Microspheres

Abstract

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

Description

microspheres

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the Chinese invention patent application with application number 202211138917.9, filed with the State Intellectual Property Office of the People's Republic of China on September 19, 2022, and entitled "Microspheres," and incorporates the entire contents thereof into this disclosure by reference.

[0003] field

[0004] The present disclosure generally relates to the field of biomedicine, and more particularly, to the field of pharmaceutical preparations.

[0005] background

[0006] Glucagon-like peptide-1 (GLP-1) is a hormone mainly produced by intestinal L cells and belongs to the incretin group.

[0007] Overview

[0008] In one 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 12.5%, and 90% of the cumulative pore volume of the internal voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0009] 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 voids of the microspheres is approximately 0.013 to 0.20 mL / g.

[0010] In another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, wherein the microspheres comprise 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 voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0011] In another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, wherein the microspheres comprise 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.

[0012] On the other hand, the present disclosure relates to a method for preparing microspheres, comprising: 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 from 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 voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0013] On the other hand, the present disclosure relates to a method for preparing microspheres, comprising: 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 from 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 voids of the microspheres is approximately 0.013 to 0.20 mL / g.

[0014] In another 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 from 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 voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0015] On the other hand, the present disclosure relates to microspheres prepared by a method comprising the following steps: 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 from 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 voids of the microspheres is approximately 0.013 to 0.20 mL / g.

[0016] In another aspect, the present disclosure relates to a method for treating diabetes, comprising administering a therapeutically effective amount of the microspheres described herein, the pharmaceutical composition described herein, or the microspheres prepared by the method described herein to an individual in need thereof.

[0017] In another aspect, the present disclosure relates to a method for reducing body weight, comprising administering an effective amount of the microspheres of the present disclosure, the pharmaceutical composition of the present disclosure, or the microspheres prepared by the method of the present disclosure to an individual in need thereof.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG1 shows the pore volume / pore size distribution curve of the microspheres of Example 1;

[0020] FIG2 shows the pore volume / pore size distribution curve of the microspheres of Example 2;

[0021] FIG3 shows the pore volume / pore size distribution curve of the microspheres of Example 3;

[0022] FIG4 shows the pore volume / pore size distribution curve of the microspheres of Example 4;

[0023] FIG5 shows the pore volume / pore size distribution curve of the microspheres of Example 5;

[0024] FIG6 shows the in vitro release curve of the microspheres of Example 1;

[0025] FIG7 shows the in vitro release curve of the microspheres of Example 2;

[0026] FIG8 shows the in vitro release curve of the microspheres of Example 3;

[0027] FIG9 shows the in vitro release curve of the microspheres of Example 4;

[0028] FIG10 shows the in vitro release curve of the microspheres of Example 5;

[0029] FIG11 shows the in vitro release curve of the microspheres of Example 6;

[0030] FIG12 shows the drug concentration-time curve of the microspheres of Example 1;

[0031] FIG13 shows the drug concentration-time curve of the microspheres of Example 2;

[0032] FIG14 shows the drug concentration-time curve of the microspheres of Example 3;

[0033] FIG15 shows the drug concentration-time curve of the microspheres of Example 4; and

[0034] FIG16 shows the drug concentration-time curve of the microspheres of Example 5.

[0035] Details

[0036] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can still be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0037] Unless otherwise required in this application, throughout the specification and the appended claims, the words "including," "comprising," "containing," and "having" should be interpreted in an open, inclusive sense, that is, "including but not limited to."

[0038] Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that at least one embodiment includes the specific referenced elements, structures, or features described in connection with that embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0039] definition

[0040] In this disclosure, the term "pore volume" refers to the volume of internal voids per unit mass of a porous solid.

[0041] In this disclosure, the term "cumulative pore volume" refers to the cumulative volume of internal voids per unit mass of a porous solid.

[0042] In this disclosure, the term "semaglutide", also known as semaglutide, refers to N ε26[(S)-(22,40-dicarboxylic acid-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetracon-1-yl)] [Aib 8 ,Arg 34 ]GLP-1-(7-37) peptide, the structural formula of which is shown below:

[0043] In this disclosure, the term "bioavailability" refers to the relative amount of a drug that reaches the blood circulation from the site of administration.

[0044] In this disclosure, the term "AUC inf ” refers to the area under the drug concentration-time curve of the preparation extrapolated to infinite time.

