Sustained-release microparticle preparation containing semaglutide or a pharmaceutically acceptable salt thereof and method for producing the same

Abstract

The present invention relates to a sustained-release microparticle comprising semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer, which has no rapid initial burst of the drug, contains a high content of the drug compared to the particle size, has a high bioavailability, and can minimize the pain and inflammatory response of patients that may occur upon administration to the human body, and is useful for the prevention or treatment of diabetes, preservation of beta-cell function, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, or neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

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 the 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 a number of 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 (preproglucagon 92 - 128). GLP-1(7-36) amide or GLP-1(7-37) acid are the biologically active forms of GLP-1 that exhibit 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 under development.

[0003] GLP-1 agonists such as semaglutide are peptides, and the administration of such peptides is often mainly through injection due to various barriers such as enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption from the intestinal mucosa, and first pass metabolism in the liver. Recently, oral dosage forms have also been commercialized, but they have a very low bioavailability compared to injections and require a relatively large dosage. Furthermore, formulations containing semaglutide are formulated in a form that can be directly administered (self-administered) by the patient for the continuous management of obesity and diabetes, and it is very important to manage pain, inflammatory reactions, etc. that may occur at the administration site.

[0004] On the other hand, a technique of encapsulating semaglutide in microspheres composed of biodegradable polymers for long-term elution of semaglutide is known. In this case, the bioavailability of semaglutide encapsulated in the microspheres is low, or the drug content contained in the microspheres is low, and a large amount of microspheres must be administered to show a long-term effective pharmacological effect. However, when a large amount of microspheres are administered into the body, it is difficult for the patient to directly administer (self-administer) due to the difficulty of subcutaneous injection, and there is a problem that pain and inflammatory reactions at the administration site are also greatly increased.

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention has been proposed to solve the above problems, and provides a pharmaceutical composition containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a sustained-release microsphere composed of a biodegradable polymer, which has a high bioavailability of semaglutide and exhibits characteristics of stable drug release for a long period of time, and a pharmaceutical composition containing a sustained-release microsphere composed of semaglutide or a pharmaceutically acceptable salt thereof and a biodegradable polymer, which has a high drug content and exhibits safe drug release characteristics with low initial release, and a method for producing the sustained-release microsphere.

Means for Solving the Problems

[0006] Hereinafter, the present invention will be described in detail.

[0007] The term "one or more" in the present invention means a number corresponding to one or more. In the present invention, when a certain component is one or more, it may preferably be 1 kind, 2 or more kinds, 3 or more kinds, 1 to 3 kinds, 1 to 2 kinds, but is not limited thereto.

[0008] To achieve the above object, In one aspect, the present invention provides a pharmaceutical composition comprising biodegradable polymer microparticles containing semaglutide, wherein the semaglutide content is 8% by weight or more as semaglutide based on the total weight of the microparticles, and the bioavailability improver is 2.5% to 250% by weight based on the weight of semaglutide.

[0009] In another aspect, the present invention provides a sustained-release microparticle 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 contained at 8% by weight or more as semaglutide based on the total weight of the microparticles, and the initial release inhibitor is contained at 5 ppm to 2000 ppm, for use in the prevention or treatment of diabetes, type 2 diabetes, preservation of beta-cell function, obesity, non-alcoholic steatohepatitis, or neurodegenerative diseases.

[0010] As another aspect, the biodegradable polymer is selected from the group consisting of polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide) (PLGA) which is a copolymer of lactide and glycolide, polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and block copolymers of poly (butylene succinate lactide) (PBSLA); simple mixtures of two or more of these; copolymers of the polymer and polyethylene glycol (PEG);and may be one or more selected from the group consisting of a polymer-sugar complex in which the polymer or copolymer is bound to a sugar;

[0011] As another aspect, the bioavailability improver 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, detergent, arginine, glycine, guanidine 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 carbonateIt 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.

[0012] In another aspect, the pharmaceutically acceptable salt of semaglutide may be the sodium salt, acetate, benzoate, hydroxynaphthoate, napadisylate, or pamoate of semaglutide.

[0013] In another aspect, it may be characterized in that the intrinsic viscosity of poly(lactide-co-glycolide), polyglycolide, or polylactide in the biodegradable polymer is 0.16 to 1.7 dL / g.

[0014] In another aspect, the average particle size of the microspheres containing semaglutide or its pharmaceutically acceptable salt and the bioavailability improver may be 5 μm to 100 μm.

[0015] In another aspect, it may be characterized in that the span value of the microspheres containing semaglutide or its pharmaceutically acceptable salt and the bioavailability improver is 1.5 or less.

[0016] As another aspect, the weight of the microspheres containing the semaglutide or a pharmaceutically acceptable salt thereof and the bioavailability improver may be 20 to 1000 mg, 20 mg to 800 mg, 20 mg to 600 mg, 20 mg to 400 mg, 20 mg to 200 mg, 20 mg to 100 mg, 30 mg to 1000 mg, 30 mg to 800 mg, 30 mg to 600 mg, 30 mg to 400 mg, 30 mg to 200 mg, 30 mg to 100 mg, 40 mg to 1000 mg, 40 mg to 800 mg, 40 mg to 600 mg, 40 mg to 400 mg, 40 mg to 200 mg, 40 mg to 100 mg, 50 mg to 1000 mg, 50 mg to 800 mg, 50 mg to 600 mg, 50 mg to 400 mg, 50 mg to 200 mg, or 50 mg to 100 mg.

[0017] As another aspect, it may additionally contain 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, napadisylate, naphthalenesulfonic acid, and pamoic acid.

[0018] As another aspect, the microspheres can contain 1 to 100 mg / kg of Na.

[0019] As another aspect, the microspheres can contain 10 to 500 mg / kg of P.

[0020] As another aspect, the present invention provides a method for producing sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver.

[0021] As another aspect, the production method 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 microparticles containing semaglutide and maintains the pH of the continuous phase at 7.0 or higher.

[0023] As another aspect, as the initial release inhibitor, 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 can be used. 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, there is provided a pharmaceutical composition containing sustained-release microparticles containing a biodegradable polymer and having a semaglutide content of 8% by weight or more as semaglutide based on the total weight of the microparticles and an initial drug release of 10% or less, and a method for producing the same.

Advantages 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 the body, shows a long-term sustained effect, and can reduce the dose, so that it can minimize the pain and inflammatory reaction of patients that may occur during administration.

Brief Description of the Drawings

[0026]

Figure 1

Figure 2

Figure 3a

Figure 3b

Mode for Carrying Out the Invention

[0027] Hereinafter, the present invention will be described in detail.

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

[0029] Semaglutide is a GLP-1 receptor agonist N 6.26 -{18-[N-(17-carboxy-heptadecanoyl)-L-γ-glutamyl]-10-oxo 3,6,12,15-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]

Chem.

