Sustained-release microgranular preparation containing tilzepatide or a pharmaceutically acceptable salt thereof, and method for producing the same.

Abstract

The present invention relates to a pharmaceutical composition useful for the prevention or treatment of diabetes, beta-cell dysfunction, hypertension, hyperlipidemia, obesity, and non-alcoholic steatohepatitis, comprising tilzepatide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and sustained-release microparticles made of a biodegradable polymer, which does not cause a rapid initial burst of the drug, contains a high concentration of the drug relative to its particle size, has high bioavailability, and can minimize patient discomfort and inflammatory responses that may occur during administration to the human body.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising sustained-release microspheres containing a high content of tirzepatide or a pharmaceutically acceptable salt thereof, and a method for producing the sustained-release microspheres.

Background Art

[0002] Tirzepatide, sold under the trademark name Mounjaro, is an antidiabetic drug used for the treatment of type 2 diabetes. Tirzepatide is administered once a week by subcutaneous injection.

[0003] The most common side effects include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, abdominal pain, etc.

[0004] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood glucose regulation. After eating food, these hormones are secreted from intestinal cells and induce insulin secretion. Tirzepatide is known as a GIP analog that activates both GLP-1 and GIP receptors to improve blood glucose regulation.

[0005] Tirzepatide was approved for medical use in the United States in May 2022, in the European Union in September 2022, in Canada in November 2022, and in Australia in December 2022. The US Food and Drug Administration (FDA) regards this as the first drug.

[0006] For effective monotherapy of tilzepatide, the development of techniques to ensure long-term effective pharmacological effects is necessary. Therefore, the inventors devised a technique to encapsulate tilzepatide in microglobules made of biodegradable polymers for long-term elution. However, in this case, the bioavailability of tilzepatide encapsulated in microglobules is low, or the drug content within the microglobules is low, requiring the administration of a large number of microglobules to achieve long-term effective pharmacological effects. However, administering a large number of microglobules into the body presents problems: subcutaneous injection is difficult, making self-administration by the patient difficult, and it also leads to very high pain and inflammatory reactions at the injection site. [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention has been proposed to solve these problems and aims to provide a pharmaceutical composition containing tilzepatide in high content and exhibiting stable drug release characteristics over a long period of time, a pharmaceutically acceptable salt thereof, a biodegradable polymer, and sustained-release microspheres containing an initial release inhibitor, and a method for producing said sustained-release microspheres. [Means for solving the problem]

[0008] The present invention will be described in detail below.

[0009] In the terminology of this invention, "one or more" means one or a number equivalent to one or more. In this invention, any configuration that is one or more may preferably be one, two or more, three or more, one to three, or one to two, but is not limited thereto. The term "one or more" may be used interchangeably with the term "one or more" in this invention.

[0010] In order to achieve the aforementioned objective, In one aspect, the present invention provides a pharmaceutical composition containing a biodegradable polymer, a tilzepatide content of 8% by weight or more of tilzepatide relative to the total weight of microparticles, and tilzepatide-releasing microparticles containing an initial release inhibitor at a concentration of 5 ppm to 2000 ppm relative to the weight of tilzepatide.

[0011] Another aspect of these biodegradable polymers is that they include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyamino acid, polyalkyl cyanoacrylate (Polyalkyl Polymers selected from the group consisting of block copolymers of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); simple mixtures of two or more of these; copolymers of the polymer with polyethylene glycol (Polyethylenglycol, PEG);It may be one or more selected from the group consisting of the polymer or copolymer and a polymer-sugar complex in which the polymer or copolymer is bonded to a sugar.

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

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

[0014] Another aspect is that the microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor may have an average particle size of 5 μm to 100 μm.

[0015] Another aspect may be that the granulocyte span value containing the tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor is 1.5 or less.

[0016] Another aspect is that the total weight of microglobules containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor in the aforementioned pharmaceutical composition is 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, and 30 mg to 40 0mg, 30mg to 200mg, 30mg to 100mg, 40mg to 1000mg, 40mg to 800mg, 40mg to 600mg, 40mg to 400mg, 40mg to 200mg, 40m g 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] Another aspect may be the inclusion of one or more release regulators selected from butyric acid, varreic acid, caproic acid, enanthic acid, caprylic acid, ferargonic acid, capruic 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, hydroxynaphthic acid, napadisyl acid, naphthalenesulfonic acid, and pamoic acid.

[0018] Another aspect is that the microparticles may contain 10 to 500 mg / kg of Na.

[0019] Another aspect is that the microglobules may contain 1 to 100 mg / kg of P.

[0020] Another aspect of the present invention is the provision of a method for producing sustained-release microglobules containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial-release inhibitor.

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

[0022] Another aspect is that any initial release inhibitor can be used as long as it is a substance that allows the pH of the continuous phase to be set to 7 or higher when dissolved in the continuous phase.

[0023] In another aspect, the initial release inhibitor can be one or more substances selected from phosphates, hydroxide salts, phosphide salts, phosphite salts, carbonate salts, bicarbonate 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, percyanide salts, and nitride salts of alkali metals, alkaline earth metals or ammonium. In another aspect, the initial release inhibitor can be one or more selected from the group consisting of disodium phosphate, dipotassium phosphate, and diammonium phosphate. In another aspect, there is provided a pharmaceutical composition containing a biodegradable polymer and sustained-release microspheres containing a tiludronate content of 8% by weight or more as tiludronate based on the total weight of the microspheres while the initial release of the drug is 10% or less, and a method for producing the same.

Advantages of the Invention

[0024] The sustained-release pharmaceutical composition containing tiludronate or a pharmaceutically acceptable salt thereof and an initial release inhibitor according to one production example of the present invention suppresses rapid initial release by the initial release inhibitor despite containing a high content of tiludronate, reduces the dosage of the microspheres due to the high content, not only shows a high bioavailability, but also has a high bioavailability when administered in the body, shows a sustained drug effect for a long period of one month or more, and can reduce the dosage of the microspheres, and has the effect of minimizing the pain of the patient that may occur during administration and the side effects at the administration site.

Brief Description of the Drawings

[0025] [Figure 1a] Scanning electron micrographs confirming the morphological characteristics of the microspheres produced according to each of Example 1 and Comparative Example 1. [Figure 1b] Scanning electron micrographs confirming the morphological characteristics of the microspheres produced according to each of Example 1 and Comparative Example 1.

Modes for Carrying Out the Invention

[0026] The present invention will be described in detail below.

[0027] The present invention comprises tilzepatide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] Tirzepatide is an acylated peptide engineered to activate GIP and GLP-1 receptors, core mediators of insulin secretion, which are also expressed in brain regions that regulate food intake. Tirzepatide is designed for subcutaneous administration once a week.

[0029] The structure of tilzepatide is as shown in Chemical Formula 1 below. [ka]

[0030] Tilzepatide may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Any salt commonly used in the industry may be used without limitation. The term "pharmaceutically acceptable salt" in this invention means any organic or inorganic addition salt of the aforementioned compound that is relatively non-toxic to the patient and has a harmless active effect, such that the side effects resulting from the salt do not diminish the beneficial efficacy of the active ingredient. Specific examples include, but are not limited to, sodium salts, acetates, benzoates, hydroxynaphthates, napadisylates, or pamoate of tilzepatide.

[0031] The active ingredient of the present invention, tilzepatide, or a pharmaceutically acceptable salt thereof, may be in various forms, such as amorphous or crystalline.

[0032] The pharmaceutical composition according to the present invention provides the area under the blood concentration-time curve (AUC) of tilzepatide up to 24 hours after administration. 0-24hr ) is the area under the total blood concentration-time curve (AUC). totalIt may be 20% or less, 10% or less, 5% or less, 0.1 to 20%, 1 to 10%, or 1 to 5% compared to ).

