Microgranules containing tilzepatide, a method for producing the same, and a pharmaceutical composition containing the same.

Abstract

The present invention relates to microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof, and a biocompatible polymer, a method for producing the same, and a pharmaceutical composition containing the same. The microgranulocytes containing tilzepatide according to the present invention exhibit stable drug release over a long period, maintaining effective drug concentrations in the blood over a long period. This extends the drug administration cycle, improves patient adaptation to medication, and reduces side effects caused by rapid initial drug release.

Description

Technical Field

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2023-0065250 filed on May 19, 2023, and all the contents disclosed in the literature of the Korean patent application are included as part of this specification.

[0002] The present invention relates to microparticles containing tirzepatide, a method for producing the same, and a pharmaceutical composition containing the same.

Background Art

[0003] T2D is the most common form of diabetes, accounting for about 90% of all diabetes. T2D is characterized by high blood glucose levels caused by insulin resistance. Current standard treatments for T2D include dietary therapy and exercise therapy, along with available oral and injectable hypoglycemic drugs. Nevertheless, many T2D patients remain inadequately controlled. Currently marketed incretin mimetics or dipeptidyl peptidase-IV (DPP-IV) inhibitors use only a single established mechanism of action for blood glucose control. Therefore, compounds for T2D using a dual mechanism of action are required.

[0004] GIP is a 42-amino acid gastrointestinal regulatory peptide that plays a physiologically important role in glucose homeostasis by stimulating insulin secretion from pancreatic β-cells and protecting pancreatic β-cells in the presence of glucose. GLP-1 is a 37-amino acid peptide that stimulates insulin secretion, protects pancreatic β-cells, induces weight loss, and suppresses glucagon secretion, gastric emptying, and food intake. GIP and GLP-1 are known as incretins, and incretin receptor signaling has important physiological related actions in glucose homeostasis. In a normal physiological state, GIP and GLP-1 are secreted from the gastrointestinal tract after a meal, and these incretins promote physiological responses to food, including satiety, insulin secretion, and nutrient processing. T2D patients exhibit an impaired incretin response.

[0005] The administration of GLP-1 analogs has been shown to be limited by adverse effects, such as nausea and vomiting, and as a result, it cannot achieve full efficacy in blood glucose control and weight loss. GIP alone has only a slight blood glucose-lowering effect in patients with type 2 diabetes. Both natural GIP and GLP-1 are rapidly inactivated by the ubiquitous protease DPP IV and can therefore only be used for short-term metabolic control.

[0006] Certain GIP analogs exhibiting activity of both GIP and GLP-1 are disclosed in International Publications WO2013 / 164483, WO2014 / 192284, and WO2011 / 119657. Mounjaro and Zepbound (tirzepatide) are commercially available as such GIP analogs.

[0007] Chilzepatide is often administered in injectable form due to multiple barriers, including enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption from the intestinal mucosa, and first-pass metabolism in the liver.

[0008] Injectable preparations containing tilzepatide are formulated for self-administration by patients for the ongoing management of obesity and diabetes, and it is extremely important to manage any pain, inflammatory reactions, etc. that may occur at the injection site.

[0009] Therefore, in order to facilitate the management of pain, inflammatory responses, etc., as described above, and to improve the convenience of medication administration, there is a need for the development of a formulation that maintains long-term effects with a single injection. Currently available liquid injection formulations of tilzepatide (administered once a week) are easy to manufacture and administer, but increasing the dose may cause serious side effects. Therefore, there are limitations to their use for the purpose of maintaining effective effects over a long period of time.

[0010] In recent years, various formulation technologies have been used to compensate for these shortcomings by providing sustained and controlled release of pharmacologically active substances. Among these, injectable formulations containing long-acting microspheres are injectable formulations in which the pharmacologically active substance is encapsulated within a biocompatible polymer and delivered in the form of microspheres, designed to allow for uniform release of the drug from the microspheres during subcutaneous or intramuscular injection.

[0011] For long-acting, sustained-release formulations using microbulbs to effectively improve the convenience of drug administration and reduce the required dosage, it is necessary to develop technologies that allow for the inclusion of high doses of the drug within the microbulbs. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] International Publication No. WO2013 / 164483 [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] As a result of extensive research to solve the aforementioned problems of the prior art, the inventors have developed microglobules that contain a high concentration of tilzepatide, do not experience initial burst release, and release it continuously over a long period of time.

[0014] Accordingly, the present invention aims to provide tilzepatide microparticles, a method for producing the same, and a pharmaceutical composition containing the same, which can exhibit stable drug release over a long period, maintain effective drug concentrations in the blood for an extended period, thereby extending the drug administration cycle, improving patient adaptation to medication, and reducing side effects caused by rapid initial drug release. [Means for solving the problem]

[0015] To solve the aforementioned problems, the present invention provides

[0016] Microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof, and a biocompatible polymer,

[0017] The aforementioned tilzepatide or a pharmaceutically acceptable salt thereof is present in an amount of 9% by weight or more relative to the total weight of the microglobules.

[0018] The biocompatible polymer is polylactic acid-coglycolic acid (PLGA) with an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g, and the microspheres provided have a lactic acid to glycolic acid molar ratio of 50:45 to 55.

[0019] Furthermore, the present invention is (a) A step of dispersing tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer in one or more solvents to prepare a dispersed phase. (b) The steps of adding the manufactured dispersed phase to a continuous phase and stirring to form fine particles, (c) A method for producing microspheres is provided, which includes the step of removing the solvent.

[0020] Furthermore, the present invention is (1) A step of preparing an internal aqueous phase (W1) by dissolving or dispersing tilzepatide or a pharmaceutically acceptable salt thereof in a solvent, (2) A step of dissolving a biocompatible polymer in one or more solvents to produce an oil phase (O), (3) A step of dispersing an internal aqueous phase (W1) in the oil phase (O) to produce a water in oil (W1 / O) type emulsion. (4) The steps of dispersing the water in oil (W1 / O) type emulsion in an external continuous phase (W2) to produce a water in oil (W1 / O / W2) type emulsion and forming fine particles, and (5) A method for producing microspheres is provided, which includes the step of removing the solvent.

[0021] The present invention also provides a pharmaceutical composition for preventing or treating diabetes, obesity, hypertension, hyperlipidemia, non-alcoholic steatohepatitis, metabolic-associated steatohepatitis, cardiovascular diseases or neurodegenerative diseases, which comprises the microspheres of the present invention and a pharmaceutically acceptable carrier.