[0045] In the present disclosure, the term "drug loading" refers to the weight percentage of the drug contained in the microparticle preparation, that is, drug loading = weight of the drug contained in the microparticle preparation / total weight of the microparticle preparation × 100%.

[0046] In the present disclosure, the term "poly(lactide-co-glycolide) (PLGA)" is also known as poly(lactic acid-co-glycolide), which is formed by the condensation polymerization of two monomers, lactic acid and glycolic acid, or the ring-opening polymerization of lactide and glycolide. DETAILED DESCRIPTION

[0047] In one aspect, the present 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 voids of the microspheres is about 0.013 to 0.15 mL / g.

[0048] 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 voids of the microspheres is approximately 0.013 to 0.20 mL / g.

[0049] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.1%.

[0050] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.2%.

[0051] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.3%.

[0052] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.4%.

[0053] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.5%.

[0054] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.6%.

[0055] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.7%.

[0056] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.8%.

[0057] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.9%.

[0058] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.0%.

[0059] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.1%.

[0060] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.2%.

[0061] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.3%.

[0062] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.4%.

[0063] In certain 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%, 18.0%, 18.1%, 18. .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%.

[0064] 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%.

[0065] In certain embodiments, 90% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is between about 0.017 and 0.12 mL / g.

[0066] In certain embodiments, 90% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.014 to 0.19 mL / g, 0.015 to 0.18 mL / g, 0.016 to 0.17 mL / g, 0.017 to 0.18 mL / g, 0.017 to 0.17 mL / g, 0.017 to 0.16 mL / g, or 0.017 to 0.15 mL / g.

[0067] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.013 to 0.079 mL / g.

[0068] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.016 to 0.066 mL / g.

[0069] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.013 to 0.11 mL / g, 0.014 to 0.10 mL / g, 0.015 to 0.09 mL / g, or 0.016 to 0.08 mL / g.

[0070] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.009 to 0.016 mL / g.

[0071] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.011 to 0.014 mL / g.

[0072] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.011 to 0.022 mL / g, 0.011 to 0.021 mL / g, 0.011 to 0.020 mL / g, 0.011 to 0.019 mL / g, 0.011 to 0.018 mL / g, 0.011 to 0.017 mL / g, or 0.011 to 0.016 mL / g.

[0073] In certain embodiments, illustrative examples of pharmaceutically acceptable polymers that can be used in the present disclosure include, but are not limited to, poly(lactide-co-glycolide) (PLGA).

[0074] In certain embodiments, the poly(lactide-co-glycolide) (PLGA) content of the microspheres is about 80% to about 85% by weight based on the weight of the microspheres.

[0075] In certain embodiments, the poly(lactide-co-glycolide) (PLGA) content of the microspheres is about 75% to 85% by weight, 76% to 85% by weight, 77% to 85% by weight, or 78% to 85% by weight based on the weight of the microspheres.

[0076] In certain embodiments, the microspheres of the present disclosure may further contain sucrose.

[0077] In certain embodiments, the sucrose content of the microspheres is about 1% to about 3% by weight based on the weight of the microspheres.

[0078] In certain embodiments, the sucrose content of the microspheres is about 2% by weight based on the weight of the microspheres.

[0079] In certain embodiments, the microspheres of the present disclosure have improved bioavailability.

[0080] In certain embodiments, semaglutide is released from the microspheres of the present disclosure over a period of about 2 weeks or more.

[0081] In certain embodiments, semaglutide is sustained-released from the microspheres of the present disclosure.

[0082] In another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, wherein the microspheres comprise 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 voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0083] In another aspect, the present disclosure relates to a pharmaceutical composition comprising microspheres, wherein the microspheres comprise 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.

[0084] On the other hand, the present disclosure relates to a method for preparing microspheres, comprising: 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 from 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 voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0085] On the other hand, the present disclosure relates to a method for preparing microspheres, comprising: 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 from 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 voids of the microspheres is approximately 0.013 to 0.20 mL / g.

[0086] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.1%.

[0087] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.2%.

[0088] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.3%.

[0089] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.4%.

[0090] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.5%.

[0091] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.6%.

[0092] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.7%.

[0093] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.8%.

[0094] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.9%.

[0095] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.0%.

[0096] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.1%.

[0097] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.2%.

[0098] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.3%.

[0099] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.4%.

[0100] In certain 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%, 15.6%, 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 ... 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%.

[0101] 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%.

[0102] In certain embodiments, 90% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is between about 0.017 and 0.12 mL / g.