[0031] Such semaglutide can be produced as described in Production Example 4 of International Patent Publication WO2006 / 097537, and commercially available semaglutide can also be used.

[0032] Semaglutide may exist in the form of salts, especially pharmaceutically acceptable salts. Salts that are commonly used in the art can be used without limitation. The term "pharmaceutically acceptable salt" in the present invention means any and all organic or inorganic addition salts of said compound that are relatively non-toxic and harmless to the patient and, at a concentration having an effective action, do not reduce the beneficial efficacy of the active ingredient due to side effects caused by this salt. Specific examples include, but are not limited to, the sodium salt, acetate, benzoate, hydroxynaphthoate, napadisilate or pamoate of semaglutide.

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

[0034] In the present invention, the "bioavailability improver" is a substance that is encapsulated within microspheres together with semaglutide, which is the active ingredient, or a pharmaceutically acceptable salt thereof, to improve bioavailability. Specifically, when microspheres containing semaglutide or a pharmaceutically acceptable salt thereof are administered into the body, it refers to a substance that increases the area under the blood concentration-time curve (AUC) of semaglutide compared to microspheres that do not contain the "bioavailability improver". More specifically, when sustained-release microspheres are administered to rats, when administered at 1 mg / kg as semaglutide, the area under the blood concentration-time curve (AUC total / (mg / kg)) is shown to be 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 a specific uniform state, the bioavailability improver is Sodium decanoate, Disodium phosphate, Choline, Meglumine, Basic aluminum carbonate, Dihydroxyaluminum sodium carbonate, Ammonium phosphate, Histidine, HEPES (Hydroxyethyl piperazine Ethane Sulfonicacid), HEPPS (4-(2-Hydroxyethyl)piperazine-1-propanesulfonic acid), Spermine, Spermidine, Putrescine, Methylene blue, Proline, Sugars, Glycerol, Detergent, Arginine, Glycine, Guanidine hydrochloride, Urea, Sodium chloride, Potassium chloride, Triethylamine, Ethanolamine, Triethanolamine, Ethylenediamine, Poloxamer, Benzathine, Procaine, Lidocaine, Bupivacaine, Ropivacaine, Oxytetracycline, Sunitinib, Rhizolutin, Benzofuran, Magnesium carbonate, Magnesium hydroxide (MagnesiumOne or more selected from the group consisting of 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 may also be used.

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

[0037] Even more specifically, the bioavailability improver 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 a specific embodiment, the bioavailability improver may be contained in an amount of 2.5 wt% to 250 wt%, 2.5 to 200 wt%, 2.7 to 150 wt%, or 2.7 to 100 wt% based on the weight of semaglutide, but is not limited thereto.

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

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

[0041] Further, the pharmaceutical composition according to the present invention may be a pharmaceutical composition containing sustained-release microspheres in which the semaglutide content is 12% by weight or more as semaglutide with respect to the total weight of the microspheres, and the initial release of the drug is less than 10% within 24 hours.

[0042] The biodegradable polymers contained in the semaglutide sustained-release microspheres included in the pharmaceutical composition according to the present invention are polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA) which is a copolymer of lactide and glycolide, polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate (Polyalkyla polymer selected from the group consisting of cyanoacrylate, Polyphosphazene, Polyphosphoester, Polysaccharide, and poly(butylene succinate lactide) (PBSLA), a simple mixture of two or more kinds, a copolymer of the polymer and polyethylene glycol (PEG), and a polymer-sugar complex in which the polymer or copolymer is bound to a sugar.

[0043] As a specific embodiment, the pharmaceutical composition according to the present invention can include microspheres containing two or more kinds of the biodegradable polymers. As another specific embodiment, the pharmaceutical composition according to the present invention can include two or more kinds of microspheres each containing one or more of two or more polymers selected from the biodegradable polymers.

[0044] The two or more polymers selected from the group consisting of the poly-lactide-co-glycolide and polylactide polymers may have an intrinsic viscosity of, but not limited to, 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.

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

[0046] The content of the biodegradable polymer in the sustained-release microspheres containing semaglutide or its pharmaceutically acceptable salts and the 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 based on the total weight of the microspheres, but is not limited thereto.

[0047] The content of semaglutide or a pharmaceutically acceptable salt thereof in the sustained-release microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention is preferably 8% by weight or more, 12% by weight or more, 14% by weight or more, 37% by weight or less, 35% by weight or less, or 33% by weight or less as semaglutide based on the total weight of the microparticles. When the content of semaglutide or a pharmaceutically acceptable salt thereof in the microparticles is less than 8% by weight based on semaglutide, the amount of the polymer used may be excessively large compared to the drug, and the bioavailability of semaglutide or a pharmaceutically acceptable salt thereof may decrease. If the content is excessively high, there is a problem that the initial release of semaglutide or a pharmaceutically acceptable salt thereof increases, which is not preferable.

[0048] The microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention preferably have a uniform particle size distribution with an average particle size 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, 60 μm to 100 μm, 60 μm to 80 μm, 60 μm to 70 μm, 20 μm to 90 μm, 20 μm to 70 μm, 20 μm to 60 μm, 30 μm to 80 μm, 30 μm to 60 μm, 40 μm to 70 μm, 40 μm to 50 μm, 30 μm to 40 μm, 20 μm to 30 μm, 5 μm to 30 μm, 5 μm to 20 μm, 10 μm to 20 μm, or 5 μm to 10 μm. The term "average particle size" used in the present invention means the particle size corresponding to 50% of the volume% in the particle size distribution curve, which means the median diameter and is represented by D50 or D(v, 0.5).

[0049] When the average particle size of the microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver is less than 5 μm, the release of semaglutide or a pharmaceutically acceptable salt drug thereof from the microparticles becomes excessively fast, which is not preferable. When the average particle size exceeds 100 μm, the injection needle becomes excessively thick during human administration, which may induce pain during injection or the drug may leak from the injection site after injection, which is not preferable.

[0050] The microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver of the present invention preferably have a uniform particle size distribution. The microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver having a uniform particle size distribution have a smaller deviation during injection and can be administered in a more accurate amount compared to non-uniform microparticles. The Span value of the microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver of the present invention is preferably 1.5 or less. More preferably, the Span value is preferably 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, 0.4 to 0.8. The term "Span value" used in the present invention is an index indicating the uniformity of the particle size of the microparticles, and means the value obtained by the formula Span value = (Dv0.9 - Dv0.1) / Dv0.5. Here, Dv0.1 means the particle size corresponding to 10% of the volume% in the particle size distribution curve of the microparticles, Dv0.5 means the particle size corresponding to 50% of the volume% in the particle size distribution curve of the microparticles, and Dv0.9 means the particle size corresponding to 90% of the volume% in the particle size distribution curve of the microparticles.