Advantages of the Invention

[0022] The tilsertide microspheres of the present invention show stable drug release over a long period, and thus can maintain the effective blood concentration of the drug for a long time. Therefore, it has the effects of extending the drug administration period, improving the compliance of patients with taking medicine, and reducing the side effects caused by the rapid initial drug release.

[0023] In addition, the method for manufacturing the tilsertide microspheres of the present invention enables efficient production of microspheres having excellent loading amount and encapsulation rate. Further, the pharmaceutical composition of the present invention exhibits excellent effects in the treatment of diabetes, obesity and the like by including the tilsertide microspheres.

Brief Description of the Drawings

[0024] [Figure 1] It is a graph showing the drug cumulative release rate with respect to the elapsed time after the in vivo administration of the microspheres produced in Example 5 of the present invention.

Modes for Carrying Out the Invention

[0025] Hereinafter, the present invention will be described in more detail.

[0026] All technical terms used in the present invention, unless otherwise defined, are used in the same meaning as commonly understood by those of ordinary skill in the relevant field of the present invention. Also, in the present invention, those similar or equivalent to those described as preferred methods or samples are also included in the scope of the present invention. The content of all publications described as references in this specification is incorporated herein by reference in its entirety.

[0027] In the present invention, tilzepatide or its pharmaceutically acceptable salts may be collectively referred to as tilzepatide.

[0028] This invention relates to microglobules containing tilzepatide or a pharmaceutically acceptable salt thereof, and biocompatible polymers.

[0029] Currently, tilzepatide is marketed as a liquid injection formulation (administered once a week). While liquid injection formulations are easy to manufacture and administer, increasing the dose may cause serious side effects. Therefore, there are limitations to its use for maintaining effective effects over a long period.

[0030] The present invention provides tilzepatide microgravules to solve the problems of the prior art described above. The tilzepatide microgravules of the present invention exhibit stable drug release over a long period of time, thereby maintaining the effective concentration of the drug in the blood over a long period of time. Therefore, it is possible to extend the drug administration cycle, improve patient adaptation to the drug, and reduce side effects caused by rapid initial drug release.

[0031] Furthermore, the present invention contains a high dose of tilzepatide within microglobules, exhibiting an excellent dose reduction effect, thereby improving the convenience of medication administration for patients.

[0032] The aforementioned tirzepatide is a GLP-1 / GIP receptor agonist, and is characterized by the following properties: Ltyrosyl-2-methylalanyl-L-α-glutamylglycyl-L-threonyl-Lphenylalanyl-L-threonyl-L-seryl-L-α-aspartylLtyrosyl-Lseryl-L-isoleucyl-2-methylalanyl-L-leucyl-L-α-aspartyl-Llysyl-L-isoleucyl-L-alanyl-Lglutaminyl-N 6-[(22S)-22,42-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazadotetracontan-1-oyl]-L-lysyl-L-alanyl-L-phenylalanyl-Lvalyl-L-gluta minyl-L-tryptophyl-L-leucylL-isoleucyl-Lalanylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-Lprolyl-L-prolyl-L-prolyl-Lserinamide(CAS# 2023788-19-2).

[0033] The aforementioned tilzepatide can be used for the prevention or treatment of diabetes (specifically type 2 diabetes), obesity, preservation of β-cell function, hypertension, hyperlipidemia, non-alcoholic steatohepatitis, metabolic disorder-related steatohepatitis, cardiovascular disease, or neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0034] As pharmaceutically acceptable salts of tilzepatide, any salt commonly used in this field may be used without limitation. In this invention, the term "pharmaceutically acceptable salt" means any organic or inorganic addition salt of tilzepatide that is relatively nontoxic to patients, has harmless and effective efficacy, and whose side effects do not reduce the beneficial efficacy of the active ingredient. Specific examples of pharmaceutically acceptable salts include, but are not limited to, sodium salts, ammonium, magnesium, calcium, potassium, acetic acid, benzoic acid, hydroxynaphthoic acid, napadisylate, pamoate, fumaric acid, oxalic acid, citric acid, tartaric acid, hydrochloric acid, phosphoric acid, maleic acid, mesylic acid, edicylic acid, succinic acid, aspartic acid, pamoic acid, sulfuric acid, besylic acid, and tosylates. The aforementioned tilzepatide salt can be produced by conventional techniques, such as adding an acid to liberated tilzepatide to convert it into an acid addition salt, or converting one acid addition salt into another salt.

[0035] In the present invention, microspheres refer to microspheres manufactured using a biocompatible polymer in which tilzepatide or a pharmaceutically acceptable salt thereof is encapsulated, and these are simply referred to as tilzepatide-containing microspheres, tilzepatide microspheres, or microspheres, etc. Any microsphere manufactured using a biocompatible polymer in which tilzepatide or a pharmaceutically acceptable salt thereof is encapsulated may be included within the scope of the present invention depending on the molar ratio and intrinsic viscosity of the biocompatible polymer used.

[0036] The tilzepatide or a pharmaceutically acceptable salt thereof may be present in an amount of 9% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, or 45% or more by weight relative to the total weight of the microglobules. If the amount of drug contained in the microglobules is less than 9% by weight, release after 30 days or more may be difficult. In addition, the tilzepatide or a pharmaceutically acceptable salt thereof may be present in an amount of 60% or less, 50% or less, 40% or less, 35% or less, 30% or less, 25% or less, or 20% or less by weight relative to the total weight of the microglobules.

[0037] The tilzepatide or a pharmaceutically acceptable salt thereof may be included within the range determined by the combination of the lower and upper limits.

[0038] In the present invention, the term "biocompatible polymer" refers to a polymer whose safety is ensured, such as that which does not induce cytotoxicity or inflammatory reactions in living organisms. In this specification, it may also be simply referred to as a polymer.

[0039] In the present invention, the biocompatible polymer may have an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g, preferably 0.15 dL / g to 1.5 dL / g, and more preferably 0.15 dL / g to 1.3 dL / g.

[0040] If the intrinsic viscosity of the biocompatible polymer is less than 0.15 dL / g, the degradation of the polymer may be too rapid, making it difficult to sustainably release tilzepatide for the desired time. If it exceeds 1.7 dL / g, the degradation of the polymer may be too slow, resulting in a small amount of tilzepatide being released and potentially preventing the drug's effect from being observed.