[0103] In certain embodiments, 90% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.014 to 0.19 mL / g, 0.015 to 0.18 mL / g, 0.016 to 0.17 mL / g, 0.017 to 0.18 mL / g, 0.017 to 0.17 mL / g, 0.017 to 0.16 mL / g, or 0.017 to 0.15 mL / g.

[0104] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.013 to 0.079 mL / g.

[0105] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.016 to 0.066 mL / g.

[0106] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.013 to 0.11 mL / g, 0.014 to 0.10 mL / g, 0.015 to 0.09 mL / g, or 0.016 to 0.08 mL / g.

[0107] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.009 to 0.016 mL / g.

[0108] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.011 to 0.014 mL / g.

[0109] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.011 to 0.022 mL / g, 0.011 to 0.021 mL / g, 0.011 to 0.020 mL / g, 0.011 to 0.019 mL / g, 0.011 to 0.018 mL / g, 0.011 to 0.017 mL / g, or 0.011 to 0.016 mL / g.

[0110] In certain embodiments, semaglutide and sucrose are dissolved in water to provide a first aqueous solution.

[0111] In certain embodiments, the pharmaceutically acceptable polymer is dissolved in an organic solvent to provide an oily solution.

[0112] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, dichloromethane, ethyl acetate, and acetone.

[0113] In certain embodiments, the first aqueous solution and the oily solution are emulsified by homogenization or ultrasound to obtain a water-in-oil (W / O) emulsion.

[0114] In certain embodiments, the emulsifier and osmotic pressure regulator are dissolved in water to provide a second aqueous solution.

[0115] In certain embodiments, illustrative examples of emulsifiers that can be used in the present disclosure include, but are not limited to, anionic surfactants and nonionic surfactants.

[0116] In certain embodiments, illustrative examples of anionic surfactants that can be used in the present disclosure include, but are not limited to, sodium oleate, sodium stearate, and sodium lauryl sulfate.

[0117] In certain embodiments, illustrative examples of nonionic surfactants that can be used in the present disclosure include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, and gelatin.

[0118] In certain embodiments, illustrative examples of polyoxyethylene sorbitan fatty acid esters that can be used in the present disclosure include, but are not limited to, Tween 80 and Tween 60.

[0119] In certain embodiments, illustrative examples of osmotic pressure regulating agents that can be used in the present disclosure include, but are not limited to, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, and proline.

[0120] In certain embodiments, polyvinyl alcohol and sodium chloride are dissolved in water to provide a second aqueous solution.

[0121] In certain embodiments, the water-in-oil (W / O) emulsion is mixed with the second aqueous solution using overhead stirring, a homogenizer, or a static mixer to obtain a water-in-oil-in-water (W / O / W) emulsion.

[0122] In certain embodiments, the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion is removed by purging the emulsion with a gas to obtain hardened microspheres.

[0123] In certain embodiments, illustrative examples of gases that can be used in the present disclosure include, but are not limited to, nitrogen, helium, compressed air, argon, and neon.

[0124] In certain embodiments, the solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion is removed by purging the emulsion with gas while stirring to obtain hardened microspheres.

[0125] In certain embodiments, illustrative examples of stirring means that can be used in the present disclosure include, but are not limited to, mechanical stirring and magnetic levitation stirring.

[0126] In certain embodiments, illustrative examples of mechanical agitation that can be used in the present disclosure include, but are not limited to, cantilevered stirring paddles.

[0127] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 100 to 200 nm.

[0128] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 110 to 200 nm.

[0129] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 120 to 200 nm.

[0130] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 130 to 200 nm.

[0131] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 140 to 200 nm.

[0132] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 150 to 200 nm.

[0133] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 160 to 200 nm.

[0134] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 170 to 200 nm.

[0135] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 180 to 200 nm.

[0136] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 190 to 200 nm.

[0137] In certain embodiments, the hardened microspheres are washed.

[0138] In certain embodiments, illustrative examples of wash solutions that can be used in the present disclosure include, but are not limited to, water for injection and purified water.

[0139] In certain embodiments, the washed microspheres are lyophilized to obtain lyophilized microsphere powder.

[0140] On the other hand, the present disclosure relates to microspheres prepared by a method comprising the following steps: 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 from 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 approximately 11.0% to 12.5%, and 90% of the cumulative pore volume of the internal voids of the microspheres is approximately 0.013 to 0.15 mL / g.

[0141] On the other hand, the present disclosure relates to microspheres prepared by a method comprising the following steps: 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 from 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 voids of the microspheres is about 0.013 to 0.20 mL / g.