[0033] The pharmaceutical composition according to the present invention provides the area under the blood concentration-time curve (AUC) of tilzepatide from administration to the inter-dosing day. 0-QXM ) is the area under the total blood concentration-time curve (AUC). total In comparison to rats, the percentages for humans can be 70% or less, 65% or less, 60% or less, 20 to 70%, 20 to 65%, 20 to 60%, 25 to 70%, 25 to 65%, 25 to 60%, 30 to 70%, 30 to 65%, or 30 to 60%, while for rats they can be 95% or less, 93% or less, 90% or less, 50 to 95%, 50 to 93%, 50 to 90%, 55 to 95%, 55 to 93%, 55 to 90%, 60 to 95%, 60 to 93%, or 60 to 90%.

[0034] Furthermore, the pharmaceutical composition according to the present invention may be a pharmaceutical composition containing sustained-release microglobules in which the tilzepatide content is 8% by weight or more of tilzepatide relative to the total microglobule weight, while the initial release of the drug is less than 10% within 24 hours.

[0035] The biodegradable polymer contained in the tilzepatide sustained-release microspheres included in the pharmaceutical composition according to the present invention is, for example, but is not limited to, polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyamino acid, polyalkyl cyanoacrylate (PolyalkylThe polymer is selected from the group consisting of cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA), a simple mixture of two or more of the selected polymers, a copolymer of the polymer and polyethylene glycol (PEG), and a polymer-sugar complex in which the polymer or copolymer is bonded to a sugar.

[0036] Furthermore, if the biodegradable polymer is a simple mixture of two or more polymers (i.e., a simple mixture containing two or more polymers selected from above), it may also contain two or more polymers of different types from the non-restrictively exemplified polymers, and may be a combination or blend of polymers of the same type, but the polymers of the same type may be a combination of polymers having different intrinsic viscosities and / or monomer proportions (for example, a combination or blend of two or more poly(lactide-co-glycolide) having different intrinsic viscosities), or may have different terminal groups (for example, the same type of polymer may have an ester terminal group or an acid terminal group).

[0037] In one specific embodiment, the pharmaceutical composition according to the present invention may include microparticles containing two or more of the biodegradable polymers. In another specific embodiment, the pharmaceutical composition according to the present invention may contain two or more types of microparticles, each containing one or more polymers selected from the biodegradable polymers.

[0038] The biodegradable polymer may have an intrinsic viscosity of 0.16 to 1.7 dL / g, 0.2 to 1.3 dL / g, or 0.24 to 1.2 dL / g, taking into consideration factors such as the drug release characteristics and the manufacturing process. The intrinsic viscosity is measured using an Ubbelohde viscometer at 25°C with a concentration of 0.1% (w / v) chloroform.

[0039] In the case of the polylactide-co-glycolide, the molar ratio of lactide to glycoside in the copolymer may be 40:60 to 90:10, 45:55 to 85:15, or 50:50 to 75:25, for example, 45:55, 50:50, 75:25, or 85:15.

[0040] If the intrinsic viscosity of the biodegradable polymer is less than 0.16 dL / g, the molecular weight of the polymer is insufficient, making it difficult to exhibit a sustained-release effect of tilzepatide or its pharmaceutically acceptable salt. If the intrinsic viscosity of the biodegradable polymer exceeds 1.7 dL / g, the release of tilzepatide or its pharmaceutically acceptable salt may be too slow. Furthermore, when producing microspheres using a polymer with high intrinsic viscosity, there is a problem in that the high viscosity of the polymer necessitates the use of an excessive amount of the manufacturing solvent, making it difficult to produce reproducible microspheres.

[0041] Examples of commercially available polymers possessing the aforementioned properties include Evonik's Resomer® series RG502H, RG503H, RG504H, RG502, RG503, RG504, RG653H, RG752H, RG753H, RG752S, RG755S, RG750S, RG757S, RG858S, R202H, R203H, R205H, R202S, R203S, R205S, R206S, and R207S, as well as Corbion's PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG 7502, PDLG 7507, PDLG 5002A, PDLG 5002, PDLG 5004A, and PDLG 5004.

[0042] The biodegradable polymer content in sustained-release microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor according to the present invention can be selected as an upper limit of 60% by weight or more, 62% by weight or more, 65% by weight or more, 67% by weight or more, or 70% by weight or more, based on the total weight of the microspheres, and as a lower limit of 92% by weight or less, 91% by weight or less, 90% by weight or less, 89% by weight or less, or 88% by weight or less, or can be included in a range consisting of a combination of the above upper and lower limits. For example, it may be, but is not limited to, 60% to 92% by weight, 65% to 90% by weight, or 70% to 88% by weight.

[0043] In the sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt and an initial release inhibitor according to the present invention, the content of tilzepatide or a pharmaceutically acceptable salt is preferably 8% or more, 12% or more, 14% or more, 37% or less, 35% or less, or 33% or less by weight of tilzepatide relative to the total weight of the microglobulins. If the content of tilzepatide or a pharmaceutically acceptable salt in the microglobulins is less than 8% by weight relative to the tilzepatide standard, the amount of high molecular weight used may be too large compared to the drug, which may reduce the bioavailability of tilzepatide or a pharmaceutically acceptable salt. If the content is excessively high, it may be undesirable because it may lead to a problem of increased initial release of tilzepatide or a pharmaceutically acceptable salt.

[0044] The pharmaceutical composition containing sustained-release microparticles according to the present invention may contain an amount less than a certain threshold of the initial release inhibitor among the microparticles.

[0045] In the present invention, the initial release inhibitor is a substance included in the continuous phase to suppress the rapid release of the active ingredient in the microsphere manufacturing process, and is characterized by being present in less than a certain amount in the microspheres according to the present invention. The continuous phase means a substance that allows the dispersion phase containing the active ingredient, such as tilzepatide, and a biodegradable polymer to disperse when using emulsion and solvent extraction evaporation methods in the microsphere manufacturing method, and the present invention is not limited thereto, but may be an aqueous solution containing a surfactant. The initial release inhibitor according to the present invention may be included in the continuous phase used in such a manufacturing method, and after being manufactured therein, a certain amount may be present in the microspheres according to the present invention. Matters concerning the continuous phase can be similarly applied to matters described in the microsphere manufacturing method according to the present invention described below.

[0046] Specifically, the initial release inhibitor is present in concentrations of 5 ppm or more, 10 ppm or more, 20 ppm or more, 30 ppm or more, 40 ppm or more, 50 ppm or more, 100 ppm or more, 150 ppm or more, 200 ppm or more, 250 ppm or more, 200 ppm or more, 300 ppm or more, 350 ppm or more, 400 ppm or more, 450 ppm or more, 500 ppm or more, 550 ppm or more, 600 ppm or more, 650 ppm or more, 700 ppm or more, 750 ppm or more, 800 ppm or more, 850 ppm or more, 900 ppm or more, 950 ppm or more, 1000 ppm or more, and 110 ppm relative to the total particle weight. The upper limit may include 0 ppm or more, 1200 ppm or more, 1300 ppm or more, 1400 ppm or more, or 1500 ppm or more, and the lower limit may include 2000 ppm or less, 1900 ppm or less, 1800 ppm or less, 1700 ppm or less, 1600 ppm or less, 1500 ppm or less, 1400 ppm or less, 1300 ppm or less, 1200 ppm or less, 1100 ppm or less, 1000 ppm or less, 900 ppm or less, 800 ppm or less, 700 ppm or less, 600 ppm or less, or 500 ppm or less, and the range may include combinations of the above upper and lower limits. For example, the initial release inhibitor may be present in an amount of 5 ppm to 2000 ppm relative to the total particle weight, preferably 10 to 1500 ppm, more preferably 20 to 1000 ppm, and most preferably 20 to 500 ppm.

