Microspheres

Abstract

Disclosed are microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal voids of the microspheres is approximately 0.013 to 0.20 mL / g.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This disclosure claims the full benefit of Chinese invention patent application bearing application number 202211138917.9 and entitled "Microspheres," filed with the State Intellectual Property Office of the People's Republic of China on September 19, 2022, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to the field of biopharmaceuticals, and more particularly, the disclosure relates to the field of drug formulations. [Background technology]

[0003] Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is produced primarily by intestinal L cells. Summary of the Invention

[0004] In one aspect, the disclosure relates to microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is between 11.0% and 12.5%, and 90% of the cumulative pore volume of the internal void of the microspheres is between about 0.013 and 0.15 mL / g.

[0005] In another aspect, the present disclosure relates to microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0006] In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, the microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0007] In a further aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, the microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0008] In another aspect, the disclosure relates to a method for preparing microspheres, comprising the steps of providing a first aqueous solution containing semaglutide, providing an oily solution containing a pharmaceutically acceptable polymer, emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion, mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion, and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0009] In yet another aspect, the disclosure relates to a method for preparing microspheres, comprising the steps of providing a first aqueous solution containing semaglutide, providing an oily solution containing a pharmaceutically acceptable polymer, emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion, mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion, and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0010] In a further aspect, the present disclosure relates to microspheres prepared by a method comprising the steps of: providing a first aqueous solution containing semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is 11.0% to 12.5% ​​and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0011] In another aspect, the disclosure relates to microspheres prepared by a method comprising the steps of: providing a first aqueous solution containing semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is 11.0% to 20.0% and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0012] In yet another aspect, the present disclosure relates to a method of treating diabetes comprising administering to an individual in need thereof a therapeutically effective amount of a microsphere described herein, a pharmaceutical composition described herein, or a microsphere prepared by a method described herein.

[0013] In a further aspect, the present disclosure relates to a method for reducing weight, comprising administering to an individual in need thereof an effective amount of a microsphere described herein, a pharmaceutical composition described herein, or a microsphere prepared by a method described herein. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows the pore volume / pore size distribution curve of the microspheres of Example 1. [Figure 2] 1 shows the pore volume / pore size distribution curve of the microspheres of Example 2. [Figure 3] 1 shows the pore volume / pore size distribution curve of the microspheres of Example 3. [Figure 4] 1 shows the pore volume / pore size distribution curve of the microspheres of Example 4. [Figure 5] 1 shows the pore volume / pore size distribution curve of the microspheres of Example 5. [Figure 6] 1 shows the in vitro release curve of the microspheres of Example 1. [Figure 7] 1 shows the in vitro release curve of the microspheres of Example 2. [Figure 8] 1 shows the in vitro release curve of the microspheres of Example 3. [Figure 9] 1 shows the in vitro release curve of the microspheres of Example 4. [Figure 10] 1 shows the in vitro release curve of the microspheres of Example 5. [Figure 11] 1 shows the in vitro release curve of the microspheres of Example 6. [Figure 12] 1 shows the drug concentration-time curve of the microspheres of Example 1. [Figure 13] 1 shows the drug concentration-time curve of the microspheres of Example 2. [Figure 14] 1 shows the drug concentration-time curve of the microspheres of Example 3. [Figure 15] 1 shows the drug concentration-time curve of the microspheres of Example 4. [Figure 16] 1 shows the drug concentration-time curve of the microspheres of Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0015] The following description includes certain specific details to provide a comprehensive understanding of the disclosed embodiments, but those skilled in the art will recognize that the embodiments may be practiced using other methods, components, materials, etc., without one or more of these specific details.

[0016] Unless otherwise required in this application, throughout the specification and the appended claims, the terms "comprises," "includes," and "having" are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0017] Throughout this specification, the terms "one embodiment," "an embodiment," "another embodiment," or "in an embodiment" mean that at least one embodiment includes the particular referenced element, structure, or feature described in that embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "another embodiment" or "in an embodiment" in different places throughout the specification do not necessarily refer to the same embodiment. Furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments. definition

[0018] In this disclosure, the term "pore volume" refers to the volume of internal voids per unit mass of a porous solid.

[0019] In this disclosure, the term "cumulative pore volume" refers to the cumulative volume of internal voids per unit mass of a porous solid.

[0020] In this disclosure, the term "semaglutide" means N ε26 [(S)-(22,40-dicarboxylic acid-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetracontane-1-acyl)][Aib 8 , Arg 34 ] refers to the GLP-1-(7-37) peptide, the structural formula of which is shown below. JPEG2025530453000002.jpg62153

[0021] In this disclosure, the term "bioavailability" refers to the relative amount of drug that reaches the blood circulation from the site of administration.