[0041] In the present invention, the biocompatible polymer may be present in an amount of 91% by weight or less relative to the total weight of the microspheres. If the biocompatible polymer is present in an amount exceeding 91% by weight, the relative proportion of the biocompatible polymer will be high, which may result in a reduced release of tilzepatide, causing the pharmacological effect to be absent or very delayed. The biocompatible polymer may be present in an amount that excludes the content range of tilzepatide or its pharmaceutically acceptable salt relative to the total weight of the microspheres. If other components that can be added to the microspheres of the present invention (e.g., PVA) are further included, these other components may be present in an additional amount of 0.01 to 3% by weight, in which case the content of the biocompatible polymer may be reduced by the amount of the other components.

[0042] As the biocompatible polymer, polylactic acid-coglycolic acid (PLGA) is preferably used, and more preferably, the polylactic acid-coglycolic acid (PLGA) is one or more copolymers selected from those having a lactic acid to glycolic acid molar ratio of 50:45 to 55 or 50:48 to 52.

[0043] In one embodiment of the present invention, the microglobules can provide encapsulated tilzepatide or a pharmaceutically acceptable salt thereof in a controlled or extended release form. The controlled or extended release form can be understood to be synonymous with "sustained release," "controlled release," or "delayed release."

[0044] In one embodiment of the present invention, the microglobules may be characterized by the sustained release of tilzepatide or a pharmaceutically acceptable salt thereof, encapsulated in an in vitro environment, for two weeks or more.

[0045] In one embodiment of the present invention, the amount of tilzepatide or a pharmaceutically acceptable salt thereof contained in the microglobules may be 30% by weight or less, 28% by weight or less, 25% by weight or less, 20% by weight or less, 16% by weight or less, 13% by weight or less, 10% by weight or less, 7% by weight or less, 5% by weight or less, 3% by weight or less, or 2% by weight or less, with an initial excess release (initial burst within 24 hours) of 30% by weight or less.

[0046] Furthermore, the microglobules of the present invention may release tilzepatide or a pharmaceutically acceptable salt thereof for 14 days or more, preferably for 25 days or more. In addition, the tilzepatide or a pharmaceutically acceptable salt thereof may be released for 30 days or more, 40 days or more, or 50 days or more.

[0047] In one embodiment of the present invention, microparticles containing tylzepatide or a pharmaceutically acceptable salt thereof may be produced by solvent evaporation or extraction using an emulsion, more preferably by an O / W (oil-in-water) emulsion containing a biocompatible polymer, tylzepatide or a pharmaceutically acceptable salt thereof, and a dispersion solvent, and then agglomerating this emulsion into fine particles using an O / W solvent evaporation method.

[0048] To produce microspheres by manufacturing the aforementioned O / W type emulsion and agglomerating it into polymer microparticles, first, an O / W type emulsion containing a biocompatible polymer, tilzepatide or a pharmaceutically acceptable salt thereof, and a dispersion solvent is manufactured.

[0049] The O / W type emulsion can be produced using conventional methods known to the art, more specifically by adding a dispersed phase containing tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer to a dispersion solvent.

[0050] Such microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof can be produced by agglomerating an emulsion into microspheres by solvent extraction and / or solvent evaporation, or by agglomeration by ammonia-added ammonia-induced ammonia-induced ammonia-induced ammonia-induced ammonia-induced hydrolysis. Water-insoluble organic solvents, which are converted into water-soluble solvents by ammonia-induced ammonia-induced hydrolysis, may be further included in the emulsion during its preparation.

[0051] In the case of the solvent evaporation method described above, but not limited to, methods described in, for example, U.S. Patents 5,271,945, 5,985,309, and 6,471,996, etc., namely, dispersing or dissolving the drug in an organic solvent phase in which a polymer compound is dissolved in an organic solvent phase, then emulsifying it in a dispersion medium such as water to produce an O / W type emulsion, and then diffusing the organic solvent in the emulsion into the dispersion medium and evaporating it through the air / water interface, thereby forming polymer microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof.

[0052] The aforementioned solvent extraction method includes conventional solvent extraction methods used for the production of microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof, as well as methods for effectively extracting organic solvents present in emulsion droplets using a large amount of solubilizing solvent.

[0053] As a method for simultaneously applying the aforementioned solvent evaporation method and solvent extraction method, for example, the methods described in U.S. Patents 4,389,840, 4,530,840, 6,368,632, 6,544,559, and 6,572,894 can be applied.

[0054] The ammonia-monolithic process described above involves, for example, the method described in Korean Patent No. 918092, in which ammonia is added to an O / W type emulsion containing a water-insoluble organic solvent to induce ammonia-monolithic, thereby converting the water-insoluble organic solvent into a water-soluble solvent and causing the fine particles to aggregate.

[0055] The aforementioned aggregation by hydrolysis process involves, for example, adding a base such as NaOH, LiOH, or KOH, or an acid solution such as HCl or H2SO4, to an O / W type emulsion containing a water-insoluble organic solvent, as described in Korean Patent Applications No. 2009-109809 and 2010-70407, thereby inducing hydrolysis, a type of ester hydrolysis reaction, and converting the water-insoluble organic solvent into a water-soluble solvent to aggregate the fine particles.

[0056] In one embodiment of the present invention, the microspheres are 、 The W1 / O / W2 (water-in-oil-in-water) type microspheres may be produced by dispersing a W1 / O (water-in-oil) type emulsion containing an internal aqueous phase (W1) in which tilzepatide or a pharmaceutically acceptable salt thereof is dispersed or dissolved in an aqueous solvent, and an oil phase (O) in which a biocompatible polymer is dissolved in a non-aqueous solvent, and then dispersing this emulsion in an external aqueous phase (W2). In this case, the microspheres can be produced by a double emulsification evaporation method.

[0057] In the present invention, microglobules containing tilzepatide or a pharmaceutically acceptable salt thereof can be produced by various microglobule production methods known in the art (e.g., O / W, O / O, or W / O / W solvent evaporation or solvent extraction methods, microglobule production methods by spray drying, microglobule production methods by phase separation, etc.).

[0058] To produce microspheres by manufacturing the aforementioned W / O / W type emulsion and agglomerating it as polymer microparticles, first, a W / O / W type emulsion containing a biocompatible polymer, tilzepatide or a pharmaceutically acceptable salt thereof, and a dispersion solvent is manufactured.