[0047] In specific embodiments, the initial release inhibitor can be any substance that allows the pH of the continuous phase to be set to 7 or higher when dissolved in the continuous phase. The initial release inhibitor may be one or more selected from alkali metals, alkaline earth metals or ammonium phosphates, hydroxide salts, phosphide salts, phosphite salts, carbonate salts, bicarbonate salts, chromate salts, dichromate salts, oxides, oxalates, silicates, sulfates, sulfide salts, sulfites, tartrates, tetraborate salts, thiosulfates, arsenate salts, arsenite salts, citrates, pericyanide salts, and nitride salts, but is not limited thereto.

[0048] In specific embodiments, the initial release inhibitor may be one or more selected from the group consisting of two or more alkali metal phosphates, one or more alkali metal carbonate salts, one or more alkali metal bicarbonate salts, and two or more ammonium phosphates, but is not limited thereto.

[0049] More specifically, the phosphates of two or more alkali metals mean phosphates containing two or more alkali metal ions, for example, disodium phosphate (Na2HPO4) or dipotassium phosphate (K2HPO4); the bicarbonate salts of one or more alkali metals mean bicarbonate salts containing one or more alkali metal ions, for example, sodium bicarbonate (NaHCO3); the carbonate salts of two or more alkali metals mean carbonate salts containing two or more alkali metal ions, for example, sodium carbonate (Na2CO3); and the phosphates of two or more ammoniums mean phosphates containing two or more ammonium ions, for example, diammonium phosphate ((NH4)2HPO4). These can be used individually or in mixtures of two or more.

[0050] Microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor according to the present invention have 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, It is preferable to have a uniform particle distribution of 60μm to 80μm, 60μm to 70μm, 20μm to 90μm, 20μm to 70μm, 20μm to 60μm, 30μm to 80μm, 30μm to 60μm, 40μm to 70μm, 40μm to 50μm, 30μm to 40μm, 20μm to 30μm, 5μm to 30μm, 5μm to 20μm, 10μm to 20μm, or 5μm to 10μm. In this invention, the term "average particle size" refers to the particle size corresponding to 50% of the volume in the particle size distribution curve, and is indicated as D50 or D(v, 0.5) to mean the median diameter.

[0051] If the average particle size of microglobules containing tilzepatide or a pharmaceutically acceptable salt and an initial release inhibitor is less than 5 μm, the release of tilzepatide or a pharmaceutically acceptable salt from the microglobules may be too rapid, which is undesirable. If the average particle size exceeds 100 μm, it may be undesirable because the injection needle may become too thick during administration to the human body, causing pain during injection or leakage of the drug at the injection site after injection.

[0052] The microparticles containing tilzepatide or a pharmaceutically acceptable salt and an initial release inhibitor of the present invention preferably have a uniform particle distribution. Microparticles containing tilzepatide or a pharmaceutically acceptable salt and an initial release inhibitor having a uniform particle distribution exhibit less deviation during injection compared to non-uniform microparticles, allowing for more accurate dosage administration. The span value of the microparticles containing tilzepatide or a pharmaceutically acceptable salt and an initial release inhibitor of the present invention is preferably 1.5 or less. More preferably, the span value is 1.2 or less. More specifically, the span value may be 1.5 or less, 1.2 or less, 0.1 to 1.5, 0.3 to 1.5, 0.5 to 1.5, 0.1 to 1.0, 0.4 to 1.0, 0.6 to 1.0, 0.2 to 0.8, or 0.4 to 0.8. In this invention, the term "span value" refers to an index indicating the uniformity of particle size of microspheres, and means the value obtained by the formula Span value = (Dv0.9 - Dv0.1) / Dv0.5. Here, Dv0.1 represents the particle size corresponding to 10% of the volume % in the particle size distribution curve of the microspheres, Dv0.5 represents the particle size corresponding to 50% of the volume % in the particle size distribution curve of the microspheres, and Dv0.9 represents the particle size corresponding to 90% of the volume % in the particle size distribution curve of the microspheres.

[0053] The sustained-release microglobulins of the present invention, containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial-release inhibitor, are administered via an injection route, for example, subcutaneous injection, and are particularly suitable for self-administration, so it is preferable that tilzepatide is released over a relatively long period of time. Preferably, the sustained-release microglobulins of the pharmaceutical composition according to the present invention are not limited to those described herein, but can release tilzepatide or a pharmaceutically acceptable salt thereof for 1 month or more, 2 months or more, 3 months or more, 1 to 2 months, 1 to 3 months, 1 to 4 months, 1 to 5 months, 1 to 6 months, 2 to 6 months, 2 to 5 months, 2 to 4 months, 2 to 3 months, 3 to 5 months, or 3 to 4 months. Furthermore, the sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor of the present invention are not particularly limited to such release modes, but it is preferable that when administered into the body, tilzepatide or a pharmaceutically acceptable salt thereof is released within 24 hours at a release rate (amount released) with an upper limit of less than 10%, less than 15%, or less than 20%, or at a release rate with a lower limit of 0.001% or more, 0.01% or more, 0.1% or more, or 1% or more, or at a release rate within the range of a combination of the above upper and lower limits.

[0054] Furthermore, the total amount (total weight) of the sustained-release microgranular preparation containing the tilzepatide or a pharmaceutically acceptable salt thereof and an initial-release inhibitor in the pharmaceutical composition of the present invention is 30 to 3000 mg, 30 to 2500 mg, 30 to 2000 mg, 30 to 1500 mg, 30 to 1250 mg, 30 to 1000 mg, 60 to 3000 mg, 60 to 2500 mg, 60 to 2000 mg The composition may be in the range of mg, 60 to 1500 mg, 60 to 1250 mg, 100 to 3000 mg, 100 to 2500 mg, 100 to 2000 mg, 100 to 1500 mg, 200 to 3000 mg, 200 to 2500 mg, 200 to 1500 mg, 400 to 3000 mg, 400 to 2500 mg, 400 to 2000 mg, or 400 to 1500 mg. The composition contains sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial-release inhibitor within the above ranges, and the composition according to the present invention has the advantage of not only minimizing the inflammatory response at the administration site but also enabling patient self-administration.

[0055] Microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor may further contain a release regulator. Examples of substances used as release regulators include, but are not limited to, one or more selected from butyric acid, varreic acid, caproic acid, enanthic acid, caprylic acid, ferargonic acid, capruic 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, hydroxynaphthic acid, napadisylic acid, naphthalenesulfonic acid, and pamoic acid. Preferably, the release regulator may be, but is not limited to, hydroxynaphthic acid, napadisylic acid, or pamoic acid.

[0056] The pharmaceutical composition comprising microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor according to the present invention can be formulated into various forms of formulations, for example, known parenteral formulations. Thus, the pharmaceutical composition according to the present invention may further contain, in addition to tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor, thickeners, stabilizers, isotonic agents, surfactants, excipients and / or carriers. Usable isotonic agents may be water-soluble excipients or sugars such as mannitol, sucrose, sorbitol, trehalose, lactose, and sodium chloride, and thickeners may include carmellose sodium, carboxymethylcellulose sodium, and povidone. Stabilizers that can be used include monohydrogen phosphate, anhydrous citric acid, sodium hydroxide, and sodium chloride.