[0022] In this disclosure, "AUC inf The term "area under the drug concentration-time curve of a formulation extrapolated to infinite time."

[0023] In the present disclosure, "drug loading" refers to the weight percentage of the drug contained in the microparticle formulation, i.e., drug loading = weight of drug contained in the microparticle formulation / total weight of the microparticle formulation x 100%.

[0024] In this disclosure, the term "poly(lactide-co-glycolide) (PLGA)" is also referred to as poly(lactic-co-glycolic acid), which is produced by the condensation polymerization of two monomers, lactic acid and glycolic acid, or by the ring-opening polymerization of lactide and glycolide. Specific Embodiments

[0025] In one aspect, the disclosure relates to microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is about 11.0% to 12.5% ​​and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0026] In another aspect, the present disclosure relates to microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0027] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.1%.

[0028] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.2%.

[0029] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.3%.

[0030] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.4%.

[0031] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.5%.

[0032] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.6%.

[0033] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.7%.

[0034] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.8%.

[0035] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.9%.

[0036] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.0%.

[0037] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.1%.

[0038] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.2%.

[0039] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.3%.

[0040] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.4%.

[0041] In some embodiments, the drug loading of the microspheres of the present disclosure is about 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%, 15.2%, 15.3%, 15.4%, 15.5%, 15.6%, 15.7%, 15.8%, 15.9%, 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, or 20.0%.

[0042] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.0% to 19.0%, 11.0% to 18.0%.

[0043] In one embodiment, 90% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.017-0.12 mL / g.

[0044] In some embodiments, 90% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.014-0.19 mL / g, 0.015-0.18 mL / g, 0.016-0.17 mL / g, 0.017-0.18 mL / g, 0.017-0.17 mL / g, 0.017-0.16 mL / g, or 0.017-0.15 mL / g.

[0045] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.013 to 0.079 mL / g.

[0046] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.016 to 0.066 mL / g.

[0047] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.013-0.11 mL / g, 0.014-0.10 mL / g, 0.015-0.09 mL / g, or 0.016-0.08 mL / g.

[0048] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.009-0.016 mL / g.

[0049] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.011-0.014 mL / g.

[0050] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.011-0.022 mL / g, 0.011-0.021 mL / g, 0.011-0.020 mL / g, 0.011-0.019 mL / g, 0.011-0.018 mL / g, 0.011-0.017 mL / g, or 0.011-0.016 mL / g.

[0051] In certain embodiments, illustrative examples of pharmaceutically acceptable polymers that may be used in the present disclosure include, but are not limited to, poly(lactide-co-glycolide) (PLGA).

[0052] In one embodiment, the content of poly(lactide-co-glycolide) (PLGA) in the microspheres is about 80% to 85% by weight, based on the weight of the microspheres.

[0053] In some embodiments, the content of poly(lactide-co-glycolide) (PLGA) in the microspheres is about 75% to 85%, 76% to 85%, 77% to 85%, or 78% to 85% by weight, based on the weight of the microspheres.

[0054] In some embodiments, the microspheres of the present disclosure may further contain sucrose.

[0055] In one embodiment, the content of sucrose in the microspheres is about 1% to 3% by weight, based on the weight of the microspheres.

[0056] In one embodiment, the content of sucrose in the microspheres is about 2% by weight, based on the weight of the microspheres.

[0057] In certain embodiments, the microspheres of the present disclosure have improved bioavailability.

[0058] In one embodiment, semaglutide has a release period from the microspheres of the present disclosure of about 2 weeks or more.

[0059] In some embodiments, semaglutide is released sustainedly from the microspheres of the present disclosure.

[0060] In another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, the microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0061] In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, the microspheres comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0062] In a further aspect, the disclosure relates to a method for preparing microspheres comprising the steps of providing a first aqueous solution containing semaglutide, providing an oily solution containing a pharmaceutically acceptable polymer, emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion, mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion, and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0063] In another aspect, the disclosure relates to a method for preparing microspheres, comprising the steps of providing a first aqueous solution containing semaglutide, providing an oily solution containing a pharmaceutically acceptable polymer, emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion, mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion, and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0064] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.1%.

[0065] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.2%.

[0066] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.3%.

[0067] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.4%.

[0068] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.5%.

[0069] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.6%.

[0070] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.7%.

[0071] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.8%.