[0051] The sustained-release microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver of the present invention are administered by an injection route, for example, subcutaneous injection, and are particularly self-administerable. Therefore, it is preferable that semaglutide is released for a relatively long period. Preferably, the sustained-release microparticles in the pharmaceutical composition according to the present invention 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, although not limited thereto. Further, the sustained-release microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver of the present invention, although such a release pattern is not particularly limited, when administered in vivo, it is preferable that less than 10%, less than 15%, or less than 20% of semaglutide or a pharmaceutically acceptable salt thereof is released within 24 hours.

[0052] Also, in the pharmaceutical composition of the present invention, the total amount of the sustained-release microparticle preparation containing the semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver may be 20 to 1000 mg, 20 mg to 800 mg, 20 mg to 600 mg, 20 mg to 400 mg, 20 mg to 200 mg, 20 mg to 100 mg, 30 mg to 1000 mg, 30 mg to 800 mg, 30 mg to 600 mg, 30 mg to 400 mg, 30 mg to 200 mg, 30 mg to 100 mg, 40 mg to 1000 mg, 40 mg to 800 mg, 40 mg to 600 mg, 40 mg to 400 mg, 40 mg to 200 mg, 40 mg to 100 mg, 50 mg to 1000 mg, 50 mg to 800 mg, 50 mg to 600 mg, 50 mg to 400 mg, 50 mg to 200 mg, or 50 mg to 100 mg. By including the sustained-release microparticles containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver in the composition within the above range, the composition according to the present invention not only minimizes the inflammatory reaction at the administration site but also has the advantage of being self-administered by the patient.

[0053] The microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver included in the composition of the present invention can additionally contain a release regulator. Examples of substances used as the release regulator 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, napadisylate, naphthalenesulfonic acid, and pamoic acid. Preferably, the release regulator may be, but is not limited to, hydroxynaphthoic acid, napadisylate, or pamoic acid.

[0054] The pharmaceutical composition containing the microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention can be formulated into various forms of preparations, for example, it may be in the form of a known parenteral administration preparation. Thus, the pharmaceutical composition according to the present invention can further contain a viscosity increasing agent, a stabilizer, an isotonic agent, an initial release inhibitor, a surfactant, an excipient, and / or a carrier in addition to the semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver. Examples of usable isotonic agents include water-soluble excipients or saccharides such as mannitol, sucrose, sorbitol, trehalose, lactose, and sodium chloride. Examples of viscosity increasing agents include sodium carboxymethylcellulose, sodium carboxymethylcellulose, and povidone. Also, as a buffering agent, sodium monohydrogen phosphate, anhydrous citric acid, sodium hydroxide, sodium chloride, etc. can be used.

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

[0056] In the present invention, the initial release inhibitor is a substance contained in the continuous phase for suppressing the rapid release of the active ingredient in the microsphere manufacturing process, and is characterized by being present in an amount less than a certain amount in the microspheres according to the present invention.

[0057] As a specific embodiment, the initial release inhibitor may be contained 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 based on the total weight of the microspheres.

[0058] As a specific embodiment, the initial release inhibitor is a substance that 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 when dissolved in the continuous phase, and any substance that can form an anion of divalent or higher in the continuous phase can be used. The initial release inhibitor may be one or more 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, ferrocyanide salts, and nitride salts of alkali metals, alkaline earth metals or ammonium, but is not limited thereto.

[0059] As a specific embodiment, 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 composition according to the present invention can be administered in a therapeutically effective amount of semaglutide, for example, for treating diabetes, specifically type 2 diabetes, preserving beta-cell function, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, or neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The therapeutically effective amount of semaglutide can be evaluated by a physician. The pharmaceutical composition according to the present invention containing semaglutide can also be administered once a month to once a quarter. In some specific examples, the monthly dosage of the composition according to the present invention, based on semaglutide, may be 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, 2 mg to 6 mg, 4 mg to 100 mg, 4 mg to 80 mg, 4 mg to 60 mg, 4 mg to 30 mg, 4 mg to 20 mg, 8 mg to 100 mg, 8 mg to 80 mg, 8 mg to 60 mg, 8 mg to 30 mg, 10 mg to 100 mg, 10 mg to 80 mg, 10 mg to 60 mg, 10 mg to 30 mg, 20 mg to 100 mg, 20 mg to 80 mg, 20 mg to 60 mg, 20 mg to 30 mg. The pharmaceutical composition according to the present invention containing microspheres comprising semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer can also be administered parenterally, for example, through subcutaneous injection. The pharmaceutical composition according to the present invention may be composed of a drug part containing microspheres comprising semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability enhancer, and a solvent part used to suspend the microspheres, and may be in the form of a dual-chamber syringe with the drug part in one chamber and the solvent part in the other chamber, or a prefilled syringe in which the drug part is suspended in the solvent part. The solvent part used when configured in the form of a prefilled syringe in which the drug part is suspended in the solvent part may be an injectable oil containing medium-chain oil, mineral oil, etc.

[0061] In a specific embodiment, the sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention have a high drug content compared to the content of the microspheres, but suppress the initial excessive release of a drug that may cause fatal side effects, have high bioavailability, and exhibit the drug efficacy as a GLP-1 agonist sufficiently for a desired period, and are useful for the prevention or treatment of diabetes, specifically type 2 diabetes, preservation of beta-cell function, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, or neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0062] 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 improver.

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

[0064] Hereinafter, a method for producing an injection of sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention will be specifically described.

[0065] The injection of sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention can be produced, for example, using the "solvent extraction and evaporation method", but the production method is not limited thereto.

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

[0067] In another aspect, in the previous step (a), the bioavailability improver may be one or more selected from the group consisting of poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, resorcinol, 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 improver, comprising the following steps: (a') Dissolving semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver in an aqueous solution to form a primary aqueous solution phase, dissolving one or more biodegradable polymers in an organic solvent to form 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 improver, and a polymer; (b') Adding the primary emulsion containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer produced in the previous step (a') 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 the previous step (b') using the continuous phase to form microspheres; (d’) Recovering microspheres from the continuous phase of the step (c’) to produce microspheres containing semaglutide with improved bioavailability or a pharmaceutically acceptable salt thereof, and a bioavailability improver.

[0069] In another aspect, in the step (a’), the bioavailability improver may be at least one selected from the group consisting of sodium decanoate, disodium hydrogen phosphate, choline, meglumine, basic aluminum carbonate, sodium aluminum carbonate dihydroxide, ammonium phosphate, histidine, HEPES, HEPPS, spermine, spermidine, putrescine, methylene blue, proline, saccharides, glycerol, surfactants, arginine, glycine, guanidine hydrochloride, urea, sodium chloride, potassium chloride, triethylenediamine, ethanolamine, triethanolamine, and ethylenediamine.