[0059] In this case, the W / O / W type emulsion can be produced using conventional methods known to the art, more specifically by adding a dispersed phase containing tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer to a dispersed solvent.

[0060] Microspheres containing such tilzepatide or a pharmaceutically acceptable salt thereof can be produced by agglomerating an emulsion into microspheres by solvent extraction and / or solvent evaporation, or by agglomeration by ammonia-added ammonia monolysis or hydrolysis by added acid or base. Water-insoluble organic solvents, which are converted into water-soluble solvents by ammonia monolysis or hydrolysis, may be further included in the emulsion during its preparation.

[0061] In the case of the solvent evaporation method described above, but not limited to, methods described in, for example, U.S. Patents 5,271,945, 5,985,309, and 6,471,996, etc., namely, dispersing or dissolving a drug in an organic solvent phase in which a polymer compound is dissolved in an organic solvent phase, then emulsifying it in a dispersion medium such as water to produce a W / O / W type emulsion, and then diffusing the organic solvent in the emulsion into the dispersion medium and evaporating it through the air / water interface, thereby forming polymer microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof.

[0062] The aforementioned solvent extraction method includes conventional solvent extraction methods used for the production of microspheres containing tilzepatide or a pharmaceutically acceptable salt thereof, as well as methods for effectively extracting organic solvents present in emulsion droplets using a large amount of solubilizing solvent.

[0063] As a method for simultaneously applying the aforementioned solvent evaporation method and solvent extraction method, for example, the methods described in U.S. Patents 4,389,840, 4,530,840, 6,368,632, 6,544,559, and 6,572,894 can be applied.

[0064] The ammonia-monolithic process described above involves, for example, the method described in Korean Patent No. 918092, in which ammonia is added to an O / W type emulsion containing a water-insoluble organic solvent to induce ammonia-monolithic, thereby converting the water-insoluble organic solvent into a water-soluble solvent and causing the fine particles to aggregate.

[0065] The aforementioned aggregation by hydrolysis process involves, for example, adding a base such as NaOH, LiOH, or KOH, or an acid solution such as HCl or H2SO4, to a W / O / W type emulsion containing a water-insoluble organic solvent, as described in Korean Patent Applications No. 2009-109809 and 2010-70407, thereby inducing hydrolysis, a type of ester hydrolysis reaction, and converting the water-insoluble organic solvent into a water-soluble solvent to aggregate the fine particles.

[0066] The present invention also,

[0067] (a) A step of dispersing tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer in one or more solvents to prepare a dispersed phase.

[0068] (b) The steps of adding the manufactured dispersed phase to a continuous phase and stirring to form fine particles,

[0069] (c) A method for producing microspheres is provided, which includes the step of removing the solvent. The method for producing microspheres according to the present invention can be applied to all of the above-described information regarding microspheres. Therefore, redundant descriptions will be omitted below.

[0070] In step (a) above, the weight ratio of the biocompatible polymer to tilzepatide or a pharmaceutically acceptable salt thereof may be 9 times or less.

[0071] In one embodiment of the present invention, the type of solvent used to dissolve the biocompatible polymer or to produce a dispersed phase is not particularly limited, and for example, dimethyl sulfoxide, dichloromethane, or a mixture thereof may be used. Dichloromethane is particularly preferred.

[0072] In one embodiment of the present invention, tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer can be sequentially dissolved and mixed in the same container. In this case, dimethyl sulfoxide or dichloromethane may be used as the solvent.

[0073] Step (b) is a step of producing an emulsion solution (O / W) by dispersing the dispersed phase produced in step (a) on an external continuous phase and solidifying the microspheres.

[0074] In step (b) above, a hydrophilic polymer may be included as a surfactant, and its type is not particularly limited. Any such surfactant can be used as long as it acts to enable the dispersion phase containing tilzepatide or a pharmaceutically acceptable salt thereof, and a biocompatible polymer, to form a stable droplet dispersion phase within the outer continuous phase.

[0075] The hydrophilic polymer may preferably be selected from the group consisting of methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil derivatives, and mixtures thereof, and preferably polyvinyl alcohol may be used.

[0076] In step (b) above, the external continuous phase may be a hydrophilic polymer aqueous solution of 0.1 to 6% (w / v), preferably 0.1 to 4% (w / v), in which case the weight-average molecular weight of the hydrophilic polymer may be 7,000 to 40,000, and the degree of hydrolysis may be 80 to 90%.

[0077] In step (b), the dispersed phase containing tilzepatide or a pharmaceutically acceptable salt thereof produced in step (a) and a biocompatible polymer is added to the external continuous phase containing the hydrophilic polymer by a drop-by-drop method or by using an in-line mixer, and the mixture is vigorously stirred to produce an emulsion solution (O / W).

[0078] Subsequently, in step (c), the solvent is removed, and after normal filtration and washing, the desired microspheres can be obtained. That is, if necessary, the process may include a step of washing the obtained microspheres with an organic solvent such as ethanol to improve the initial release suppression effect.

[0079] The present invention also, (1) A step of preparing an internal aqueous phase (W1) by dissolving or dispersing tilzepatide or a pharmaceutically acceptable salt thereof in a solvent, (2) A step of dissolving a biocompatible polymer in one or more solvents to produce an oil phase (O), (3) A step of dispersing an internal aqueous phase (W1) in the oil phase (O) to produce a water in oil (W1 / O) type emulsion. (4) The steps of dispersing the water in oil (W1 / O) type emulsion in an external continuous phase (W2) to produce a water in oil (W1 / O / W2) type emulsion and forming fine particles, and (5) A method for producing microspheres is provided, which includes the step of removing the solvent.

[0080] The present invention's method for producing microspheres can be applied to all of the above-mentioned details concerning microspheres and methods for producing microspheres that are suitable for the production method (such as the type of biocompatible polymer and its intrinsic viscosity). Therefore, redundant descriptions will be omitted below.

[0081] Step (1) above may be, for example, a step of dissolving tilzepatide or a pharmaceutically acceptable salt thereof in distilled water to produce an aqueous phase (W1).

[0082] In step (2) above, the type of solvent is not particularly limited, and for example, dimethyl sulfoxide, dichloromethane, or a mixture thereof may be used. Dichloromethane may be particularly preferred.

[0083] In step (3) above, the weight ratio of the biocompatible polymer to tilzepatide or a pharmaceutically acceptable salt thereof may be 9 times or less.