[0057] The pharmaceutical composition according to the present invention can be administered in a therapeutically effective dose of tilzepatide, for example, an effective dose for treating diabetes, specifically type 2 diabetes, beta-cell dysfunction, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis or Alzheimer's disease, and degenerative neurological diseases such as Parkinson's disease. The therapeutically effective dose of tilzepatide can be evaluated by a physician. The pharmaceutical composition according to the present invention, containing tilzepatide, can also be administered once a month to once a quarter. Some specific examples include the monthly doses of the compositions according to the present invention, based on tilzepatide, being 5 mg 500 mg, 5 mg 400 mg, 5 mg 300 mg, 5 mg 150 mg, 5 mg 100 mg, 5 mg 50 mg, 5 mg 40 mg, 5 mg 30 mg, 10 mg 500 mg, 10 mg 400 mg, 10 mg 300 mg, 10 mg 150 mg, 10 mg 100 mg, 10 mg 50 mg, 10 mg 40 mg, and 10 mg 30 mg The dosage may be mg, 20 mg to 500 mg, 20 mg to 400 mg, 20 mg to 300 mg, 20 mg to 150 mg, 20 mg to 100 mg, 40 mg to 500 mg, 40 mg to 400 mg, 40 mg to 300 mg, 40 mg to 150 mg, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 150 mg, 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, or 100 mg to 150 mg. The pharmaceutical composition according to the present invention, comprising tilzepatide or a pharmaceutically acceptable salt thereof and microgranules containing an initial release inhibitor, can be administered parenterally, for example, by subcutaneous injection. The pharmaceutical composition according to the present invention may consist of a drug portion containing microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor, and a solvent portion used to suspend the microparticles, and may be in the form of a double-chamber syringe in which the drug portion is in one chamber and the solvent portion is in the other chamber, or a pre-field syringe in which the drug portion is suspended in the solvent portion. When the composition is in the form of a pre-field syringe in which the drug portion is suspended in the solvent portion, the solvent portion used may be an injectable oil containing heavy chain oil, mineral oil, etc.

[0058] As a specific embodiment, sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor, as contained in the pharmaceutical composition according to the present invention, have a high drug content compared to the microglobulin content, while suppressing the initial excessive release of the drug which can cause fatal side effects, exhibiting high bioavailability and sufficient efficacy as a GIP analog over the desired period, and are useful for the prevention or treatment of diabetes, specifically type 2 diabetes, beta-cell dysfunction, hypertension, hyperlipidemia, obesity, non-alcoholic steatohepatitis, Alzheimer's disease, or Parkinson's disease.

[0059] In another embodiment, the present invention provides a method for producing sustained-release granules containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial-release inhibitor.

[0060] In another embodiment, the present invention provides a method for producing sustained-release granulocytes in which initial release is significantly suppressed despite containing a high content of tilzepatide or a pharmaceutically acceptable salt thereof.

[0061] The following describes in detail a method for producing a sustained-release microglobulin injection containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial-release inhibitor of the present invention.

[0062] The sustained-release microglobulin injection preparation according to the present invention, containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor, can be manufactured, for example, by the "emulsion solvent extraction and evaporation method," but the manufacturing method is not limited thereto.

[0063] As one specific embodiment of the manufacturing method, the present invention provides a method for producing sustained-release microspheres in an O / W emulsion comprising the following steps: (a) A step of preparing an oil phase (O phase) as a dispersed phase, in which tilzepatide or a pharmaceutically acceptable salt thereof and one or more biodegradable polymers are dissolved in an organic solvent; (b) A step of preparing a continuous phase (W phase) by adding an initial release inhibitor to an aqueous solution containing a surfactant, and adding the dispersed phase from step (a) above to produce a dispersed phase in an emulsion state; (c) A step of extracting an organic solvent from the emulsion-state dispersed phase produced in step (b) into a continuous phase (W phase) and evaporating it to form microspheres; and, (d) The stage of collecting microspheres.

[0064] Another aspect of the present invention is the provision of a method for producing sustained-release microspheres in a W / O / W emulsion, comprising the following steps: (a') A step of preparing an aqueous phase (W1 phase) by dissolving tilzepatide or a pharmaceutically acceptable salt thereof in an aqueous solution, preparing an oil phase (O phase) by dissolving one or more biodegradable polymers in an organic solvent, and preparing a primary W1 / O emulsion as a dispersed phase by mixing the aqueous phase (W1 phase) and the oil phase (O phase); (b') A step of preparing a continuous phase (W2 phase) by adding an initial release inhibitor to an aqueous solution containing a surfactant, and adding the dispersed phase from step (a') to produce a dispersed phase in a secondary W1 / O / W2 emulsion state; (c') A step of extracting and / or evaporating an organic solvent from the dispersed phase in the secondary W1 / O / W2 emulsion state of step (b') into the continuous phase (W2 phase) to form microspheres; (d') The stage of collecting microgranules.

[0065] Another aspect is that the pH of the continuous phase used in the manufacturing method may be 7 or higher.

[0066] In the production of sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor according to the present invention, while containing a high amount of tilzepatide or a pharmaceutically acceptable salt thereof relative to the weight of the microglobulins, the excessive release of initial tilzepatide or a pharmaceutically acceptable salt thereof is suppressed, resulting in high bioavailability and 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, the following biodegradable polymers can be used, but are not limited thereto. Specifically, these include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide (PLGC). Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarateIt is preferable to use polymers selected from the group consisting of fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate lactide) (PBSLA), simple mixtures of two or more of the selected polymers, copolymers of the selected polymers with polyethylene glycol (Polyethylenglycol, PEG), and polymer-sugar complexes in which the selected polymers or copolymers are bonded to sugars, preferably two or more polymers. In a specific embodiment, in the production method according to the present invention, poly(lactide-co-glycolide) and / or polylactide polymers can be used as biodegradable polymers.

[0067] In the present invention, two or more different biodegradable polymers may include two or more polymers with different repeating units constituting the polymer, and two or more polymers with different molar ratios of repeating units. For example, the microspheres may be a mixture of microspheres containing polylactide-coglycolide and microspheres containing polylactide polymer, or microspheres containing both polylactide-coglycolide and polylactide polymer.

[0068] Furthermore, as a specific example, if there are two different biodegradable polymers, the content ratio of these biodegradable polymers may be, but is not limited to, 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 by weight.

[0069] Furthermore, unless otherwise defined, the content of the biodegradable polymer described in the present invention with respect to microspheres can be applied as is.

[0070] In a more specific embodiment, when using polylactide-co-glycolides as two or more biodegradable polymers to produce sustained-release microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor 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.

[0071] In the case of the polylactide-co-glycolide, the molar ratio of lactide to glycoside in the copolymer may be 40:60 to 90:10, 45:55 to 85:15, or 50:50 to 75:25, for example, 45:55, 50:50, 75:25, or 85:15.

[0072] Furthermore, unless otherwise defined, the content of the biodegradable polymer described in the present invention with respect to microspheres can be applied as is.

[0073] The organic solvent used to dissolve one or more biodegradable polymers in step (a) or (a') of the specific manufacturing method described above is one or more organic solvents. Alternatively, a mixed organic solvent, which is a mixture of two or more organic solvents, may be used. In one specific embodiment, the mixed solvent may be a mixture of an organic solvent that is miscible with water and an organic solvent that is not miscible with water. In this case, it is preferable to use the organic solvent that is not miscible with water in an amount of at least 50% (v / v), 60% (v / v) 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 water-immiscible property of the organic solvent, the dispersed phase can be homogeneously mixed in the continuous phase containing the surfactant in step (b) or (b') described later to form an emulsion. The type of organic solvent used to dissolve one or more such biodegradable polymers is not particularly limited, but preferably a mixed solvent of one or more solvents selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol can be used. More preferably, one solvent selected from dichloromethane and ethyl acetate and one or more organic solvents selected from dimethyl sulfoxide, enmethylpyrrolidone, methyl alcohol, and acetic acid can be used. In one example, a mixture of dichloromethane and acetic acid (glacial acetic acid) can be used as the organic solvent.