[0070] 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 improver, comprising the following steps: (a”) Dissolving semaglutide or a pharmaceutically acceptable salt thereof and one or more biodegradable polymers in an organic solvent, suspending a bioavailability improver in this solution to produce a suspension (dispersion 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 the step (a”) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion; (c”) Extracting and evaporating the organic solvent from the dispersed phase in the emulsion state produced in the step (b”) as the continuous phase to form microspheres; and (d”) Recovering microspheres from the continuous phase of the step (c”) to produce microspheres containing semaglutide with improved bioavailability or a pharmaceutically acceptable salt thereof, and a bioavailability improver.

[0071] As another aspect, in the step (a”), the bioavailability improver may be at least one 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.

[0072] As another aspect, the pH of the continuous phase used in the manufacturing method may be 7 or higher.

[0073] In the production of sustained-release microparticles containing semaglutide or a pharmaceutically acceptable salt thereof according to the present invention and a bioavailability improver, while containing a high amount of semaglutide or a pharmaceutically acceptable salt thereof compared to the weight of the microparticles, excessive release of the initial semaglutide or a pharmaceutically acceptable salt thereof is suppressed, and the bioavailability is high. For release at a constant concentration over a desired long period, for example, 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, biodegradable polymers such as the following can be used, but are not limited thereto. Specifically, polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA) which is a copolymer of lactide and glycolide, polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarateOne or more 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 (PEG), and polymer-sugar conjugates in which the polymer or copolymer is bonded to a sugar, preferably two or more polymers, are preferably used. In a specific embodiment, poly(lactide-co-glycolide) and / or polylactide polymers can be used as the biodegradable polymer in the production method according to the present invention.

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

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

[0076] As a more specific embodiment, when using polylactide-co-glycolide as two or more biodegradable polymers to produce sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver according to the present invention, at least one biodegradable polymer 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 production method is one or more organic solvents. Also, a mixed organic solvent obtained by mixing two or more organic solvents can be used as the organic solvent. As a specific embodiment, the mixed solvent may be a mixed solvent of an organic solvent miscible with water and an organic solvent immiscible with water. In this case, it is preferable to use an organic solvent having a property of being immiscible with water at least 50% (v / v) or more, 60 (v / v)% or more, 50 to 99.9 (v / v)%, 50 to 90 (v / v)%, 50 to 80 (v / v)%, 50 to 70 (v / v)%, 60 to 90 (v / v)%, or 60 to 80 (v / v)%. By using the property of the organic solvent being immiscible with water, the dispersed phase can be homogeneously mixed with the continuous phase containing a surfactant in step (b), (b'), or (b") described below to form an emulsion. The type of the organic solvent for dissolving 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, and 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 of homogeneously mixing the continuous phase containing the dispersed phase and the surfactant in the step (b), (b’), or (b”) is not particularly limited, and it can be carried out using a high-speed stirrer, an in-line mixer, a membrane emulsion method, a microfluidics 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. Therefore, it is preferable to additionally perform a sieving process or the like between the subsequent step (c) and step (d), between step (c’) and step (d’), or between step (c”) and step (d”).

[0079] The type of the surfactant used in the step (b), (b’), or (b”) is not particularly limited, and any surfactant can be used as long as it can help the dispersed phase form a stable droplet dispersed phase in the continuous phase. Polyvinyl alcohol can be used as the surfactant.

[0080] In the step (b), (b’), or (b”), the content of the surfactant 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. When the content of the surfactant is less than 0.01 w / v%, a dispersed phase or emulsion in droplet form may not be formed in the continuous phase. When the content of the surfactant exceeds 20 w / v%, it may be difficult to remove the surfactant after fine particles are formed in the continuous phase due to the excessive surfactant.

[0081] Water can be used as the continuous phase used in the step (b), (b’), or (b”). When dissolved in water to control the initial release of the microspheres encapsulated with a high content of the drug, it may additionally contain a substance that forms a polyvalent anion as an initial release inhibitor.

[0082] In the above step (b), (b'), or (b"), the type of the initial release inhibitor is not particularly limited, and any basic salt that can be dissolved in the continuous phase and maintain a pH of 7.0 or higher can be used. As the initial release inhibitor, one or more substances 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 can be used.

[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 the above step (b), (b'), or (b"), the content of the initial release inhibitor contained in the continuous phase used is 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. When the content of the initial release inhibitor exceeds 20 w / v%, the phenomenon of emulsion droplets rupturing may occur during the production of microspheres. Conversely, when it is lower than 0.05 w / v%, the initial release of microspheres containing a high content of semaglutide may not be sufficiently suppressed.

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

[0086] The continuous phase used in the step (b), (b’), or (b”) can be water, and water that contains one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate can be used to adjust the extraction rate of the organic solvent from the dispersed phase in the emulsion state.

[0087] Also, the pH of the continuous phase may be 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, but is not limited thereto. When the pH of the continuous phase is adjusted within the above range, the bioavailability of the microspheres containing semaglutide or a pharmaceutically acceptable salt thereof can be further increased.

[0088] In the step (c), (c’), or (c”), if an emulsion containing a dispersed phase in droplet form and a continuous phase containing a 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 as the continuous phase from the semaglutide or a pharmaceutically acceptable salt thereof in droplet form as the dispersed phase, the bioavailability improver, and the polymer solution. A part of the organic solvent extracted as the continuous phase may evaporate from the surface. While the organic solvent is extracted and evaporated from the semaglutide or a pharmaceutically acceptable salt thereof in droplet form, the bioavailability improver, and the polymer solution, the dispersed phase in droplet form can be solidified to form microspheres.

[0089] In the step (c), (c’), or (c”), heat can be applied to the continuous phase for a certain period of time to additionally and efficiently remove the organic solvent. The heating temperature is not limited and can be appropriately adjusted by a person skilled in the art according to the organic solvent used. For example, when dichloromethane is used as the organic solvent, heat can be applied so that the temperature is maintained at 30°C or higher, 40°C or higher, 45°C or higher, 30 to 50°C, 40 to 50°C, or 45°C.

[0090] In the said step (d), (d'), or (d''), the method for recovering the microspheres containing semaglutide or its pharmaceutically acceptable salt and the bioavailability improver can be carried out using various known techniques. For example, methods such as filtration or centrifugation can be used.

[0091] Between the said step (c) and step (d), between step (c') and step (d'), or between step (c'') and step (d''), the surfactant remaining can be removed through filtration and washing, and then filtered again to recover the microspheres.

[0092] The washing step for removing the remaining surfactant can usually be carried out using water, and the said washing step can be repeated several times.

[0093] Also, as described above, between the said step (c) and step (d), between step (c') and step (d') or between step (c'') and step (d''), uniform microspheres can be obtained by additionally using a sieving process. The sieving process can be carried out using known techniques, and sieves with different sizes can be used to filter the microspheres of small particles and large particles to obtain microspheres of a uniform size.