[0072] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.9%.

[0073] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.0%.

[0074] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.1%.

[0075] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.2%.

[0076] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.3%.

[0077] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.4%.

[0078] In some embodiments, the drug loading of the microspheres of the present disclosure is about 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%, 15.2%, 15.3%, 15.4%, 15.5%, 15.6%, 15.7%, 15.8%, 15.9%, 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, or 20.0%.

[0079] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.0% to 19.0%, 11.0% to 18.0%.

[0080] In one embodiment, 90% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.017-0.12 mL / g.

[0081] In some embodiments, 90% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.014-0.19 mL / g, 0.015-0.18 mL / g, 0.016-0.17 mL / g, 0.017-0.18 mL / g, 0.017-0.17 mL / g, 0.017-0.16 mL / g, or 0.017-0.15 mL / g.

[0082] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.013 to 0.079 mL / g.

[0083] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.016 to 0.066 mL / g.

[0084] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.013-0.11 mL / g, 0.014-0.10 mL / g, 0.015-0.09 mL / g, or 0.016-0.08 mL / g.

[0085] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.009-0.016 mL / g.

[0086] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.011-0.014 mL / g.

[0087] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.011-0.022 mL / g, 0.011-0.021 mL / g, 0.011-0.020 mL / g, 0.011-0.019 mL / g, 0.011-0.018 mL / g, 0.011-0.017 mL / g, or 0.011-0.016 mL / g.

[0088] In one embodiment, semaglutide and sucrose are dissolved in water to provide a first aqueous solution.

[0089] In some embodiments, the pharmaceutically acceptable polymer is dissolved in an organic solvent to provide an oily solution.

[0090] In certain embodiments, illustrative examples of organic solvents that may be used in the present disclosure include, but are not limited to, dichloromethane, ethyl acetate, and acetone.

[0091] In one embodiment, the first aqueous solution and the oily solution are emulsified by homogenization or sonication to obtain a water-in-oil (W / O) emulsion.

[0092] In some embodiments, the emulsifier and osmolality adjusting agent are dissolved in water to provide a second aqueous solution.

[0093] In embodiments, illustrative examples of emulsifiers that may be used in the present disclosure include, but are not limited to, anionic surfactants and nonionic surfactants.

[0094] In embodiments, illustrative examples of anionic surfactants that may be used in the present disclosure include, but are not limited to, sodium oleate, sodium stearate, and sodium lauryl sulfate.

[0095] In certain embodiments, illustrative examples of nonionic surfactants that may be used in the present disclosure include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, and gelatin.

[0096] In certain embodiments, illustrative examples of polyoxyethylene sorbitan fatty acid esters that may be used in the present disclosure include, but are not limited to, Twain 80 and Twain 60.

[0097] In certain embodiments, illustrative examples of tonicity adjusting agents that may be used in the present disclosure include, but are not limited to, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, and proline.

[0098] In some embodiments, polyvinyl alcohol and sodium chloride are dissolved in water to provide a second aqueous solution.

[0099] In some embodiments, an overhead stirrer, homogenizer, or static mixer is used to mix the water-in-oil (W / O) emulsion and the second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion.

[0100] In some embodiments, a gas is used to purge a water-in-oil-in-water (W / O / W) emulsion to remove the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion, resulting in hardened microspheres.

[0101] In certain embodiments, illustrative examples of gases that may be used in the present disclosure include, but are not limited to, nitrogen gas, helium gas, compressed air, argon gas, and neon gas.

[0102] In some embodiments, when agitated, a gas is used to purge the water-in-oil-in-water (W / O / W) emulsion to remove the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion, resulting in hardened microspheres.

[0103] In certain embodiments, illustrative examples of stirring modes that may be used in the present disclosure include, but are not limited to, mechanical stirring and magnetic levitation stirring.

[0104] In certain embodiments, illustrative examples of mechanical stirring that may be used in the present disclosure include, but are not limited to, overhead stirring paddles.

[0105] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 100 to 200 nm.

[0106] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 110 to 200 nm.

[0107] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 120 to 200 nm.

[0108] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 130 to 200 nm.

[0109] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 140 to 200 nm.

[0110] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 150 to 200 nm.

[0111] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 160 to 200 nm.

[0112] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 170 to 200 nm.

[0113] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 180 to 200 nm.

[0114] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 190 to 200 nm.

[0115] In some embodiments, the hardened microspheres are washed.

[0116] In certain embodiments, illustrative examples of irrigation solutions that may be used in the present disclosure include, but are not limited to, water for injection and purified water.