[0074] The method for homogeneously mixing the dispersed phase and the continuous phase containing the surfactant in step (b) or (b') is not particularly limited, but can be carried out using a high-speed stirrer, an in-line mixer, a membrane emulsion method, a microfluidic emulsion method, an ultrasonic mixer, or a static mixer, either alone or using two or more of them. When forming an emulsion using a high-speed stirrer, an in-line mixer, an ultrasonic mixer, or a static mixer, it is difficult to obtain a uniform emulsion, so it is preferable to perform an additional sieving step or the like between step (c) and step (d), or between step (c') and step (d'), as described later.

[0075] The type of surfactant used in step (b) or (b') is not particularly limited, and any surfactant that can help the dispersed phase form a stable droplet dispersion phase within the continuous phase can be used. The surfactant can be polyvinyl alcohol, methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, etc., either alone or in combination of two or more.

[0076] The surfactant content in the continuous phase containing the surfactant in step (b) or (b') above may be 0.01 w / v% to 20 w / v%, preferably 0.03 w / v% to 18 w / v%, 0.05 w / v% to 15 w / v%, 0.07 w / v% to 10 w / v%, or 0.1 w / v% to 5 w / v%, based on the total volume of the continuous phase containing the surfactant. If the surfactant content is less than 0.01 w / v%, droplet-shaped dispersed phase or emulsion may not be formed in the continuous phase, and if the surfactant content exceeds 20 w / v%, fine particles may be formed in the continuous phase due to the excess surfactant, and it may be difficult to remove the surfactant afterward.

[0077] The continuous phase used in step (b) or (b') above may be an aqueous solution containing a surfactant and an initial release inhibitor. Alternatively, the continuous phase may be added to an aqueous solution containing a surfactant to reach the final concentration of the initial release inhibitor.

[0078] By using the aforementioned initial release inhibitor, the initial release of microspheres containing high concentrations of the drug can be controlled, and a substance that can set the pH of the continuous phase to 7.0 or higher can be used as the initial release inhibitor.

[0079] The type of initial release inhibitor is not particularly limited, and any basic salt that can dissolve in the continuous phase and maintain a pH of 7.0 or higher can be used. The initial release inhibitor can be one or more substances selected from alkali metals, alkaline earth metals or ammonium phosphates, hydroxide salts, phosphide salts, phosphite salts, carbonate salts, bicarbonate salts, chromate salts, dichromate salts, oxides, oxalates, silicates, sulfates, sulfide salts, sulfites, tartrates, tetraborate salts, thiosulfates, arsenate salts, arsenite salts, citrates, pericyanide salts, and nitride salts.

[0080] In specific embodiments, the initial release inhibitor may be one or more selected from the group consisting of two or more alkali metal phosphates, one or more alkali metal carbonate salts, one or more alkali metal bicarbonate salts, and two or more ammonium phosphates, but is not limited thereto.

[0081] In a more specific embodiment, the two or more alkali metal phosphates are disodium phosphate (Na2HPO4) or dipotassium phosphate (K2HPO4), the one or more alkali metal carbonate salts are sodium bicarbonate (NaHCO3) or sodium carbonate (Na2CO3), and the two or more ammonium phosphates are diammonium phosphate ((NH4)2HPO4), and these can be used individually or in combination of two or more.

[0082] The final concentration of the initial release inhibitor in the continuous phase may be 0.1 to 5.0 (w / v)%, preferably 0.1 to 4.0 (w / v)%, more preferably 0.2 to 4.0 (w / v)%, even more preferably 0.3 to 3.5 (w / v)%, particularly preferably 0.4 to 3.0 (w / v)%, and particularly more preferably 0.5 to 2.5 (w / v)%.

[0083] If the initial release inhibitor content exceeds 5.0 w / v%, emulsion droplets may rupture during microbulb production. Conversely, if it is lower than 0.1 w / v%, the initial release of microbulbs containing high concentrations of tilzepatide may not be sufficiently suppressed.

[0084] When the initial release inhibitor is included in the continuous phase during microbulb production, the initial release in microbulbs containing 12(w / w) or more tilzepatide can be preferably reduced to 10% or less, more preferably to 8% or less, and most preferably to 5% or less.

[0085] The continuous phase used in step (b) or (b') may further include one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate in order to adjust the extraction rate of the organic solvent from the dispersed phase in emulsion state.

[0086] The initial release inhibitor may be added at the time when the continuous phase is prepared in step (b) or (b'), or it may be added at any point during the supply of the continuous phase in step (c) or (c'), and the method of addition is not limited.

[0087] Furthermore, the pH of the continuous phase may be, but is not limited to, 7.0 or higher, 7.2 or higher, 7.4 or higher, 8.0 or higher, 8.5 or higher, 9.0 or higher, 7.0 to 9.0, or 7.0 to 8.5. Adjusting the pH of the continuous phase to within the aforementioned range may further increase the bioavailability of microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof.

[0088] In step (c) or (c') above, if the emulsion comprising a droplet-form dispersed phase 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 can be extracted from the droplet-form tylzepatide or its pharmaceutically acceptable salt and polymer solution in the dispersed phase into the continuous phase. A portion of the organic solvent extracted in the continuous phase can be evaporated from the surface. While the organic solvent is extracted and evaporated from the droplet-form tylzepatide or its pharmaceutically acceptable salt and polymer solution, the droplet-form dispersed phase can solidify to form microspheres.

[0089] In step (c) or (c') above, the temperature of the continuous phase may be heated for a certain period of time in order to further efficiently remove the organic solvent. The heating temperature is not limited and can be adjusted as appropriate by a typical technician of the art depending on the organic solvent used. For example, when dichloromethane is used as the organic solvent, the heating may be 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 step (d) or (d') above, the method for recovering the microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor can be carried out using various known techniques, such as filtration or centrifugation.

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

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

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

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

[0095] Aside from the matters mentioned above, the same provisions as those defined in the aforementioned pharmaceutical composition apply to all other matters not separately defined, including tilzepatide, initial release inhibitors, biodegradable polymers, and their content.

[0096] The present invention provides a method for producing sustained-release microglobulin injections containing highly bioavailable tilzepatide or a pharmaceutically acceptable salt, which maintains an effective concentration over a desired period without a sudden, transient release. Furthermore, it is possible to produce sustained-release microglobulin injections containing tilzepatide or a pharmaceutically acceptable salt with uniform particles that offer good administration efficiency, along with an initial release inhibitor.

[0097] The sustained-release microglobulins according to the present invention can also be manufactured by microglobulin blending, which involves two or more drug microglobulins containing the same drug but differing in one or more aspects of composition and manufacturing conditions. In the case of microglobulin blending containing two or more drug microglobulins as described above, it can be done for purposes such as optimizing the drug release profile and adjusting between release devices.

[0098] Specifically, the aforementioned different compositions and manufacturing conditions may be one or more selected from the group consisting of the amount of drug used, the type of polymer, particle size distribution (e.g., average particle size), circularity, amount of polymer used, type and amount of dispersed phase solvent used, type and amount of co-solvent used, type and amount of continuous phase used, solidification temperature and time, theoretical drug content, etc., and are not limited thereto.

[0099] The aforementioned granulocyte blending may involve, for example, mixing one or more drug granulocytes with different compositions and manufacturing conditions in a specific proportion.