[0142] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.1%.

[0143] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.2%.

[0144] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.3%.

[0145] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.4%.

[0146] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.5%.

[0147] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.6%.

[0148] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.7%.

[0149] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.8%.

[0150] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 11.9%.

[0151] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.0%.

[0152] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.1%.

[0153] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.2%.

[0154] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.3%.

[0155] In certain embodiments, the drug loading of the microspheres of the present disclosure is about 12.4%.

[0156] In certain 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%, 16. %, 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%.

[0157] 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%.

[0158] In certain embodiments, 90% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is between about 0.017 and 0.12 mL / g.

[0159] In certain embodiments, 90% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.014 to 0.19 mL / g, 0.015 to 0.18 mL / g, 0.016 to 0.17 mL / g, 0.017 to 0.18 mL / g, 0.017 to 0.17 mL / g, 0.017 to 0.16 mL / g, or 0.017 to 0.15 mL / g.

[0160] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.013 to 0.079 mL / g.

[0161] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.016 to 0.066 mL / g.

[0162] In certain embodiments, 50% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.013 to 0.11 mL / g, 0.014 to 0.10 mL / g, 0.015 to 0.09 mL / g, or 0.016 to 0.08 mL / g.

[0163] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.009 to 0.016 mL / g.

[0164] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.011 to 0.014 mL / g.

[0165] In certain embodiments, 10% of the cumulative pore volume of the interior voids of the microspheres of the present disclosure is about 0.011 to 0.022 mL / g, 0.011 to 0.021 mL / g, 0.011 to 0.020 mL / g, 0.011 to 0.019 mL / g, 0.011 to 0.018 mL / g, 0.011 to 0.017 mL / g, or 0.011 to 0.016 mL / g.

[0166] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 100 to 200 nm.

[0167] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 110 to 200 nm.

[0168] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 120 to 200 nm.

[0169] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 130 to 200 nm.

[0170] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 140 to 200 nm.

[0171] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 150 to 200 nm.

[0172] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 160 to 200 nm.

[0173] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 170 to 200 nm.

[0174] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 180 to 200 nm.

[0175] In certain embodiments, the particle size of the water-in-oil (W / O) emulsion is about 190 to 200 nm.

[0176] In certain embodiments, the microspheres disclosed herein have a higher encapsulation efficiency. Further, the encapsulation efficiency of the microspheres disclosed herein is higher than 80%, or even higher than 85%.

[0177] In certain embodiments, the microspheres of the present disclosure have improved bioavailability.

[0178] In certain embodiments, the microspheres of the present disclosure have improved AUC inf .

[0179] In certain embodiments, the microspheres disclosed herein have an ideal and acceptable low burst release, thereby facilitating the maintenance of a stable blood drug concentration in vivo after administration.

[0180] In certain embodiments, the disclosed microspheres can be administered to a subject in need thereof in a smaller amount and in a lower volume, while still maintaining excellent bioavailability. Furthermore, a smaller amount of microspheres administered and a lower volume can reduce local irritation and alleviate pain in patients.

[0181] In certain embodiments, semaglutide is released from the microspheres of the present disclosure over a period of about 2 weeks or more.

[0182] In certain embodiments, semaglutide is sustained-released from the microspheres of the present disclosure.

[0183] In another aspect, the present disclosure relates to a method for treating diabetes, comprising administering a therapeutically effective amount of the microspheres described herein, the pharmaceutical composition described herein, or the microspheres prepared by the method described herein to an individual in need thereof.

[0184] In certain embodiments, the microspheres described herein, the pharmaceutical compositions described herein, or the microspheres prepared by the methods described herein are administered to an individual at a frequency of 2 weeks or more.

[0185] In certain embodiments, the diabetes is type 2 diabetes.

[0186] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0187] In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, humans.

[0188] In another aspect, the present disclosure relates to a method for reducing body weight, comprising administering an effective amount of the microspheres of the present disclosure, the pharmaceutical composition of the present disclosure, or the microspheres prepared by the method of the present disclosure to an individual in need thereof.

[0189] In certain embodiments, the microspheres described herein, the pharmaceutical compositions described herein, or the microspheres prepared by the methods described herein are administered to an individual at a frequency of 2 weeks or more.

[0190] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0191] In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, humans.