[0084] Step (3) is a step to produce a water in oil (W1 / O) type emulsion by dispersing the internal aqueous phase (W1) produced in step (1) into the oil phase (O) produced in step (2).

[0085] In step (3) above, the weight ratio of the oil phase (O) to the internal aqueous phase (W1) may be 1:10 or less.

[0086] Step (4) is a step in which the water in oil (W1 / O) type dispersed phase produced in step (3) is dispersed in the external continuous phase (W2) to produce a water in oil (W1 / O / W2) type emulsion solution and solidify the fine particles.

[0087] In step (4) above, the continuous phase (W2) may contain a hydrophilic polymer as a surfactant, but the type is not particularly limited. Any type of surfactant can be used as long as it acts to enable the dispersion phase containing tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer to form a stable droplet dispersion phase within the continuous phase.

[0088] The hydrophilic polymer may preferably be selected from the group consisting of methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil derivatives, and mixtures thereof, and preferably polyvinyl alcohol may be used.

[0089] In step (4) above, the external continuous phase may be a hydrophilic polymer aqueous solution of 0.1 to 6% (w / v), preferably 0.1 to 4% (w / v), in which case the weight-average molecular weight of the hydrophilic polymer may be 7,000 to 40,000, and the degree of hydrolysis may be 80 to 90%.

[0090] In step (4), a dispersed phase (W1 / O) containing tilzepatide or a pharmaceutically acceptable salt thereof produced in step (3) and a biocompatible polymer is added to the external continuous phase containing the hydrophilic polymer by a drop-by-drop method or by using an in-line mixer, and the mixture is vigorously stirred to produce a water in oil in water (W1 / O / W2) type emulsion solution.

[0091] Subsequently, the solvent is removed in step (5) above, and after normal filtration and washing, the desired microspheres can be obtained. That is, if necessary, the process may include a step of washing the obtained microspheres with an organic solvent such as ethanol to improve the initial release suppression effect.

[0092] Furthermore, the present invention provides a pharmaceutical composition comprising the aforementioned microparticles and a pharmaceutically acceptable carrier for the prevention or treatment of diabetes, obesity, hypertension, hyperlipidemia, non-alcoholic steatohepatitis, metabolic disorder-related steatohepatitis, cardiovascular disease, or neurodegenerative disease.

[0093] The pharmaceutical composition according to the present invention can be formulated for parenteral administration.

[0094] The aforementioned parenteral pharmaceutical composition may contain the microglobules alone, or may further contain a pharmaceutically acceptable parenteral carrier that can be added to a pharmaceutical composition. It may also further contain an excipient or diluent. The carrier includes all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads, and microsomes.

[0095] The parenteral administration carrier may contain water, a suitable oil, physiological saline, aqueous glucose and glycol, and may further contain stabilizers and preservatives.

[0096] Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0097] The pharmaceutical composition of the present invention may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, etc., in addition to the above-mentioned components. Other pharmaceutically acceptable carriers and formulations can be referenced from the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

[0098] The parenteral administration method of the present invention may, but is not limited to, administering the drug to a patient (for example, a human requiring such a drug) or other animal by intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, intravenous, intravaginal, intraintestinal, intravaginal, intrapulmonary, suppository, topical, sublingual, or rectal administration.

[0099] In this invention, "treatment" means all actions that improve or beneficially alter (acute or chronic) diseases, disorders, and the symptoms caused thereby by administering a pharmaceutical composition. Furthermore, "treatment" broadly includes the meaning of "prevention," which means all actions that suppress or delay the onset of a disease and the symptoms caused thereby by administering a pharmaceutical preparation. "Treatment" includes, for example, interference, mitigation, improvement, cessation, suppression, delay, and reversal of the progression of (acute or chronic) diseases, disorders, and the symptoms caused thereby.

[0100] The preferred total dose of the pharmaceutical composition or agent of the present invention may be approximately 0.001 mg to 2,000 mg, based on tilzepatide. However, the dose, frequency, and duration of the pharmaceutical composition may vary depending on factors such as the nature and severity of the condition to be treated, the age and general health status of the subject (host), and the subject's (host's) tolerance to the active ingredient. Considering these points, a person with ordinary skill in the art can determine an appropriate effective dose of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited in dosage form, route of administration, and method of administration, as long as it achieves the effects of the present invention.

[0101] The present invention will be described in detail below with reference to examples. However, the examples of the present invention can be modified into various different forms, and the scope of the present invention should not be construed as being limited to the examples detailed below. The examples of the present invention are provided to give a more complete explanation of the present invention to a person of average skill in the industry. [Examples]

[0102] Example 1: Production of tilzepatide microspheres

[0103] <Continuous phase manufacturing> 1,000 mL of distilled water and 10 g of PVA were weighed and added to the reactor. The mixture was stirred at 1,000 rpm using a homogenizer (Overhead (IKA)) to produce a 1% (w / v) PVA aqueous solution.

[0104] <Dispersed phase production> 0.09 g of tilzepatide and 2 mL of dimethyl sulfoxide were weighed into an 8 mL vial and mixed at 150 rpm until dissolved. After the aforementioned solution dissolved, 0.8 g of PLGA (with an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g) and 2 mL of dichloromethane were added and the mixture was stirred at 150 rpm until dissolved.

[0105] <Microbulb recovery> After the above process was completed, the dispersed phase was immediately collected using a syringe and added to a 1 L reactor containing the continuous phase for 7 seconds while being stirred in a homogenizer. The granules were then allowed to solidify for 24 hours. After solidification was complete, the granules were filtered through a 5 μm filter to obtain the granules. The obtained granules were then freeze-dried in a freeze-dryer for more than 20 hours.

[0106] Example 2: Production of tilzepatide microglobules

[0107] <Continuous phase manufacturing> 1,000 mL of distilled water and 10 g of PVA were weighed and added to the reactor. The mixture was stirred at 1,000 rpm using a homogenizer (Overhead (IKA)) to produce a 1% (w / v) PVA aqueous solution.

[0108] <Dispersed phase production> 0.08 g of tilzepatide and 2 mL of dimethyl sulfoxide were weighed into an 8 mL vial and mixed at 150 rpm until dissolved. After the aforementioned solution dissolved, 0.7 g of PLGA (with an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g) and 2 mL of dichloromethane were added and the mixture was stirred at 150 rpm until dissolved.