[0094] The manufacturing method of the present invention can dry the obtained microspheres using a normal drying method after the said step (d), step (d'), or step (d'') or after the said filtration and washing step to finally obtain dried microspheres.

[0095] Matters such as semaglutide, the bioavailability improver, the biodegradable polymer, and their contents, which are not otherwise defined separately, all apply as they are to the matters defined in the said pharmaceutical composition.

[0096] By the production method of the present invention, a sustained-release microsphere injection containing semaglutide or a pharmaceutically acceptable salt thereof with high bioavailability, in which the semaglutide or a pharmaceutically acceptable salt thereof is maintained at an effective concentration for a desired period without rapid temporary release, can be produced. Further, a sustained-release microsphere injection containing semaglutide or a pharmaceutically acceptable salt thereof with uniform particles having good administrability and a bioavailability improver can be produced.

Example

[0097] [Example] Hereinafter, the present invention will be described in more detail by the following production examples. However, the following production examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following production examples.

[0098] Production Example Production of biodegradable polymer microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver

[0099] Production Example 1 (w / o / w method): Production of biodegradable polymer microparticles containing semaglutide dissolved in the internal aqueous phase and a bioavailability improver As a drug, 0.15 g of semaglutide sodium salt (manufacturer: Chengdu, China) and 0.33 g of poloxamer F127 as a bioavailability improver were dissolved in 1.66 g of tertiary distilled water to prepare a primary aqueous phase. The organic phase was prepared by mixing RG653H and RG753H (manufacturer: Evonik, Germany) as biodegradable polymers in a weight ratio of 1:1 to 1.52 g and dissolving them in 20.8 g of dichloromethane (manufacturer: J.T Baker, USA). A primary emulsion (dispersion phase) was prepared by dispersing the aqueous phase into the organic phase using a homogenizer. As the continuous phase, 2,000 mL of an aqueous solution of 0.1% polyvinyl alcohol (viscosity: 4.8 - 5.8 mPa·s) was used. After connecting the continuous phase to an emulsifying device equipped with a porous membrane with a diameter of 40 μm, the prepared dispersion phase was injected into the porous membrane together with the continuous phase to produce an emulsion in which biodegradable polymer fine droplets containing semaglutide were dispersed. 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. After the injection of the dispersion phase was completed, the organic solvent was removed while maintaining the temperature of the suspension at 40°C for 3 hours. Then, after cooling the temperature to 25°C, it was filtered to remove the residual polyvinyl alcohol with tertiary distilled water and freeze-dried.

[0100] Production Example 2 (w / o / w method): Production of biodegradable polymer microparticles containing semaglutide dissolved in the internal aqueous phase, a bioavailability improver, and an initial release inhibitor contained in the continuous phase As a drug, 0.2 g of semaglutide sodium salt and 0.02 g of Disodium phosphate as a bioavailability improver were dissolved in 1.0 g of tertiary distilled water to produce a primary aqueous phase. 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 (dispersion phase) was produced by dispersing the aqueous phase in the organic phase using a Homogenizer. As 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 emulsifying device equipped with a porous membrane with a diameter of 40 μm, the prepared dispersion phase was injected into the porous membrane together with the continuous phase to produce an emulsion in which biodegradable polymer fine droplets containing semaglutide were dispersed. The suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0101] The temperature of the preparation container was maintained at 25°C, and after the injection of the dispersion phase was completed, the organic solvent was removed while maintaining the temperature of the suspension at 40°C for 3 hours. Then, after cooling the temperature to 25°C, it was filtered to remove the remaining polyvinyl alcohol with tertiary distilled water and freeze-dried.

[0102] Production Example 3 (w / o / w method): Production of biodegradable polymer microparticles containing semaglutide, a release regulator, and a bioavailability improver dissolved in the internal aqueous phase, and an initial release inhibitor contained in the continuous phase As a drug, 0.2 g of semaglutide free base (manufacturer: Chengdu, China), 0.02 g each of sodium decanoate and disodium phosphate as a release regulator and a bioavailability improver were dissolved in 1.8 g of tertiary distilled water to prepare a primary aqueous phase. The organic phase was prepared by dissolving 0.76 g of PDLG 7504A (manufacturer: Corbion, Netherlands) as a biodegradable polymer in 14.4 g of dichloromethane. The aqueous phase was dispersed in the organic phase using a homogenizer to prepare a primary emulsion (dispersion phase). As 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 emulsifying device equipped with a porous membrane with a diameter of 40 μm, the prepared dispersion phase was injected into the porous membrane together with the continuous phase to produce an emulsion in which biodegradable polymer fine droplets containing semaglutide were dispersed. The suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0103] The temperature of the preparation container was maintained at 25°C. After the injection of the dispersion phase was completed, the organic solvent was removed while maintaining the temperature of the suspension at 40°C for 3 hours. Then, after cooling the temperature to 25°C, it was filtered to remove the remaining polyvinyl alcohol with tertiary distilled water and freeze-dried.

[0104] Production Example 4 (o / w method): Production of biodegradable polymer microparticles containing semaglutide dissolved in the organic phase, a bioavailability improver, and an initial release inhibitor contained in the continuous phase The dispersed phase was prepared by sufficiently stirring 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 in 19.9 g of a mixed solvent of dichloromethane and glacial acetic acid (manufacturer: Daejeong, Republic of Korea) and methanol (manufacturer: Daejeong, Republic of Korea) (weight ratio approximately 16:4:1) for 30 minutes or more. The continuous phase used was 2,000 mL of a 0.1% aqueous polyvinyl alcohol solution containing 2% (w / w) disodium phosphate as an initial release inhibitor. After connecting the continuous phase to an emulsifying device equipped with a porous membrane with a diameter of 40 μm, the prepared dispersed phase was injected together with the continuous phase into the porous membrane to produce an emulsion in which biodegradable polymer fine droplets containing semaglutide were dispersed. The suspension was placed in a preparation container and stirred at a speed of 200 rpm.

[0105] The temperature of the preparation container was maintained at 25°C. After the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the temperature of the suspension at 40°C for 3 hours. Then, after cooling the temperature to 25°C, it was filtered to remove the remaining polyvinyl alcohol with tertiary distilled water and freeze-dried.