[0117] In some embodiments, the washed microspheres are lyophilized to obtain a microsphere lyophilized powder.

[0118] In yet another aspect, the disclosure relates to microspheres prepared by a method comprising the steps of: providing a first aqueous solution containing semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is about 11.0% to 12.5% ​​and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.15 mL / g.

[0119] In a further aspect, the present disclosure relates to microspheres prepared by a method comprising the steps of: providing a first aqueous solution containing semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; and removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres, wherein the drug loading of the microspheres is about 11.0% to 20.0% and 90% of the cumulative pore volume of the internal void of the microspheres is about 0.013 to 0.20 mL / g.

[0120] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.1%.

[0121] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.2%.

[0122] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.3%.

[0123] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.4%.

[0124] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.5%.

[0125] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.6%.

[0126] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.7%.

[0127] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.8%.

[0128] In one embodiment, the drug loading of the microspheres of the present disclosure is about 11.9%.

[0129] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.0%.

[0130] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.1%.

[0131] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.2%.

[0132] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.3%.

[0133] In one embodiment, the drug loading of the microspheres of the present disclosure is about 12.4%.

[0134] In some embodiments, the drug loading of the microspheres of the present disclosure is about 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3%, 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%, 15.2%, 15.3%, 15.4%, 15.5%, 15.6%, 15.7%, 15.8%, 15.9%, 16.0%, 16.1%, 16.2%, 16.3%, 16.4%, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, or 20.0%.

[0135] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.0% to 19.0%, 11.0% to 18.0%.

[0136] In one embodiment, 90% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.017-0.12 mL / g.

[0137] In some embodiments, 90% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.014-0.19 mL / g, 0.015-0.18 mL / g, 0.016-0.17 mL / g, 0.017-0.18 mL / g, 0.017-0.17 mL / g, 0.017-0.16 mL / g, or 0.017-0.15 mL / g.

[0138] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.013 to 0.079 mL / g.

[0139] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.016 to 0.066 mL / g.

[0140] In some embodiments, 50% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.013-0.11 mL / g, 0.014-0.10 mL / g, 0.015-0.09 mL / g, or 0.016-0.08 mL / g.

[0141] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.009-0.016 mL / g.

[0142] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.011-0.014 mL / g.

[0143] In some embodiments, 10% of the cumulative pore volume of the internal voids of the microspheres of the present disclosure is about 0.011-0.022 mL / g, 0.011-0.021 mL / g, 0.011-0.020 mL / g, 0.011-0.019 mL / g, 0.011-0.018 mL / g, 0.011-0.017 mL / g, or 0.011-0.016 mL / g.

[0144] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 100 to 200 nm.

[0145] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 110 to 200 nm.

[0146] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 120 to 200 nm.

[0147] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 130 to 200 nm.

[0148] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 140 to 200 nm.

[0149] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 150 to 200 nm.

[0150] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 160 to 200 nm.

[0151] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 170 to 200 nm.

[0152] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 180 to 200 nm.

[0153] In one embodiment, the particle size of the water-in-oil (W / O) emulsion is about 190 to 200 nm.

[0154] In certain embodiments, the microspheres of the present disclosure have higher encapsulation rates, even higher than 80% and even higher than 85%.

[0155] In certain embodiments, the microspheres of the present disclosure have improved bioavailability.

[0156] In certain embodiments, the microspheres of the present disclosure have improved AUC inf It has.

[0157] In certain embodiments, the microspheres of the present disclosure ideally have an acceptably low burst release, thereby advantageously maintaining stable blood drug levels in the body after administration.

[0158] In certain embodiments, the microspheres of the present disclosure, when administered to an individual in need thereof, result in a smaller amount of microspheres and a lower administration volume while still having excellent bioavailability. Furthermore, the smaller microsphere dose and lower administration volume can reduce local irritation reactions and reduce pain for the patient.

[0159] In one embodiment, semaglutide is released from the microspheres of the present disclosure with a periodicity of about two weeks or more.

[0160] In some embodiments, semaglutide is released sustainedly from the microspheres of the present disclosure.

[0161] In another aspect, the present disclosure relates to a method of treating diabetes comprising administering to an individual in need thereof a therapeutically effective amount of a microsphere described herein, a pharmaceutical composition described herein, or a microsphere prepared by a method described herein.

[0162] In some embodiments, the individual is administered the microspheres described herein, the pharmaceutical compositions described herein, or the microspheres prepared by the methods described herein, every two weeks or more.

[0163] In one embodiment, the diabetes is type 2 diabetes.