[0109] <Microbulb recovery> After the above process was completed, the dispersed phase was immediately collected using a syringe and added to a 1 L reactor containing the continuous phase for 7 seconds while being stirred in a homogenizer. The granules were then allowed to solidify for 24 hours. After solidification was complete, the granules were filtered through a 5 μm filter to obtain the granules. The obtained granules were then freeze-dried in a freeze-dryer for more than 20 hours.

[0110] Example 3: Production of Chilzepatide microglobules

[0111] <Continuous phase manufacturing> 1,000 mL of distilled water and 10 g of PVA were weighed and added to the reactor. The mixture was stirred at 1,000 rpm using a homogenizer (Overhead (IKA)) to produce a 1% (w / v) PVA aqueous solution.

[0112] <Manufacture of Dispersed Phase> Weigh 0.175 g of tilzepide and 2 mL of dimethyl sulfoxide into an 8 mL vial, and dissolve them by stirring at 150 rpm. After the drug is dissolved, add 0.7 g of PLGA (intrinsic viscosity 0.15 dL / g to 1.7 dL / g) and 2 mL of dichloromethane, and dissolve them by stirring at 150 rpm.

[0113] <Recovery of Microspheres> After the above process is completed, immediately collect the dispersed phase with a syringe, and while adding it to a 1 L reactor pre-filled with the continuous phase for 7 seconds, stir it with a homogenizer. Then, solidify the microspheres for 24 hours. After the solidification is completed, filter with a 5 μm filter to obtain microspheres. Then, freeze-dry the obtained microspheres with a freeze dryer for 20 hours or more.

[0114] Example 4: Manufacture of Tilzepide Microspheres

[0115] <Manufacture of Continuous Phase> Put 900 mL of distilled water into a reactor, weigh and add 4.5 g of PVA and 4.5 g of NaCl. Stir at 1,000 rpm using an overhead (IKA) homogenizer to produce a 0.5% (w / v) PVA aqueous solution.

[0116] <Manufacture of Tilzepide Solution> Weigh 0.3 g of tilzepide and 1.0 mL of distilled water into a 20 mL vial, and dissolve them by stirring at 150 rpm.

[0117] <Manufacture of PLGA Solution> Put 1.2 g of PLGA (intrinsic viscosity 0.15 dL / g to 1.7 dL / g) into 3 mL of dichloromethane, and dissolve them by stirring at 300 rpm.

[0118] <Emulsification> The PLGA solution prepared above was collected with a syringe, placed into the tiludronate solution, and then stirred at 20,000 rpm for 1 minute using a homogenizer (IKA).

[0119] <Microsphere recovery> After the emulsification process was completed, the solution was immediately collected with a syringe and stirred using a homogenizer while being poured into a 1 L reactor pre-filled with the continuous phase for 60 seconds. Thereafter, the microspheres were solidified for 20 hours. After the solidification was completed, they were filtered through a 5 μm filter to obtain microspheres (W / O / W type). Thereafter, the obtained microspheres were freeze-dried with a freeze dryer for 20 hours or more.

[0120] Example 5: Preparation of tiludronate microspheres

[0121] <Continuous phase preparation> 900 mL of distilled water was placed into a reactor, and 4.5 g of PVA and 4.5 g of NaCl were weighed and added. Stirring was performed at 1,000 rpm using an overhead (IKA) homogenizer to prepare a 0.5% (w / v) PVA aqueous solution.

[0122] <Preparation of tiludronate solution> 0.386 g of tiludronate and 1.5 mL of distilled water were weighed and added to a 20 mL vial, and dissolved by stirring at 150 rpm.

[0123] <Preparation of PLGA solution> 0.9 g of PLGA (intrinsic viscosity of 0.15 dL / g to 1.7 dL / g) was placed into 3 mL of dichloromethane and dissolved by stirring at 300 rpm.

[0124] <Emulsification> The PLGA solution prepared above was collected with a syringe, placed into the tiludronate solution, and then stirred at 20,000 rpm for 1 minute using a homogenizer (IKA).

[0125] <Microsphere recovery> After the emulsification process was completed, the solution was immediately collected with a syringe and stirred using a homogenizer while being poured into a 1 L reactor pre-filled with the continuous phase over 60 seconds. Thereafter, the microspheres were solidified for 20 hours. After the solidification was completed, they were filtered through a 5 μm filter to obtain the microspheres (W / O / W type). Thereafter, the obtained microspheres were freeze-dried using a freeze dryer for 20 hours or more.

[0126] Example 6: Production of Tilzepide Microspheres

[0127] <Continuous Phase Production> 900 mL of distilled water was placed in a reactor, and 4.5 g of PVA and 4.5 g of NaCl were weighed and added. Stirring was carried out at 1,000 rpm using an overhead (IKA) homogenizer to produce a 0.5% (w / v) PVA aqueous solution.

[0128] <Production of Tilzepide Solution> 0.324 g of tilzepide and ^{\,}1 mL of distilled water were weighed and added to a 20 mL vial, and dissolved by stirring at 150 rpm.

[0129] <Production of PLGA Solution> 0.6 g of PLGA (intrinsic viscosity of 0.15 dL / g to 1.7 dL / g) was placed in 2 mL of dichloromethane and dissolved by stirring at 300 rpm.

[0130] <Emulsification> The PLGA solution produced above was collected with a syringe, put into the tilzepide solution, and then stirred at 20,000 rpm for 1 minute using a homogenization (IKA) homogenizer.

[0131] <Microsphere Recovery> After the emulsification process was completed, the solution was immediately collected with a syringe and stirred using a homogenizer while being poured into a 1 L reactor pre-filled with the continuous phase for 60 seconds. Thereafter, the microspheres were solidified for 20 hours. After the solidification was completed, they were filtered through a 5 μm filter to obtain microspheres (W / O / W type). Thereafter, the obtained microspheres were freeze-dried using a freeze dryer for 20 hours or more.

[0132] Example 7: Production of tilupetide microspheres

[0133] <Continuous phase production> 900 mL of distilled water was placed in a reactor, and 4.5 g of PVA and 4.5 g of NaCl were weighed and added. Stirring was carried out at 1,000 rpm using an overhead (IKA) homogenizer to produce a 0.5% (w / v) PVA aqueous solution.

[0134] <Production of tilupetide solution> 0.269 g of tilupetide and 1 mL of distilled water were weighed and added to a 20 mL vial, and dissolved by stirring at 150 rpm.