[0106] Production Examples 5 to 32: Production of biodegradable polymer microparticles containing semaglutide or a pharmaceutically acceptable salt thereof As a drug, semaglutide (manufacturer: Chengdu, China) in the range of 0.125 - 0.450 g and a bioavailability improver (see Table 1) in the range of 0 - 1.2 g were used. Finally, at least one of R203H, RG203H, RG503H, RG653H, RG753H, PDL04A, and PDLG7504A as a biodegradable polymer was used in the range of 0.75 - 2.55 g and weighed so that the batch size became 1.0 - 3.0 g (in Production Examples 1 - 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 producing the dispersed phase, and Production Examples 4 - 29, 31, and 32 were homogeneously dissolved using at least one of glacial acetic acid and methanol as a co-solvent. A 40-um porous emulsification membrane was used to disperse the aqueous phase in the organic phase to produce a primary emulsion. The continuous phase used 2,000 ml of a 0.1% polyvinyl alcohol (viscosity: 4.8 - 5.8 mPa·s) and 2.0% Na2HPO4 (Disodium phosphate) aqueous solution in Production Examples 2 - 32, and 2,000 ml of a polyvinyl alcohol (viscosity: 4.8 - 5.8 mPa·s) and 1.0% NaCl aqueous solution in Production Example 1. After connecting the continuous phase to an emulsifying device equipped with a 40-um 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 fine droplets containing semaglutide were dispersed, and the suspension was placed in a preparation container and stirred at a speed of 200 - 300 rpm.

[0107] 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 temperature of the suspension at 40°C for 3 hours. Then, after cooling the temperature to 25°C, it was filtered to remove the residual polyvinyl alcohol with tertiary distilled water and freeze-dried.

[0108] In Production Examples 5 and 10, the initial release inhibitor was not included in the continuous phase.

[0109]

Table 1

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

[0111] Production Examples 33 to 37 (O / W production method): Production of biodegradable polymer microparticles containing dexamethasone acetate or a pharmaceutically acceptable salt thereof For the production of dexamethasone microspheres, the dispersed phase contains at least one of Purasorb PDLG 7502A (i.v 0.16 - 0.24 dl / g; manufacturer: Purac, Netherlands), RG 752H (i.v 0.14 - 0.22 dl / g; manufacturer: Evonik, Germany), RG 753H (i.v 0.32 - 0.44 dl / g; manufacturer: Evonik, Germany), PDL04A, PDL02, PDLG 7504A (manufacturer: Corbion, Netherlands), which are biocompatible polymers. 0.200 - 0.400 g of dexamethasone acetate (manufacturer: Pfizer, USA) was mixed with dichloromethane (manufacturer: J.T Baker, USA), dimethyl sulfoxide (manufacturer: J.T Baker, USA), and benzyl alcohol (manufacturer: Junsei, Japan) for production. The continuous phase used 2,000 ml of a 0.5% polyvinyl alcohol (viscosity: 4.8 - 5.8 mPa.s) and 2.5% NaCl aqueous solution in Production Examples 33 to 37.

[0112]

Table 2

[0113] Production Examples 33 to 37 show the production of microspheres depending on the polymer type and the amount of dexamethasone acetate used.

[0114] Production Examples 38 to 51 Semaglutide microspheres and dexamethasone acetate microspheres were co-administered and shown in Production Examples 38 to 51 (see Table 3).

[0115]

Table 3

[0116] Experimental Example 1: Measurement of the amount of semaglutide encapsulated in microparticles To measure the amount of semaglutide encapsulated in the microspheres produced in Production Examples 1 to 32 and the amount of dexamethasone encapsulated in the microspheres produced in Production Examples 33 to 37, 10 mg of the microspheres were completely dissolved in DMSO and then diluted with the mobile phase. 20 μL of the diluted solution was injected into HPLC and measured at a detection wavelength of 214 nm. The column used in this experimental example was ZORBAX 300SB-C18, 5 μm, 4.6×150 mm, and the mobile phase was used in isocratic mode with 45% 0.1% TFA acetonitrile and 55% 0.1% TFA aqueous solution. 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 blood concentration of semaglutide due to a bioavailability improver and a release regulator To evaluate the in vivo drug release profile of the semaglutide sustained-release microspheres according to the present invention, the concentration of semaglutide in the blood was measured after dosing rats.

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

[0121]

Table 5

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

[0123] Experimental Example 2-2. Improvement of semaglutide bioavailability due to benzathine content In order to evaluate the in vivo drug release pattern of the sustained-release semaglutide microspheres according to the present invention, the bioavailability (%) was measured after dosing the rats. Specifically, semaglutide sustained-release microspheres with benzathine added at 0.6 (w / w)%, 1.2 (w / w)%, 2.3 (w / w)%, and 5 (w / w)% of the benzathine content with respect to the total batch weight, and semaglutide sustained-release microspheres without benzathine added, as semaglutide contained in the sustained-release microspheres, 1.2 mg (4.0 mg / kg) or 3.6 mg (12.0 mg / kg) was dispersed in 0.5 mL of suspension and then injected into Sprague-Dawley rats (300 g). Then, as a result of analyzing the pharmacokinetic parameters to compare the improvement of bioavailability in rats, it was confirmed that Production Examples 4, 7, 8, and 9 had an approximately 2-fold or more increase in AUC compared to Production Example 6. Generally, the AUCs were similar, and a bioavailability of 40% or more was confirmed.

[0124]

Table 6

[0125] Experimental Example 2-3. Improvement of AUC due to semaglutide content To evaluate the in vivo drug release profile of the semaglutide sustained-release microparticles according to the present invention, the AUC was measured after dosing rats.

[0126] In the experiment, rats were injected with semaglutide sustained-release microparticles containing 0.125, 0.150, 0.350, and 0.400 g of semaglutide respectively and 1.2 g of benzathine as a bioavailability improver, and semaglutide sustained-release microparticles containing 0.400 g of semaglutide and no bioavailability improver. The injection of the semaglutide microparticles was carried out by dispersing 3.6 mg (12.0 mg / kg) of the semaglutide contained in the sustained-release microparticles in 0.5 mL of suspension and then injecting it into Sprague-Dawley rats (300 g).

[0127]

Table 7

[0128] It was confirmed that the AUC increased as the drug content increased. In particular, through the results of FIG. 1 showing the changes in blood drug levels and the pharmacokinetic parameters after administering the microparticles of Production Example 12 to experimental animals, it was possible to confirm that the cumulative drug release rate up to 28 days after administration was 62.28% of the total drug release amount. It was confirmed that this showed a favorable drug release profile in which the drug release rate up to the formulation administration period with respect to the total drug release amount was 80% or less.

[0129] Experimental Example 2-4. Initial release depending on the presence or absence of an initial release inhibitor The following Table 8 is a table showing the initial release depending on whether or not an initial release inhibitor is contained in the continuous phase.

[0130]

Table 8

[0131] It was confirmed that the initial release of the drug in the microparticles containing a high content of semaglutide was significantly reduced by including an initial release inhibitor in the continuous phase during the production of the microparticles according to the experimental results.

[0132] Experimental Example 3-1. Comparison of microparticle characteristics by addition of disodium phosphate and use of similar salts This experiment was conducted to compare the characteristics during the production of microparticles by using the initial release inhibitor as disodium phosphate analog salts.

[0133] The control formulation (Production Example 55) without the addition of the initial release inhibitor in Table 1 and the formulations produced by adding Na2HPO4, K2HPO4, and NaH2PO4 as the initial release inhibitor respectively are shown in Production Examples 56 to 58. Table 9 shows the main characteristics and initial release of Production Examples 55 to 58.