[0164] In certain embodiments, illustrative examples of individuals that may be used in the present disclosure include, but are not limited to, mammals.

[0165] In certain embodiments, illustrative examples of mammals that may be used in the present disclosure include, but are not limited to, humans.

[0166] In a further aspect, the present disclosure relates to a method comprising administering to an individual in need thereof an effective amount of a microsphere described herein, a pharmaceutical composition described herein, or a microsphere prepared by a method described herein.

[0167] In some embodiments, the individual is administered a microsphere described herein, a pharmaceutical composition described herein, or a microsphere prepared by a method described herein, every two weeks or more.

[0168] In certain embodiments, illustrative examples of individuals that may be used in the present disclosure include, but are not limited to, mammals.

[0169] In certain embodiments, illustrative examples of mammals that may be used in the present disclosure include, but are not limited to, humans.

[0170] The present disclosure will now be described in detail with reference to the following examples in order to better understand the various aspects of the present disclosure and its advantages. However, it should be understood that the following examples are not limiting and are only used to illustrate specific embodiments of the present disclosure. Example

[0171] The reagents and equipment used in the examples of the present disclosure are conventional and commercially available, for example: TIFF2025530453000003.tif41143

[0172] TIFF2025530453000004.tif62136 Example 1

[0173] Preparation of semaglutide microspheres TIFF2025530453000005.tif73126 Note: * will be removed in the preparation process. Preparation steps: 1. A certain amount of semaglutide drug substance and sucrose were dissolved in water to obtain an internal aqueous phase (i.e., a first aqueous solution). 2. A certain amount of PLGA was dissolved in dichloromethane to obtain an oil phase. 3. A certain amount of PVA and sodium chloride was dissolved in water to obtain an outer aqueous phase (i.e., a second aqueous solution). 4. The inner water phase and oil phase were emulsified by ultrasonication to obtain a water-in-oil emulsion with a particle size of 160.6 nm. 5. The water-in-oil emulsion obtained in 4 above was mixed with a certain proportion of external aqueous phase by homogenization to obtain a water-in-oil-in-water system. 6. While mechanically stirring, the surface of the water-in-oil-in-water system obtained in 5 above was purged with nitrogen gas, and the microspheres were dissolved in the dichloromethane in the outer aqueous phase and evaporated, hardening the microspheres. 7. The hardened microspheres were collected and washed with purified water. 8. The wet microspheres obtained in step 7 above were collected and freeze-dried. 9. The microsphere lyophilized powder obtained in step 8 was collected and dispersed through a sieve. Example 2

[0174] Preparation of semaglutide microspheres TIFF2025530453000006.tif78140 Note: * will be removed in the preparation process. Preparation steps: 1. A certain amount of semaglutide drug substance and sucrose were dissolved in water to obtain an internal aqueous phase (i.e., a first aqueous solution). 2. A certain amount of PLGA was dissolved in dichloromethane to obtain an oil phase. 3. A certain amount of PVA and sodium chloride was dissolved in water to obtain an outer aqueous phase (i.e., a second aqueous solution). 4. The inner water phase and oil phase were emulsified by ultrasonication to obtain a water-in-oil emulsion with a particle size of 180.8 nm. 5. The water-in-oil emulsion obtained in 4 above was mixed with a certain proportion of external aqueous phase by homogenization to obtain a water-in-oil-in-water system. 6. While mechanically stirring, the surface of the water-in-oil-in-water system obtained in 5 above was purged with nitrogen gas, and the microspheres were dissolved in the dichloromethane in the outer aqueous phase and evaporated, hardening the microspheres. 7. The hardened microspheres were collected and washed with purified water. 8. The wet microspheres obtained in step 7 above were collected and freeze-dried. 9. The microsphere lyophilized powder obtained in step 8 was collected and dispersed through a sieve. Example 3

[0175] Preparation of semaglutide microspheres TIFF2025530453000007.tif73131 Note: * will be removed in the preparation process. Preparation steps: 1. A certain amount of semaglutide drug substance and sucrose were dissolved in water to obtain an internal aqueous phase (i.e., a first aqueous solution). 2. A certain amount of PLGA was dissolved in dichloromethane to obtain an oil phase. 3. A certain amount of PVA and sodium chloride was dissolved in water to obtain an outer aqueous phase (i.e., a second aqueous solution). 4. The inner water phase and oil phase were emulsified by ultrasonication to obtain a water-in-oil emulsion with a particle size of 269.3 nm. 5. The water-in-oil emulsion obtained in 4 above was mixed with a certain proportion of external aqueous phase by homogenization to obtain a water-in-oil-in-water system. 6. While mechanically stirring, the surface of the water-in-oil-in-water system obtained in 5 above was purged with nitrogen gas, and the microspheres were dissolved in the dichloromethane in the outer aqueous phase and evaporated, hardening the microspheres. 7. The hardened microspheres were collected and washed with purified water. 8. The wet microspheres obtained in step 7 above were collected and freeze-dried. 9. The microsphere lyophilized powder obtained in step 8 was collected and dispersed through a sieve. Example 4