[0192] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0193] Example

[0194] The reagents and equipment used in the examples of this disclosure are conventional and commercially available. For example:

[0195] Example 1

[0196] Preparation of semaglutide microspheres Note: * removed during preparation

[0197] Preparation steps:

[0198] 1. Dissolve a certain amount of semaglutide API and sucrose in water to obtain an inner aqueous phase (i.e., the first aqueous solution).

[0199] 2. Dissolve a certain amount of PLGA in dichloromethane to obtain an oil phase.

[0200] 3. Dissolve a certain amount of PVA and sodium chloride in water to obtain an external aqueous phase (i.e., the second aqueous solution).

[0201] 4. The inner water phase and the oil phase were emulsified by ultrasound to obtain a water-in-oil emulsion with a particle size of 160.6 nm.

[0202] 5. The water-in-oil emulsion obtained in step 4 is mixed homogeneously with a certain proportion of external water to obtain a water-in-oil-in-water system.

[0203] 6. Under mechanical stirring, nitrogen is blown on the surface of the water-in-oil-in-water system obtained in step 5 above to volatilize the dichloromethane dissolved in the external aqueous phase and harden the microspheres.

[0204] 7. Collect the hardened microspheres and wash them with purified water.

[0205] 8. Collect and freeze-dry the wet bulbs obtained in step 7 above.

[0206] 9. Collect the freeze-dried powder of microspheres obtained in step 8 and sieve to disperse it.

[0207] Example 2

[0208] Preparation of semaglutide microspheres Note: * removed during preparation

[0209] Preparation steps:

[0210] 1. Dissolve a certain amount of semaglutide API and sucrose in water to obtain an inner aqueous phase (i.e., the first aqueous solution).

[0211] 2. Dissolve a certain amount of PLGA in dichloromethane to obtain an oil phase.

[0212] 3. Dissolve a certain amount of PVA and sodium chloride in water to obtain an external aqueous phase (i.e., the second aqueous solution).

[0213] 4. The inner water phase and the oil phase were emulsified by ultrasound to obtain a water-in-oil emulsion with a particle size of 180.8 nm.

[0214] 5. The water-in-oil emulsion obtained in step 4 is mixed homogeneously with a certain proportion of external water to obtain a water-in-oil-in-water system.

[0215] 6. Under mechanical stirring, nitrogen is blown on the surface of the water-in-oil-in-water system obtained in step 5 above to volatilize the dichloromethane dissolved in the external aqueous phase and harden the microspheres.

[0216] 7. Collect the hardened microspheres and wash them with purified water.

[0217] 8. Collect and freeze-dry the wet bulbs obtained in step 7 above.

[0218] 9. Collect the freeze-dried powder of microspheres obtained in step 8 and sieve to disperse it.

[0219] Example 3

[0220] Preparation of semaglutide microspheres Note: * removed during preparation

[0221] Preparation steps:

[0222] 1. Dissolve a certain amount of semaglutide API and sucrose in water to obtain an inner aqueous phase (i.e., the first aqueous solution).

[0223] 2. Dissolve a certain amount of PLGA in dichloromethane to obtain an oil phase.

[0224] 3. Dissolve a certain amount of PVA and sodium chloride in water to obtain an external aqueous phase (i.e., the second aqueous solution).

[0225] 4. The inner water phase and the oil phase were emulsified by ultrasound to obtain a water-in-oil emulsion with a particle size of 269.3 nm.

[0226] 5. The water-in-oil emulsion obtained in step 4 is mixed homogeneously with a certain proportion of external water to obtain a water-in-oil-in-water system.

[0227] 6. Under mechanical stirring, nitrogen is blown on the surface of the water-in-oil-in-water system obtained in step 5 above to volatilize the dichloromethane dissolved in the external aqueous phase and harden the microspheres.

[0228] 7. Collect the hardened microspheres and wash them with purified water.

[0229] 8. Collect and freeze-dry the wet bulbs obtained in step 7 above.

[0230] 9. Collect the freeze-dried powder of microspheres obtained in step 8 and sieve to disperse it.

[0231] Example 4

[0232] Preparation of semaglutide microspheres Note: * removed during preparation

[0233] Preparation steps:

[0234] 1. Dissolve a certain amount of semaglutide API and sucrose in water to obtain an inner aqueous phase (i.e., the first aqueous solution).

[0235] 2. Dissolve a certain amount of PLGA in dichloromethane to obtain an oil phase.

[0236] 3. Dissolve a certain amount of PVA and sodium chloride in water to obtain an external aqueous phase (i.e., the second aqueous solution).

[0237] 4. The inner water phase and the oil phase were emulsified by ultrasound to obtain a water-in-oil emulsion with a particle size of 151.5 nm.