[0134]

Table 9

[0135] Referring to Production Examples 55 to 58 in Tables 1 and 9 above, when Na2HPO4 or K2HPO4 was added as the initial release inhibitor compared with the control formulation, it was confirmed that the initial release decreased to less than 1%. However, when NaH2PO4 was added to the continuous phase as the initial release inhibitor, the initial release was 17%, which was shown to be very high compared with the control formulation, and it was confirmed that not all disodium phosphate analog salts showed the effect of suppressing the initial release. The pH of Production Example 55 was about 3, the pH of Production Examples 56 and 57 was about 7, and the pH of Production Example 58 was about 5. Although no linear data was shown, it was judged that the high initial release shown in Production Examples 55 and 58 could be due to the factor of pH. When the cross-sectional image was confirmed by SEM, it was confirmed that there were multiple internal pores in the formulation with acidic pH, and conversely, the internal pores decreased when the pH was neutral or basic. It was judged that the above results were the reasons for the suppression of the 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 during the production of microspheres using Na2CO3, NaHCO3, (NH4)2SO4, and (NH4)2HPO4 as initial release inhibitors.

[0137] The control dosage form (Production Example 66) without the addition of the initial release inhibitor in Table 1 and the dosage forms produced by adding Na2CO3, NaHCO3, (NH4)2SO4, and (NH4)2HPO4 as the initial release inhibitor respectively are shown in Production Examples 68 to 71. Table 10 shows the main characteristics and initial release of Production Examples 66 and 68 to 71.

[0138]

Table 10

[0139] Referring to Production Examples 66, 68 to 71 in Tables 1 and 10 above, it can be confirmed that the initial release is somewhat higher in Production Examples 66 and 70. Production Examples 66 and 70 with higher initial release showed pH values of about 3 and about 5 respectively, being acidic, while Production Examples 68, 69, and 71 which are neutral and basic showed an initial release of less than 3%. Based on such results, among the initial release inhibitors, when adding to the continuous phase, if the continuous phase shows an acidic pH, it will show a very high initial release of semaglutide, but when using an initial release inhibitor that makes the basic pH show pH 7 or higher (neutral or basic), it was confirmed that the initial release of semaglutide was clearly suppressed. Here, looking at the initial release of Production Examples 68, 69, and 71, it was confirmed that the initial release is suppressed when it is basic rather than when it is neutral, but the suppression of the initial release does not increase linearly with the degree of basicity.

[0140] Experimental Example 3-3. Comparison of microparticle characteristics by pH adjustment after addition of disodium 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 the microspheres was maintained even when the pH changed after using the initial release inhibitor through observation of changes in the initial release.

[0141] Specifically, the control formulation (Production Example 66) without the initial release inhibitor added in Table 1, the formulation with 2 (w / v)% disodium hydrogen phosphate added as the initial release inhibitor and the pH not intentionally adjusted was Production Example 63, the formulation with the pH adjusted to 2 (acidic) using HCl was Production Example 64, and the formulation with the pH adjusted to 12 using NaOH was Production Example 65, respectively.

[0142] Table 11 shows the main characteristics and initial release of Production Examples 63 to 66.

[0143]

Table 11

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

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

[0146] The control formulation (Production Example 55) without Na2HPO4 added in Table 1 and the formulations with 0.5 (w / v)%, 1 (w / v)%, 2 (w / v)%, 3 (w / v)%, and 4 (w / v)% of Na2HPO4 added were shown as Production Examples 59, 60, 56, 61, and 62, respectively. Table 12 shows the main characteristics and initial release of Production Examples 55, 56, 59 to 62.

[0147]

Table 12

[0148] Referring to Preparation Examples 55, 56, and 59 to 62 of Table 1 and Table 12, it was confirmed that, compared with the initial release of 4.6% of the control dosage form, in the case of the dosage form added with 0.5 (w / v)% of Na2HPO4, the initial release decreased to 0.64%. The initial release rates when the concentration of Na2HPO4 was 1 (w / v)% and 2 (w / v)% were 0.56% and 0.4%, respectively. However, when 3 (w / v)% and 4 (w / v)% of Na2HPO4 were added, the initial releases were 0.77% and 0.86%, respectively, showing a tendency to increase rather than when 2% of Na2HPO4 was added. When Na2HPO4 was used at 4 (w / v)% or more, a large amount of polymer aggregation occurred during the production of microspheres, and it was judged that the tendency of the initial release to increase as the content of Na2HPO4 increased starting from 2 (w / v)% was due to the above-mentioned polymer aggregation phenomenon.

[0149] Experimental Example 5. Method for measuring the residual amounts of sodium and phosphorus To measure the sodium and phosphorus contents in the microspheres used in the above Examples and Comparative Examples, 300 mg of microspheres were mixed with 6 mL of a nitric acid aqueous solution mixed with ultrapure water at a ratio of 1:1 and 3 mL of hydrogen peroxide, and then heated at 100 °C or higher, and acid was added until the gas generated during the dissolution process changed from yellow to white. The sample thus obtained was weighed and 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, and the results are shown in Experimental Examples 5-1 and 5-2 below.

[0150] Experimental Example 5-1. Comparison of the residual amounts of sodium and phosphorus in microparticles depending on the amount of disodium phosphate added The sodium and phosphorus residues of the microspheres according to Preparation Examples 59 to 61 and 63 were confirmed and shown in Table 13.

[0151]

Table 13

[0152] Referring to Table 13, it was confirmed that as the addition amount of Na2HPO4 increased, the residual amounts of sodium and phosphorus significantly increased, and the content of the initial release inhibitor remaining in the microspheres 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 the residual amounts of sodium and phosphorus in microparticles by changes in biodegradable polymer and addition of benzathine The residual amounts of Na and P in Production Examples 16, 63, and 67 were confirmed and shown in Table 14.

[0154]

Table 14

[0155] Referring to Table 14, it was confirmed that depending on the production conditions of the microspheres containing semaglutide, there were differences in the contents of residual sodium and residual phosphorus due to the initial release inhibitor contained in the continuous phase, and the content of the initial release inhibitor remaining in the microspheres was 50 ppm to 500 ppm based on sodium and 10 ppm to 100 ppm based on phosphorus.

[0156] Experimental Example 6. Comparison of SEM observation results of microparticles depending on the presence or absence of disodium 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, in the case of microspheres produced using only 0.1% PVA in the continuous phase, it was confirmed that there were multiple pores (pores) in the cross-section of the microspheres. In the case of microspheres produced using 0.1 (w / v)% PVA and 2 (w / v)% Na2HPO4 in the continuous phase, it was confirmed that most of the pores disappeared or, even if pores were present, the number and size of the pores significantly decreased, which is judged to have shown the effect of reducing the channels that may affect the initial release of the drug.