[0135] <Production of PLGA solution> 0.5 g of PLGA (intrinsic viscosity of 0.15 dL / g to 1.7 dL / g) was placed in 2 mL of dichloromethane and dissolved by stirring at 300 rpm.

[0136] <Emulsification> The PLGA solution produced above was collected with a syringe, placed in the tilupetide solution, and then stirred at 20,000 rpm for 1 minute using a homogenization (IKA) homogenizer.

[0137] <Microsphere recovery> After the emulsification process was completed, the solution was immediately collected with a syringe and stirred using a homogenizer while being introduced into a 1-L reactor pre-filled with the continuous phase for 60 seconds. Thereafter, the microspheres were solidified for 20 hours. After the solidification was completed, the microspheres were filtered through a 5-μm filter to obtain microspheres (W / O / W type). Thereafter, the obtained microspheres were freeze-dried using a freeze dryer for 20 hours or more.

[0138] Example 8: Production of Tilzepide Microspheres

[0139] <Production of Continuous Phase> 900 mL of distilled water was placed in a reactor, and 4.5 g of PVA and 4.5 g of NaCl were weighed and introduced. Stirring was performed at 1,000 rpm using an overhead (IKA) homogenizer to produce a 0.5% (w / v) PVA aqueous solution.

[0140] <Production of Tilzepide Solution> 0.4 g of tilzepide and 1 mL of distilled water were weighed and introduced into a 20-mL vial, and dissolved by stirring at 150 rpm.

[0141] <Production of PLGA Solution> 0.6 g of PLGA (intrinsic viscosity of 0.15 dL / g to 1.7 dL / g) was placed in 2 mL of dichloromethane and dissolved by stirring at 300 rpm.

[0142] <Emulsification> The PLGA solution produced above was collected with a syringe, placed in the tilzepide solution, and then stirred at 20,000 rpm for 1 minute using a homogenization (IKA) homogenizer.

[0143] <Recovery of Microspheres> After the emulsification step was completed, the solution was immediately collected with a syringe and stirred using a homogenizer while being poured into a 1 L reactor pre-filled with the continuous phase over 60 seconds. Thereafter, the microspheres were solidified for 20 hours. After the solidification was completed, the microspheres were filtered through a 5 μm filter to obtain W / O / W type microspheres. Thereafter, the obtained microspheres were lyophilized in a freeze dryer for 20 hours or more.

[0144] Comparative Example 1: Production of tilzepide microspheres

[0145] <Continuous phase production> 900 mL of distilled water, 4.5 g of PVA (manufactured by Sigma), and 4.5 g of NaCl were weighed and put into a reactor. Using an overhead (IKA) homogenizer, stirring was carried out at 1,000 rpm to produce a 0.5% (w / v) PVA aqueous solution.

[0146] <Production of tilzepide solution> 0.24 g of tilzepide and 2.4 mL of distilled water were weighed and put into a 20 mL vial, and dissolved by stirring at 150 rpm.

[0147] <Production of PLGA solution> 4.8 g of PLGA (intrinsic viscosity of 0.10 dL / g to 0.31 dL / g) and PLGA (intrinsic viscosity of 0.32 dL / g to 0.74 dL / g) were put into 12 mL of dichloromethane and dissolved by stirring at 300 rpm.

[0148] <Emulsification> The PLGA solution produced above was collected with a syringe, put into the tilzepide solution, and then stirred at 20,000 rpm for 1 minute using a homogenization (IKA).

[0149] <Microsphere recovery> After the emulsification process was completed, the solution was immediately collected with a syringe and poured into a 1 L reactor pre-filled with the continuous phase while stirring at a speed of 3,500 rpm with a homogenizer for 60 seconds. Then, the microspheres were solidified for 24 hours. After the solidification was completed, they were filtered through a 5 μm filter to obtain microspheres (W / O / W type). Then, the obtained microspheres were freeze-dried with a freeze dryer for 20 hours or more.

[0150] Comparative Example 2: Preparation of Tilzepatide Microspheres

[0151] <Continuous Phase Preparation> 900 mL of distilled water was put into a reactor, and 4.5 g of PVA and 4.5 g of NaCl were weighed and added. It was stirred at 1,000 rpm using an overhead (IKA) homogenizer to produce a 0.5% (w / v) PVA aqueous solution.

[0152] <Preparation of Tilzepatide Solution> 0.323 g of tilzepatide and 1 mL of distilled water were weighed and put into a 20 mL vial, and it was stirred and dissolved at 150 rpm.

[0153] <Preparation of PLGA Solution> 0.6 g of PLGA (intrinsic viscosity 0.32 dL / g to 0.44 dL / g) was put into 2 mL of dichloromethane and stirred and dissolved at 3,000 rpm.

[0154] <Emulsification> The PLGA solution prepared above was collected with a syringe, put into the tilzepatide solution, and then stirred at 20,000 rpm for 1 minute using a homogenization (IKA) homogenizer.

[0155] <Microsphere Recovery> After the emulsification process was completed, the solution was immediately collected with a syringe and stirred using a homogenizer while being poured into a 1 L reactor pre-filled with the continuous phase over 60 seconds. Thereafter, the microspheres were solidified for 20 hours. After the solidification was completed, the mixture was filtered through a 5-μm filter to obtain microspheres (W / O / W type). Thereafter, the obtained microspheres were freeze-dried using a freeze dryer for 20 hours or more.

[0156] Comparative Example 3: Production of Tilzepide Microspheres

[0157] <Production of Continuous Phase> 900 mL of distilled water was placed in a reactor, and 4.5 g of PVA and 4.5 g of NaCl were weighed and added. Stirring was performed at 1,000 rpm using an overhead (IKA) homogenizer to produce a 0.5% (w / v) PVA aqueous solution.

[0158] <Production of Tilzepide Solution> 0.41 g of tilzepide and 1 mL of distilled water were weighed and added to a 20-mL vial, and the mixture was stirred and dissolved at 150 rpm.

[0159] <Production of PLGA Solution> 0.6 g of PLGA (intrinsic viscosity of 0.32 dL / g to 0.44 dL / g) was placed in 2 mL of dichloromethane and stirred and dissolved at 300 rpm.

[0160] <Emulsification> The PLGA solution produced above was collected with a syringe, placed in the tilzepide solution, and then stirred at 20,000 rpm for 1 minute using a homogenization (IKA) homogenizer.