[0100] Specifically, when blending microglobulins, the mixing ratio (by weight or by the number of microglobulins) can be appropriately adjusted, taking into account the bioavailability of the active ingredients of each microglobulin.

[0101] As a specific example, the two different drug microspheres described above may be drug microspheres with different constituent components and compositional ratios (hereinafter referred to as drug microspheres having different compositions) and / or drug microspheres with different drug release characteristics. For example, they may differ in one or more elements selected from the group consisting of the type of polymer, polymer content, drug content, etc. The difference in the type of polymer of the microspheres may be due to one or more elements selected from the group consisting of the repeating units of the polymer, terminal groups of the polymer, molecular weight of the polymer, and intrinsic viscosity of the polymer.

[0102] The aforementioned microsphere blending can be achieved by manufacturing and mixing each microsphere separately, or by manufacturing them in a single process. Specifically, an O / W emulsion method for manufacturing microsphere blending in a single process can include, as an example, the following steps 1 to 4.

[0103] Step 1: A step in which two or more dispersed phase solutions are prepared separately by dissolving biodegradable polymers and drugs having different compositions in organic solvents. Step 2 involves injecting two or more dispersed phases prepared in Step 1 into aqueous solutions (continuous phases) containing surfactants to form emulsions of two or more dispersed phases; Step 3 involves extracting and evaporating an organic solvent from the dispersed phase emulsion produced in Step 2 to form microspheres on the continuous phase side; and, This may include a step (step 4) in which microglobules are collected after step 3 as described above.

[0104] Specifically, a W / O / W emulsion method that produces microsphere blending in a single manufacturing process can be manufactured by including the following steps 1 to 4 as an example.

[0105] Step 1 involves preparing an aqueous phase (W1 phase) by dissolving a drug in an aqueous solution, preparing two or more oil phases (O phase) by dissolving biodegradable polymers having different compositions in organic solvents, and separately preparing a dispersed phase solution by mixing the aqueous phase (W1 phase) and the two or more oil phases (O phase); Step 2 involves injecting two or more dispersed phases prepared in Step 1 into aqueous solutions containing surfactants (W2 phase, continuous phase) to form emulsions of two or more dispersed phases; Step 3 involves extracting and evaporating an organic solvent from the dispersed phase emulsion produced in Step 2 to form microspheres in the continuous phase (W2 phase); and, This may include a step (step 4) in which microglobules are collected after step 3 as described above. [Examples]

[0106] The present invention will be described in more detail below with reference to the following manufacturing examples. However, the following manufacturing examples are illustrative of the present invention and do not limit the content of the present invention to the following manufacturing examples.

[0107] Examples 1-1 to 1-3 (O / W method): Production of biodegradable polymer microspheres containing tilzepatide and an initial release inhibitor. Chilzepatide (manufacturer: Zhejiang Peptides Biotech Co., Ltd., China) was used as the drug, and RG653H and RG753H (manufacturer: Evonik, Germany) were used as the biodegradable polymers in a 1:1 weight ratio, weighed to have a placement size of 0.5 to 1.5 g (0.5 g for Examples 1-1 and 1-2, and 1.5 g for Example 1-3). An oil phase (O phase) was prepared as the dispersed phase by homogeneously dissolving the drug and polymer in a mixed solvent of dichloromethane (DCM) and glacial acetic acid as a cosolvent.

[0108] In the continuous phase (W phase), a 0.1(w / v)% aqueous solution of polyvinyl alcohol (viscosity: 4.8~5.8 mPa.s) was used, to which Na2HPO4 (Disodium phosphate) was added as an initial release inhibitor to achieve a final concentration of 2.0(w / v)%.

[0109] The continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm, and the prepared dispersed phase was injected into the porous membrane together with the continuous phase. An emulsion containing biodegradable polymer microdroplets containing tilzepatide was produced, and the suspension was placed in a compounding container and stirred at a speed of 200 to 300 rpm.

[0110] The temperature of the compounding container was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After that, the temperature was cooled to 25°C, filtered, and the remaining polyvinyl alcohol was removed with tertiary distilled water, followed by freeze-drying.

[0111] [Table 1]

[0112] *T / L: Target Loading

[0113] Examples 2-1 to 2-9 (O / W method): Production of biodegradable polymer microspheres containing tilzepatide and an initial release inhibitor (differences in the type or concentration of the initial release inhibitor) The drug used was tilzepatide (manufacturer: Chengdu Shengnuo Biopharm Co., Ltd., China), and the biodegradable polymers RG653H and RG753H (manufacturer: Evonik, Germany) were used in a 1:1 weight ratio, weighed to achieve a placement size of 0.5g. Target Loading 20% The aforementioned drugs and polymers were homogeneously dissolved in a mixed solvent of dichloromethane (DCM) and glacial acetic acid (acetic acid) to prepare an oil phase (O phase) as the dispersed phase.

[0114] In the continuous phase (W phase), an initial release inhibitor was added to a 0.1 (w / v)% polyvinyl alcohol (viscosity: 4.8-5.8 mPa.s) aqueous solution to achieve the final concentration.

[0115] The continuous phase was connected to an emulsifier equipped with a 40 μm diameter porous membrane, and the prepared dispersed phase was injected into the porous membrane together with the continuous phase. An emulsion containing biodegradable polymer microdroplets containing tilzepatide was produced, and the suspension was placed in a compounding container and stirred at a speed of 200 to 300 rpm.

[0116] The temperature of the compounding container was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After that, the temperature was cooled to 25°C, filtered, and the remaining polyvinyl alcohol was removed with tertiary distilled water, followed by freeze-drying.

[0117] [Table 2]

[0118] Examples 3-1 to 3-2 (O / W method): Production of biodegradable polymer microspheres containing tilzepatide and an initial release inhibitor (differences in polymer type)

[0119] The drug used was tilzepatide (manufacturer: Chengdu Shengnuo Biopharm Co., Ltd., China), and the biodegradable polymer used was RG503H or RG203H (manufacturer: Evonik, Germany), weighed to a placement size of 0.5g. Target Loading 20%A dispersed phase (O phase) was prepared by homogeneously dissolving the aforementioned drug and polymer in a mixed solvent of dichloromethane (DCM) and glacial acetic acid as a cosolvent.

[0120] In the continuous phase (W phase), a 0.1(w / v)% aqueous solution of polyvinyl alcohol (viscosity: 4.8~5.8 mPa.s) was used, to which Na2HPO4 (Disodium phosphate) was added as an initial release inhibitor to achieve a final concentration of 2.0(w / v)%.

[0121] The continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm, and the prepared dispersed phase was injected into the porous membrane together with the continuous phase. An emulsion containing biodegradable polymer microdroplets containing tilzepatide was produced, and the suspension was placed in a compounding container and stirred at a speed of 200 to 300 rpm.

[0122] The temperature of the compounding container was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After that, the temperature was cooled to 25°C, filtered, and the remaining polyvinyl alcohol was removed with tertiary distilled water, followed by freeze-drying.

[0123] [Table 3]

[0124] Examples 4-2 to 4-3 (W / O / W method): Production of biodegradable polymer microspheres containing tilzepatide and an initial release inhibitor (differences in drug loading content or polymer type) The primary aqueous phase (W1 phase) was prepared by dissolving tilzepatide (Chengdu Shengnuo Biopharm Co., Ltd., China) as a drug in tertiary distilled water. The oil phase (O phase) was prepared by dissolving RG653H and RG753H (manufacturer: Evonik, Germany) in a 1:1 weight ratio, or RG503H (manufacturer: Evonik, Germany) alone, in dichloromethane (DCM) as biodegradable polymers. The primary W1 / O emulsion (dispersed phase) was prepared by dispersing the aqueous phase in the oil phase using a homogenizer.

