate.

26. The manufacturing method according to any one of claims 15 to 20, wherein the continuous phase of step (b), (b'), or (b'') comprises an initial release inhibitor.

27. The manufacturing method according to claim 26, wherein the initial release inhibitor is included in an amount of 0.05 w / v% to 20 w / v% based on the total volume of the continuous phase.

28. The manufacturing method according to claim 26, wherein the initial release inhibitor is one or more selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium phosphate.

29. The manufacturing method according to any one of claims 15 to 20, wherein the pH of the continuous phase in step (b), (b'), or (b'') is 7 or higher.

30. A method for producing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, wherein when sustained-release microglobules containing the produced semaglutide or a pharmaceutically acceptable salt thereof are administered in vivo, the release rate of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours is less than 15%, according to any one of claims 15 to 20.

31. A method for producing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improving agent, wherein when sustained-release microglobules containing the produced semaglutide or a pharmaceutically acceptable salt thereof are administered in vivo, the release rate of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours is less than 10%, according to any one of claims 15 to 20.

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