Claims

1. A sustained-release microparticle comprising semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer, wherein the semaglutide or a pharmaceutically acceptable salt thereof is contained in an amount of 8% by weight or more as semaglutide based on the total weight of the microparticle, and the bioavailability improver is contained in an amount of 2.5% to 250% by weight based on the weight of semaglutide, a pharmaceutical composition for preventing or treating diabetes, type 2 diabetes, preservation of beta-cell function, obesity, non-alcoholic steatohepatitis, or degenerative neurological diseases.

2. A sustained-release microparticle 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 contained in an amount of 8% by weight or more as semaglutide based on the total weight of the microparticle, and the initial release inhibitor is contained in an amount of 5 ppm to 2000 ppm, a pharmaceutical composition for preventing or treating diabetes, type 2 diabetes, preservation of beta-cell function, obesity, non-alcoholic steatohepatitis, or degenerative neurological diseases.

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

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

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

6. The biodegradable polymer is a polymer selected from the group consisting of polylactide (Polyactide, PLA), polyglycolide (Polyglycolide, PGA), poly(lactide-co-glycolide) (Polylactide-co-glycolide, PLGA) which is a copolymer of lactide and glycolide, polydioxanone, polycaprolactone (Polycaprolactone, PCL), poly(lactide-co-glycolide-co-caprolactone) (Polylactide-co-glycolide-co-caprolactone, PLGC), poly(lactide-co-hydroxymethyl glycolide) (Polylactide-co-hydroxymethyl glycolide, PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (Polytrimethylene carbonate, PTMC), poly(lactide-co-trimethylene carbonate) (Polylactide-co-trimethylene carbonate, PLTMC), polyhydroxybutyric acid (Polyhydroxybutyric acid, PHB), polyhydroxybutyrate-co-hydroxyvalerate (Polyhydroxybutyrate-co-hydroxyvalerate, PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyamino acid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate lactide) (PBSLA); copolymers or simple mixtures of two or more of these; copolymers of the polymer and polyethylene glycol (Polyethylene glycol, PEG);The pharmaceutical composition according to claim 1 or claim 2, which is one or more selected from the group consisting of the polymer or copolymer and the polymer-sugar complex in which the sugar is bound to the polymer.

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

8. The bioavailability improver is 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, detergent, arginine, glycine, guanidine hydrochloride, urea, sodium chloride, potassium chloride, triethylamine, ethanolamine, triethanolamine, ethylenediamine, poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, rhizolutein, benzofuran, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxideThe pharmaceutical composition according to claim 1, which is 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 initial release inhibitor is one or more substances 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. The pharmaceutical composition according to claim 2 or claim 9.

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 microspheres 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. The 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, napadisyl acid, naphthalenesulfonic acid, and pamoic acid.

15. (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 (dispersion 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 phase (continuous phase) containing a surfactant to produce an emulsion; (c) Extracting and evaporating the organic solvent from the dispersed phase in the emulsion state produced in step (b) using the continuous phase to form microspheres; and A method for producing microparticles comprising semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer, the method including the step of recovering the microparticles from the continuous phase of step (c).

16. The production method according to claim 15, wherein the bioavailability improver is one or more selected from the group consisting of poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, resorcinol, and benzofuran.

17. (a') After dissolving semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver in an aqueous solution to form a primary aqueous phase and dissolving one or more biodegradable polymers in an organic solvent to form an oil phase, 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 improver, and a polymer; (b') Adding the primary emulsion containing semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a polymer produced in step (a') to an aqueous solution phase (continuous phase) containing a surfactant to produce a W / O / W emulsion (secondary emulsion); (c') Extracting and evaporating the organic solvent from the oil phase in the state of the secondary emulsion produced in step (b') as the continuous phase to form microparticles; (d') A method for producing microparticles comprising semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer, the method including the step of recovering the microparticles from the continuous phase of step (c').

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

19. (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 (dispersion 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 phase (continuous phase) containing a surfactant to produce an emulsion; (c”) Extracting and evaporating the organic solvent from the dispersed phase in the emulsion state produced in step (b”) using the continuous phase to form microspheres; and (d”) Recovering the microspheres from the continuous phase of step (c”). A method for producing microspheres comprising semaglutide or a pharmaceutically acceptable salt thereof, a bioavailability improver, and a biodegradable polymer.

20. The method according to claim 19, wherein the bioavailability improver 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 polymer is a polymer selected from the group consisting of polylactide (Polyactide, PLA), polyglycolide (Polyglycolide, PGA), poly(lactide-co-glycolide) (Polylactide-co-glycolide, PLGA) which is a copolymer of lactide and glycolide, polydioxanone, polycaprolactone (Polycaprolactone, PCL), poly(lactide-co-glycolide-co-caprolactone) (Polylactide-co-glycolide-co-caprolactone, PLGC), poly(lactide-co-hydroxymethyl glycolide) (Polylactide-co-hydroxymethyl glycolide, PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (Polytrimethylene carbonate, PTMC), poly(lactide-co-trimethylene carbonate) (Polylactide-co-trimethylene carbonate, PLTMC), polyhydroxybutyric acid (Polyhydroxybutyric acid, PHB), polyhydroxybutyrate-co-hydroxyvalerate (Polyhydroxybutyrate-co-hydroxyvalerate, PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyamino acid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate lactide) (PBSLA); copolymers or simple mixtures of two or more of these; copolymers of the above polymers and polyethylene glycol (Polyethylene glycol, PEG);The production method according to any one of claims 15 to 20, which is one or more selected from the group consisting of a polymer or copolymer and a polymer-sugar complex in which the sugar is bound to the polymer or copolymer.;

22. The manufacturing method according to any one of claims 15 to 20, further comprising producing microspheres by additionally including 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, napadisylate, and pamoic acid.

23. The organic solvent in the step (a) or (a') or (a") is at least one organic solvent selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol, and the production method according to any one of claims 15 to 20.

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

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

26. The continuous phase in the step (b) or (b') or (b") contains an initial release inhibitor, and the production method according to any one of claims 15 to 20.

27. The initial release inhibitor is contained at 0.05 w / v% to 20 w / v% based on the total volume of the continuous phase, and the production method according to claim 26.

28. The initial release inhibitor is at least one selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium phosphate, and the production method according to claim 26.

29. The pH of the continuous phase in the step (b) or (b') or (b") is 7 or more, and the production method according to any one of claims 15 to 20.

30. When administered in vivo to sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver, the release rate of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours is less than 15%, and the production method according to any one of claims 15 to 20.

31. When administered in vivo to sustained-release microspheres containing semaglutide or a pharmaceutically acceptable salt thereof and a bioavailability improver, the release rate of semaglutide or a pharmaceutically acceptable salt thereof within 24 hours is less than 10%, and the production method according to any one of claims 15 to 20.

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