[0125] In the continuous phase (W2 phase), a 0.1(w / v)% aqueous solution of polyvinyl alcohol (viscosity: 4.8~5.8 mPa.s) was used, to which Na2HPO4 (Disodium phosphate) was added as an initial release inhibitor to achieve a final concentration of 2.0(w / v)%.

[0126] After connecting the continuous phase to an emulsifier equipped with a porous membrane with a diameter of 40 μm, the prepared dispersed phase was injected into the porous membrane together with the continuous phase. A secondary W1 / O / W2 emulsion containing biodegradable polymer microdroplets containing tilzepatide was prepared, and the suspension was placed in a compounding container and stirred at a speed of 200 to 300 rpm.

[0127] The temperature of the compounding container was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After that, the temperature was cooled to 25°C, filtered, and the remaining polyvinyl alcohol was removed with tertiary distilled water, followed by freeze-drying.

[0128] [Table 4]

[0129] Comparative Example 1 (O / W method): Production of biodegradable polymer microspheres containing tilzepatide without an initial release inhibitor. 0.045g of tilzepatide (manufacturer: Zhejiang Peptides Biotech Co., Ltd., China) was used as the drug, and 0.255g of biodegradable polymers RG653H and RG753H (manufacturer: Evonik, Germany) were used in a 1:1 weight ratio, weighed to achieve a placement size of 0.3g. Target Loading 15% Dichloromethane (DCM) was used as the solvent for preparing the dispersed phase, and glacial acetic acid was used as a co-solvent to homogeneously dissolve the substance.

[0130] The continuous phase was a 2,000 ml aqueous solution of 0.1% polyvinyl alcohol (viscosity: 4.8-5.8 mPa.s).

[0131] The continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm, and the prepared dispersed phase was injected into the porous membrane together with the continuous phase. An emulsion containing biodegradable polymer microdroplets containing tilzepatide was produced, and the suspension was placed in a compounding container and stirred at a speed of 200 to 300 rpm.

[0132] The temperature of the compounding container was maintained at 25°C, and after the dispersed phase injection was complete, the organic solvent was removed while maintaining the suspension temperature at 40°C for 3 hours. After that, the temperature was cooled to 25°C, filtered, and the remaining polyvinyl alcohol was removed with tertiary distilled water, followed by freeze-drying.

[0133] [Table 5]

[0134] Experimental Example 1. Measurement of the amount of tilzepatide inclusions within microglobules. To measure the amount of tilzepatide encapsulated in the microparticles produced from the aforementioned examples and comparative examples, 10 mg of microparticles were completely dissolved in DMSO. 20 μL of the diluted solution was injected into an HPLC and measured at a detection wavelength of 280 nm. The column used in this experiment was a ZORBAX 300SB-C18, 5 μm, 4.6 x 150 mm column, and the mobile phase was a mixture of acetonitrile containing 0.1% (w / w) trifluoroacetic acid and an aqueous solution of 0.1% (w / w) trifluoroacetic acid in a ratio of 40:60 (v / v).

[0135] [Table 6]

[0136] As shown in Table 6, The results of Examples 1-1 to 1-3, manufactured using the O / W method, show a tendency for the encapsulation rate to remain above 70% up to T / L 20%. The results of Examples 2-1 to 2-9, which were manufactured using the O / W method and varied in the type or concentration of the initial release inhibitor, show a tendency for the encapsulation rate to remain between 50% and 70%. The results of Examples 3-1 to 3-2, which were manufactured using the O / W method and varied in polymer type, show a tendency for the encapsulation rate to remain between 50% and 70%. The results of Examples 4-2 to 4-3, in which the drug loading content or type of polymer was varied using the W / O / W method, show a tendency for the encapsulation rate to remain above 70% up to T / L 30%.

[0137] Experimental Example 2. Measurement of initial drug release of tilzepatide microglobulins in vitro. The following experiment was conducted to confirm the initial drug release of microglobulins produced from the aforementioned examples and comparative examples. 10 mg of microglobulins were placed in an HDPE wide-mouthed bottle, filled with 50 mL of release test solution, and stored in a 37°C incubator. After 24 hours, 1 mL of this test solution was taken, and the supernatant obtained by centrifugation was analyzed for tilzepatide content and release rate using HPLC under the same analytical conditions as in Experimental Example 1. The release test solution used for this measurement was a pH 7.4 PBS solution containing sodium dodecyl sulfate and sodium azide.

[0138] [Table 7]

[0139] As shown in Table 7, it was confirmed that including an initial release inhibitor in the continuous phase during microgranule production significantly reduced the initial release of the drug in microgranules containing tilzepatide. On the other hand, in Comparative Example 1, which did not include an initial release inhibitor, the release rate on day 1 was 44.59%, confirming that an initial burst occurred.

[0140] Experimental Example 3. Morphological Analysis using an Electron Microscope The morphological characteristics of the microparticles according to the present invention were analyzed using an electron microscope. The experimental procedure was as follows: 5 mg of microparticles produced from the examples and manufacturing examples were placed on an aluminum stub with carbon tape and platinum-coated using an ION-COATER (COXEM, South Korea). The aluminum stub was mounted on a scanning electron microscope (COXEM EM-30, South Korea), and the morphological characteristics of the microparticles were observed at an acceleration voltage of 10 kV. The results are shown in Figures 1a (Example 1-1) and 1b (Comparative Example 1).

[0141] Figure 1a is a scanning electron microscope image showing the morphological characteristics of the microspheres produced from Example 1-1.

[0142] Figure 1b is a scanning electron microscope image showing the morphological characteristics of microspheres produced from Comparative Example 1.

[0143] Experimental Example 4. In-vivo pharmacokinetic evaluation using rats. To evaluate the drug release mechanism of microglobulins in the body according to the embodiments of the present invention, the concentration of tilzepatide in the blood of rats was measured after administration of the drug.

[0144] Microparticles were measured to achieve a concentration of 3.6 mg / head (12.0 mg / kg) of tilzepatide, dispersed in 0.5 mL of suspension, and then subcutaneously injected into SD rats (Sprague-Dawley rats, 300 g). 0.5 mL of blood was collected at predetermined time intervals, and the serum tilzepatide concentration was measured using HPLC.

[0145] [Table 8]

[0146] As shown in Table 8, it was confirmed that the bioavailability of the tilzepatide microgravates produced from the examples was at a good level.

[0147] Experimental Example 5. Pharmacokinetic study of single subcutaneous administration using Sprague-Dawley rats. To evaluate the potential of the present invention as a sustained-release granulocyte therapeutic agent, rat blood tilzepatide concentrations were measured by the following method.

[0148] Specifically, the tilzepatide dose was calculated by measuring microglobulins to achieve a dose of 3.6 mg / head, dispersing it in 0.5 mL of suspension, and then subcutaneously injecting it into SD rats. 0.25–0.5 mL of blood was collected at predetermined time intervals, and the tilzepatide concentration in the blood was measured using HPLC.

[0149] [Table 9]

[0150] As shown in Table 9, the microglobulins produced from the examples showed no initial burst until day 1 and exhibited an excellent sustained release profile, releasing continuously until day 49. On the other hand, the microglobulins from Comparative Example 1, which did not contain an initial release inhibitor, showed an initial burst until day 1, releasing most of the drug, and only releasing a small concentration from day 10 onwards.

[0151] Experimental Example 6. Measurement of the residual content of the initial release inhibitor in microparticles. To measure the initial release inhibitor content in the microbulbs produced from the above-described examples, the residual amounts of sodium (Na) and phosphorus (P) in the microbulbs were measured.