[0176] Preparation of semaglutide microspheres TIFF2025530453000008.tif78135 Note: * will be removed in the preparation process. Preparation steps: 1. A certain amount of semaglutide drug substance and sucrose were dissolved in water to obtain an internal aqueous phase (i.e., a first aqueous solution). 2. A certain amount of PLGA was dissolved in dichloromethane to obtain an oil phase. 3. A certain amount of PVA and sodium chloride was dissolved in water to obtain an outer aqueous phase (i.e., a second aqueous solution). 4. The inner water phase and oil phase were emulsified by ultrasonication to obtain a water-in-oil emulsion with a particle size of 151.5 nm. 5. The water-in-oil emulsion obtained in 4 above was mixed with a certain proportion of external aqueous phase by homogenization to obtain a water-in-oil-in-water system. 6. While mechanically stirring, the surface of the water-in-oil-in-water system obtained in 5 above was purged with nitrogen gas, and the microspheres were dissolved in the dichloromethane in the outer aqueous phase and evaporated, hardening the microspheres. 7. The hardened microspheres were collected and washed with purified water. 8. The wet microspheres obtained in step 7 above were collected and freeze-dried. 9. The microsphere lyophilized powder obtained in step 8 was collected and dispersed through a sieve. Example 5

[0177] Preparation of semaglutide microspheres TIFF2025530453000009.tif73117 Note: * will be removed in the preparation process. Preparation steps: 1. A certain amount of semaglutide drug substance and sucrose were dissolved in water to obtain an internal aqueous phase (i.e., a first aqueous solution). 2. A certain amount of PLGA was dissolved in dichloromethane to obtain an oil phase. 3. A certain amount of PVA and sodium chloride was dissolved in water to obtain an outer aqueous phase (i.e., a second aqueous solution). 4. The inner water phase and oil phase were emulsified by ultrasonication to obtain a water-in-oil emulsion with a particle size of 175 nm. 5. The water-in-oil emulsion obtained in 4 above was mixed with a certain proportion of external aqueous phase by homogenization to obtain a water-in-oil-in-water system. 6. While mechanically stirring, the surface of the water-in-oil-in-water system obtained in 5 above was purged with air, and the microspheres were dissolved in the dichloromethane in the outer aqueous phase and evaporated, hardening the microspheres. 7. The hardened microspheres were collected and washed with purified water. 8. The wet microspheres obtained in step 7 above were collected and freeze-dried. 9. The microsphere lyophilized powder obtained in step 8 was collected and dispersed through a sieve. Example 6

[0178] Preparation of semaglutide microspheres TIFF2025530453000010.tif78141 Note: * will be removed in the preparation process. Preparation steps: 1. A certain amount of semaglutide drug substance and sucrose were dissolved in water to obtain an internal aqueous phase (i.e., a first aqueous solution). 2. A certain amount of PLGA was dissolved in dichloromethane to obtain an oil phase. 3. A certain amount of PVA and sodium chloride was dissolved in water to obtain an outer aqueous phase (i.e., a second aqueous solution). 4. The inner water phase and oil phase were emulsified by ultrasonication to obtain a water-in-oil emulsion with a particle size of 183.4 nm. 5. The water-in-oil emulsion obtained in 4 above was mixed with a certain proportion of external aqueous phase by homogenization to obtain a water-in-oil-in-water system. 6. While mechanically stirring, the surface of the water-in-oil-in-water system obtained in 5 above was purged with air, and the microspheres were dissolved in the dichloromethane in the outer aqueous phase and evaporated, hardening the microspheres. 7. The hardened microspheres were collected and washed with purified water. 8. The wet microspheres obtained in step 7 above were collected and freeze-dried. 9. The microsphere lyophilized powder obtained in step 8 was collected and dispersed through a sieve. Example 7