[0161] <​​After the emulsion step was completed, the solution was immediately taken with a syringe and added to a 1 L reactor containing the continuous phase for 60 seconds while being stirred with a homogenizer. The granules were then allowed to solidify for 20 hours. After solidification was complete, the mixture was filtered through a 5 μm filter to obtain granules (W / O / W type). The obtained granules were then freeze-dried in a freeze-dryer for more than 20 hours.

[0162] Experimental Example 1: Confirmation of the loading rate of tilzepatide microgravities

[0163] The granules produced in Examples 1-8 and Comparative Example 1 were collected, placed in a 20 mL volumetric flask, and completely dissolved in acetonitrile containing 0.1% TFA (Trifluoroacetic Acid). The flask was then filled to the mark with distilled water containing 0.1% TFA (Trifluoroacetic Acid), and filtered through a 0.45 μm syringe filter. This solution was detected using HPLC with a UV detector.

[0164] The experimental results are shown in Table 1 below.

[0165] [Table 1]

[0166] Experimental Example 2: Evaluation of Extracellular Release Rate

[0167] The microspheres produced in Examples 1-8 were collected, placed in a vial, and mixed with pH 7.4 PBS solution at 100 rpm, maintaining the temperature at 37°C. To measure the amount released over a certain period of time, the supernatant was collected, filtered through a 0.45 μm RC filter, and used as the sample solution. A fresh sample of the released material was then placed in the vial. The sample solution was detected using an ultraviolet-visible spectrophotometer with HPLC.

[0168] The experimental results are shown in Table 2.

[0169] [Table 2]

[0170] As can be seen in Table 2, the microspheres of Examples 1 to 8, in which tilzepatide was present at 9% by weight or more relative to the total weight of the microspheres and the biocompatible polymer relative to tilzepatide was present at 91% by weight or less, showed an initial excess release of 20% or less within 24 hours, indicating that sustained release over a long period is possible. In contrast, the microspheres of Comparative Examples 2 and 3, in which the biocompatible polymer was produced in a range outside the copolymer with a lactic acid to glycolic acid molar ratio of 50:45 to 55 for polylactic acid-coglycolic acid (PLGA), showed a release rate of 85% or more on day 10, indicating that sustained release over a long period is difficult.

[0171] Therefore, it is preferable to use a biocompatible polymer that is a copolymer of polylactic acid-coglycolic acid (PLGA) with a molar ratio of lactic acid to glycolic acid of 50:45 to 55.

[0172] Experimental Example 3: In-vivo pharmacokinetic study using Beagles

[0173] After subcutaneously injecting the aforementioned tilzepatide microgranular preparation (Example 5) into a beagle, blood was collected according to a predetermined time, and the blood tilzepatide concentration was measured using LC-MS / MS.

[0174] The cumulative drug release rate from the aforementioned experiment is shown in Figure 1. As shown in Figure 1, the microspheres of Example 5, which contained 9% or more by weight of tilzepatide relative to the total weight of the microspheres and in which the weight of the biocompatible polymer relative to tilzepatide was 9 times or less, were found to exhibit excellent sustained release over a long period without initial excessive release.

Claims

1. Microparticles containing tilzepatide or a pharmaceutically acceptable salt thereof, and a biocompatible polymer, The aforementioned tilzepatide or a pharmaceutically acceptable salt thereof is present in an amount of 9% by weight or more relative to the total weight of the microglobules. The biocompatible polymer is polylactic acid-coglycolic acid (PLGA) having an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g, and is characterized by having a molar ratio of lactic acid to glycolic acid of 50:45 to 55, thereby forming microparticles.

2. The microparticles according to claim 1, characterized in that the biocompatible polymer is contained in an amount of 91% by weight or less relative to the total weight of the microparticles.

3. The granulocytes according to claim 1, characterized in that the release of tilzepatide or a pharmaceutically acceptable salt thereof is sustained for 20 days or more.

4. The granulocytes according to claim 3, characterized in that the tilzepatide contained in the granulocytes or a pharmaceutically acceptable salt thereof has an initial burst of 30% or less.

5. The aforementioned microspheres are of the O / W (oil-in-water) type, or W １ / O / W ２ The microsphere according to claim 1, characterized by being of the (water-in-oil-in-water) type.

6. (a) A step of dispersing tilzepatide or a pharmaceutically acceptable salt thereof and a biocompatible polymer in one or more solvents to prepare a dispersed phase. (b) The steps of adding the manufactured dispersed phase to a continuous phase and stirring to form fine particles, (c) A method for producing microspheres, comprising the step of removing the solvent.

7. The method for producing microparticles according to claim 6, characterized in that, in step (a), the weight ratio of the biocompatible polymer to tilzepatide or a pharmaceutically acceptable salt thereof is 9 times or less.

8. The method for producing microspheres according to claim 6, characterized in that, in step (a) above, the biocompatible polymer has an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g.

9. The method for producing microspheres according to claim 6, characterized in that the biocompatible polymer is one or more copolymers selected from polylactic acid-coglycolic acid (PLGA) having an intrinsic viscosity of 0.15 dL / g to 1.7 dL / g, and having a molar ratio of lactic acid to glycolic acid of 50:45 to 55.

10. (1) Dissolve or disperse tilzepatide or a pharmaceutically acceptable salt thereof in a solvent to form an internal aqueous phase (W １ ) Steps to manufacture (2) A step of dissolving a biocompatible polymer in one or more solvents to produce an oil phase (O), (3) The oil phase (O) contains the internal aqueous phase (W １ ) disperses in water in oil (W １ Steps to produce an O-type emulsion, (4) putting the water-in-oil (W １ / O) emulsion into an external continuous phase (W ２ ) for dispersion to produce a water-in-oil-in-water (W １ / O / W ２ ) emulsion to form microspheres, and (5) A method for producing microspheres, comprising the step of removing the solvent.

11. The method for producing microparticles according to claim 10, characterized in that, in step (3) above, the weight ratio of the biocompatible polymer to tilzepatide or a pharmaceutically acceptable salt thereof is 9 times or less.

12. A pharmaceutical composition for the prevention or treatment of diabetes, obesity, hypertension, hyperlipidemia, non-alcoholic steatohepatitis, metabolic disorder-related steatohepatitis, cardiovascular disease, or neurodegenerative disease, comprising the microparticles and a pharmaceutically acceptable carrier as described in claim 1.

13. The pharmaceutical composition according to claim 12, characterized in that the pharmaceutical composition is for use as a subcutaneous or intramuscular injection.

Images