[0152] Specifically, 300 mg of microspheres were mixed with 6 mL of nitric acid aqueous solution (a 1:1 mixture with ultrapure water) and 3 mL of hydrogen peroxide. The mixture was then heated to over 100°C, and acid was added until the gas generated during the dissolution process changed from yellow to white. The resulting sample was weighed, dissolved in ultrapure water, and then injected into an inductively coupled plasma emission spectrometer (ICP-OES) (Thermo Scientific Co., iCAP 6300 Duo, UK) and measured at a detection wavelength of 598.5 nm.

[0153] [Table 10]

[0154] As shown in Table 10, the residual sodium and phosphorus content due to the initial release inhibitor contained in the continuous phase differed depending on the granule manufacturing conditions. Based on these calculations, the residual initial release inhibitor content in the granules was found to be between 50 ppm and 500 ppm based on sodium (Na) and between 10 and 100 ppm based on phosphorus (P).

Claims

1. It comprises sustained-release microspheres consisting of tilzepatide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and a biodegradable polymer. The aforementioned tilzepatide or a pharmaceutically acceptable salt thereof is included in an amount of 8% by weight or more of tilzepatide relative to the total weight of the microglobules. The aforementioned initial release inhibitor is contained in a concentration of 5 ppm to 2000 ppm in a pharmaceutical composition for the prevention or treatment of diabetes mellitus, type 2 diabetes mellitus, beta-cell dysfunction, obesity, or non-alcoholic steatohepatitis.

2. The pharmaceutical composition according to claim 1, wherein the sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor release less than 20% of tilzepatide or a pharmaceutically acceptable salt thereof within 24 hours when administered in vivo.

3. The pharmaceutical composition according to claim 1, wherein the sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor release less than 15% of tilzepatide or a pharmaceutically acceptable salt thereof within 24 hours when administered in vivo.

4. The pharmaceutical composition according to claim 1, wherein the sustained-release microglobulins containing tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor release less than 10% of tilzepatide or a pharmaceutically acceptable salt thereof within 24 hours when administered in vivo.

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

6. The pharmaceutical composition according to claim 1, wherein the initial release inhibitor is one or more substances selected from alkali metals, alkaline earth metals or ammonium phosphates, hydroxide salts, phosphide salts, phosphite salts, carbonate salts, chromate salts, dichromate salts, oxides, oxalates, silicates, sulfates, sulfide salts, sulfites, tartrates, tetraborate salts, thiosulfates, arsenate salts, arsenite salts, citrates, pericyanide salts, and nitride salts.

7. The pharmaceutical composition according to claim 1, wherein the average particle size of the microparticles containing the tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor is 5 μm to 100 μm.

8. The pharmaceutical composition according to claim 1, wherein the total weight of microparticles containing whole tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor is 20 to 3000 mg.

9. The pharmaceutical composition according to claim 1, wherein the biodegradable polymer has an intrinsic viscosity of 0.16 dL / g to 1.7 dL / g.

10. The pharmaceutical composition according to claim 1, wherein the microparticles further comprise one or more release regulators selected from the group consisting of butyric acid, varreic acid, caproic acid, enanthic acid, caprylic acid, ferargonic acid, capruic 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, hydroxynaphthic acid, napadisylic acid, naphthalenesulfonic acid, and pamoic acid.

11. (a) A step of preparing an oil phase (O phase) as a dispersed phase, in which tilzepatide or a pharmaceutically acceptable salt thereof and one or more biodegradable polymers are dissolved in an organic solvent; (b) A step of preparing a continuous phase (W phase) by adding an initial release inhibitor to an aqueous solution containing a surfactant, and adding the dispersed phase from step (a) above to produce a dispersed phase in an emulsion state; (c) A step of extracting and evaporating an organic solvent from the emulsion-like dispersed phase produced in step (b) into a continuous phase (W phase) to form fine particles; and, (d) A step of recovering the microbulbs; a method for producing microbulbs with an O / W emulsion comprising tilzepatide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and a biodegradable polymer.

12. (a') A step of preparing a primary aqueous phase (W1 phase) by dissolving tilzepatide or a pharmaceutically acceptable salt thereof in an aqueous solution, preparing an oil phase (O phase) by dissolving one or more biodegradable polymers in an organic solvent, and preparing a primary W1 / O emulsion as a dispersed phase by mixing the aqueous phase (W1 phase) and the oil phase (O phase); (b') A step of preparing a continuous phase (W2 phase) by adding an initial release inhibitor to an aqueous solution containing a surfactant, and adding the dispersed phase from step (a') above to produce a dispersed phase in a secondary W1 / O / W2 emulsion state; (c') A step of extracting and / or evaporating an organic solvent from the dispersed phase in the secondary W1 / O / W2 emulsion state of step (b') into the continuous phase (W2 phase) to form fine particles; and, (d') A method for producing microparticles with a W / O / W emulsion comprising tilzepatide or a pharmaceutically acceptable salt thereof, an initial release inhibitor, and a biodegradable polymer, comprising the step of recovering the microparticles.

13. The biodegradable polymers include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone (Polydioxanone), polycaprolactone (PCL), polylactide-co-glycolide-cocaprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (Polyhydroxybutyric acid) cid, PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate (Polypropylene Polymers selected from the group consisting of fumarate, pseudopolyamino acids, polyalkylcyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate tractide) (PBSLA); copolymers or simple mixtures of two or more of the selected polymers; copolymers of the selected polymers with polyethylene glycol (PEG);The manufacturing method according to any one of claims 11 to 12, wherein the selected polymer or copolymer is bonded to a sugar and one or more selected from the group consisting of the polymer-sugar complex.

14. The method for producing a product according to any one of claims 11 to 12, wherein the dispersed phase of step (a) or (a') further comprises one or more release regulators selected from the group consisting of butyric acid, varreic acid, caproic acid, enanthic acid, caprylic acid, ferargonic acid, capruic 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, hydroxynaphthic acid, napadisylic acid, and pamoic acid.

15. The production method according to any one of claims 11 to 12, wherein the organic solvent in step (a) or (a') is one or more organic solvents selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methyl ethyl ketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, enmethylpyrrolidone, acetic acid, methyl alcohol, ethyl alcohol, propyl alcohol, and benzyl alcohol.

16. The manufacturing method according to any one of claims 11 to 12, wherein the surfactant in step (b) or (b') is polyvinyl alcohol.

17. The manufacturing method according to any one of claims 11 to 12, wherein the continuous phase of step (b) or (b') further comprises one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, and ethyl acetate.

18. The manufacturing method according to any one of claims 11 to 12, wherein the continuous phase of step (b) is obtained by adding an initial release inhibitor to an aqueous solution containing a surfactant so that the final concentration is 0.1 to 5.0 (w / v)%.

19. The manufacturing method according to any one of claims 11 to 12, wherein the initial release inhibitor is one or more selected from the group consisting of two or more alkali metal phosphates, one or more alkali metal carbonate salts, and two or more ammonium phosphates.

20. The manufacturing method according to any one of claims 11 to 12, wherein the pH of the continuous phase in step (b) or (b') is 7 or higher.

21. The method for producing sustained-release microglobulins containing manufactured tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor, wherein the release rate of tilzepatide or a pharmaceutically acceptable salt thereof within 24 hours of in vivo administration of the sustained-release microglobulins is less than 15%.

22. The method for producing sustained-release microglobulins containing manufactured tilzepatide or a pharmaceutically acceptable salt thereof and an initial release inhibitor, wherein the release rate of tilzepatide or a pharmaceutically acceptable salt thereof within 24 hours of in vivo administration of the sustained-release microglobulins is less than 10%.

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