[0179] Measurement of semaglutide microsphere release rate Test sample: Semaglutide microspheres prepared in Examples 1 to 6; Three parallel samples were set up for each sample. The release rate experiment was carried out using an economical precision high-temperature constant temperature bath XT5018P-GP18 and Waters high-performance liquid chromatography. Preparation of release medium Place 34.06±0.01 g of Tris(base), 2.97±0.01 g of Tris(HCl), 5±0.1 g of poloxamer (188), and 1.00±0.01 g of sodium azide in a suitable container, add 1 L of purified water, and dissolve by stirring. Adjust the pH to 9.40±0.03 with 0.1 mol / L sodium hydroxide, and then filter through a high-temperature sterilized bag filter (BP milpak 20, PVDF, 0.22 μm). Approximately 50 mg of semaglutide microspheres were precisely weighed and placed in a 50 mL blue-capped bottle. 20 mL of release medium was added and the bottle was shaken to suspend the microspheres, then placed in a constant-temperature (37°C ± 0.3°C) water bath. Samples were taken after 1, 3, 7, 10, 14, 17, 21, 24, 28, 31, 35, and 42 days of standing. Using a microsampler, 1 mL of the supernatant (after each sample was collected, an equal volume of preheated fresh medium was added) was transferred to a 2 mL centrifuge tube and centrifuged (5000 rpm, 10 min). After centrifugation, an appropriate amount of the supernatant was removed. Three parallel preparations were performed. Chromatography conditions: Chromatography column: Waters Xselect® CSH C18 3.5 μm, 4.6 × 150 mm Column temperature: 45℃ Mobile phase: 0.05 mol / L ammonium dihydrogen phosphate (pH 9.50) - acetonitrile (2:1) Flow rate: 1.0mL / min Detection wavelength: 215 nm Injection tray temperature: 10℃ Injection volume: 10μL Elution method: Isocratic elution Operating time: 10 min

[0180] The release rates of the microspheres of Examples 1 to 6 of the present disclosure are shown in Tables 1 to 6.

[0181] [Table 1] Note: d stands for days.

[0182] [Table 2] Note: d stands for days.

[0183] [Table 3] Note: d stands for days.

[0184] [Table 4] Note: d stands for days.

[0185] [Table 5] Note: d stands for days.

[0186] [Table 6] Note: d stands for days. 6-11 show the release curves of the microspheres of Examples 1-6 of the present disclosure. Example 8

[0187] Measurement of drug loading in semaglutide microspheres Test sample: Semaglutide microspheres prepared in Examples 1 to 6; Three parallel samples were set up for each sample. Detection method: 1. The PLGA in the microspheres was dissolved in acetonitrile to release semaglutide, then phosphate buffer was added to dissolve the semaglutide, causing most of the PLGA to precipitate and deposit. Finally, the PLGA was removed by centrifugation. 2. The content of semaglutide was detected by HPLC.

[0188] TIFF2025530453000017.tif36125 Example 9

[0189] Measurement of microsphere pore size distribution Approximately 200 mg of semaglutide microspheres were weighed into the dilatometer, sealed, and weighed to obtain the weight of the dilatometer assembly, which was then mounted in a machine for low and high pressure testing, increasing the pressure from 0.50 psia to 60,000 psia. Test sample: Semaglutide microspheres prepared in Examples 1 to 5 The pore volume and pore size distribution of the samples were calculated from the mercury injection curve obtained using the Washburn equation.

[0190] TIFF2025530453000018.tif52123 1-5 show the pore volume / pore size distribution curves of the microspheres of Examples 1-5 of the present disclosure. Example 10

[0191] In vivo pK of semaglutide microspheres in rats Healthy SD rats weighing 200-250g, 7-8 weeks old, were selected as study subjects. The drug was administered subcutaneously at the back of the rat's neck at a dose of 18mg / kg. Approximately 0.2mL of blood was collected from the jugular vein at regular intervals after administration. After blood collection, the blood collection tube containing the anticoagulant (K2EDTA) was inverted several times to mix well. Plasma samples were obtained by centrifugation. Using LC-MS / MS, the blood drug concentration (ng / mL) of semaglutide in the plasma samples at each time point was measured, and the drug concentration-time curves for the microspheres of Examples 1-5 were plotted. The AUC of the microspheres of Examples 1-5 was calculated. inf was calculated. 11-15 show the drug concentration-time curves of the microspheres of Examples 1-5 of the present disclosure.

[0192] TIFF2025530453000019.tif31122

[0193] In this disclosure, relational terms such as first and second are used merely to distinguish one entity or operation from another, and do not necessarily require or imply that any actual relationship or order exists between those entities or operations.

[0194] From the foregoing, it will be appreciated that, although specific embodiments of the present disclosure have been described for purposes of exemplary description, those skilled in the art may make various modifications or improvements thereto without departing from the spirit and scope of the present disclosure, all of which are intended to be included within the scope of the claims appended hereto.

Claims

1. A microsphere, A microsphere comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microsphere is 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal void of the microsphere is 0.013 to 0.15 mL / g.

2. A microsphere, A microsphere comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microsphere is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal void of the microsphere is 0.013 to 0.20 mL / g.

3. 3. The microspheres according to claim 1 or 2, further comprising sucrose, preferably having a sucrose content of 1% to 3% by weight based on the weight of the microspheres.

4. The microsphere according to any one of claims 1 to 3, wherein the pharmaceutically acceptable polymer is selected from poly(lactide-co-glycolide) (PLGA), and preferably, the content of poly(lactide-co-glycolide) (PLGA) is 75% to 85% by weight based on the weight of the microsphere.

5. The microsphere according to any one of claims 1 to 4, wherein the pharmaceutically acceptable polymer is selected from poly(lactide-co-glycolide) (PLGA), and preferably, the content of poly(lactide-co-glycolide) (PLGA) is 80% to 85% by weight based on the weight of the microsphere.

6. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising the microspheres of any one of claims 1 to 5.

7. A method for preparing microspheres, comprising: providing a first aqueous solution comprising semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres; The drug loading of the microspheres is 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal voids of the microspheres is 0.013 to 0.15 mL / g.

8. A method for preparing microspheres, comprising: providing a first aqueous solution comprising semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres; The drug loading of the microspheres is 11.0% to 20.0%, and 90% of the cumulative pore volume of the internal voids of the microspheres is 0.013 to 0.20 mL / g.

9. 9. The method according to claim 7 or 8, wherein the microspheres further comprise sucrose, and preferably the content of the sucrose is 1% to 3% by weight based on the weight of the microspheres.

10. The method according to any one of claims 7 to 9, wherein the pharmaceutically acceptable polymer is selected from poly(lactide-co-glycolide) (PLGA), and preferably, the content of poly(lactide-co-glycolide) (PLGA) is 75% to 85% by weight based on the weight of the microsphere.

11. The method according to any one of claims 7 to 10, wherein the pharmaceutically acceptable polymer is selected from poly(lactide-co-glycolide) (PLGA), and preferably, the content of poly(lactide-co-glycolide) (PLGA) is 80% to 85% by weight based on the weight of the microsphere.

12. Microspheres obtained by the method according to any one of claims 7 to 11.

13. A microsphere, A microsphere comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microsphere is 11.0% to 12.5% ​​and 90% of the cumulative pore volume of the internal void of the microsphere is 0.013 to 0.15 mL / g, and the microsphere providing a first aqueous solution comprising semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres.

14. Microspheres A microsphere comprising semaglutide and a pharmaceutically acceptable polymer, wherein the drug loading of the microsphere is 11.0% to 20.0% and 90% of the cumulative pore volume of the internal void of the microsphere is 0.013 to 0.20 mL / g, and the microsphere providing a first aqueous solution comprising semaglutide; providing an oily solution containing a pharmaceutically acceptable polymer; emulsifying the first aqueous solution and the oily solution to obtain a water-in-oil (W / O) emulsion; mixing the water-in-oil (W / O) emulsion with a second aqueous solution to obtain a water-in-oil-in-water (W / O / W) emulsion; removing the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion to obtain the microspheres.

15. The method according to claim 13 or 14, wherein the microspheres further comprise sucrose, and preferably the content of the sucrose is 1% to 3% by weight based on the weight of the microspheres.

16. The method according to any one of claims 13 to 15, wherein the pharmaceutically acceptable polymer is selected from poly(lactide-co-glycolide) (PLGA), and preferably, the content of poly(lactide-co-glycolide) (PLGA) is 75% to 85% by weight based on the weight of the microsphere.

17. The method according to any one of claims 13 to 16, wherein the pharmaceutically acceptable polymer is selected from poly(lactide-co-glycolide) (PLGA), and preferably, the content of poly(lactide-co-glycolide) (PLGA) is 80% to 85% by weight based on the weight of the microsphere.

18. 1. A method for treating diabetes, comprising:

20. A method comprising the step of administering to an individual in need thereof a therapeutically effective amount of the microspheres of any one of claims 1 to 6, 13 to 17.

19. 1. A method for weight loss comprising: A method comprising administering to an individual in need thereof a therapeutically effective amount of the microspheres of any one of claims 1 to 6 and 13 to 17.

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