[0238] 5. The water-in-oil emulsion obtained in step 4 is mixed homogeneously with a certain proportion of external water to obtain a water-in-oil-in-water system.

[0239] 6. Under mechanical stirring, nitrogen is blown on the surface of the water-in-oil-in-water system obtained in step 5 above to volatilize the dichloromethane dissolved in the external aqueous phase and harden the microspheres.

[0240] 7. Collect the hardened microspheres and wash them with purified water.

[0241] 8. Collect and freeze-dry the wet bulbs obtained in step 7 above.

[0242] 9. Collect the freeze-dried powder of microspheres obtained in step 8 and sieve to disperse it.

[0243] Example 5

[0244] Preparation of semaglutide microspheres Note: * removed during preparation

[0245] Preparation steps:

[0246] 1. Dissolve a certain amount of semaglutide API and sucrose in water to obtain an inner aqueous phase (i.e., the first aqueous solution).

[0247] 2. Dissolve a certain amount of PLGA in dichloromethane to obtain an oil phase.

[0248] 3. Dissolve a certain amount of PVA and sodium chloride in water to obtain an external aqueous phase (i.e., the second aqueous solution).

[0249] 4. The inner water phase and the oil phase are emulsified by ultrasound to obtain a water-in-oil emulsion with a particle size of 175 nm.

[0250] 5. The water-in-oil emulsion obtained in step 4 is mixed homogeneously with a certain proportion of external water to obtain a water-in-oil-in-water system.

[0251] 6. Under mechanical stirring, air is blown over the surface of the water-in-oil-in-water system obtained in step 5 above to volatilize the dichloromethane dissolved in the external aqueous phase and harden the microspheres.

[0252] 7. Collect the hardened microspheres and wash them with purified water.

[0253] 8. Collect and freeze-dry the wet bulbs obtained in step 7 above.

[0254] 9. Collect the freeze-dried powder of microspheres obtained in step 8 and sieve to disperse it.

[0255] Example 6

[0256] Preparation of semaglutide microspheres Note: * removed during preparation

[0257] Preparation steps:

[0258] 1. Dissolve a certain amount of semaglutide API and sucrose in water to obtain an inner aqueous phase (i.e., the first aqueous solution).

[0259] 2. Dissolve a certain amount of PLGA in dichloromethane to obtain an oil phase.

[0260] 3. Dissolve a certain amount of PVA and sodium chloride in water to obtain an external aqueous phase (i.e., the second aqueous solution).

[0261] 4. The inner water phase and the oil phase were emulsified by ultrasound to obtain a water-in-oil emulsion with a particle size of 183.4 nm.

[0262] 5. The water-in-oil emulsion obtained in step 4 is mixed homogeneously with a certain proportion of external water to obtain a water-in-oil-in-water system.

[0263] 6. Under mechanical stirring, air is blown over the surface of the water-in-oil-in-water system obtained in step 5 above to volatilize the dichloromethane dissolved in the external aqueous phase and harden the microspheres.

[0264] 7. Collect the hardened microspheres and wash them with purified water.

[0265] 8. Collect and freeze-dry the wet bulbs obtained in step 7 above.

[0266] 9. Collect the freeze-dried powder of microspheres obtained in step 8 and sieve to disperse it.

[0267] Example 7

[0268] Determination of the release rate of semaglutide microspheres

[0269] Sample to be tested:

[0270] Semaglutide microspheres prepared in Examples 1 to 6;

[0271] Three parallel samples were set up for each sample.

[0272] The release experiment was conducted using an economical precision high-temperature constant-temperature liquid bath XT5018P-GP18 and a Waters high-performance liquid chromatograph.

[0273] Release medium preparation

[0274] Take 34.06±0.01g of Tris (base), 2.97±0.01g of Tris (HCl), 5±0.1g of poloxamer (188), and 1.00±0.01g of sodium azide and place them in a suitable container. Add 1L of purified water and stir to dissolve. Adjust the pH to 9.40±0.03 with 0.1mol / L sodium hydroxide, and then filter through a high-temperature sterilized capsule filter (BP milpak 20, PVDF, 0.22μm).

[0275] Take approximately 50 mg of semaglutide microspheres, accurately weigh them, and place them in a 50 mL blue-capped bottle. Add 20 mL of release medium, shake to suspend the microspheres, and then place them in a constant temperature (37°C ± 0.3°C) water bath. After standing for 1 day, 3 days, 7 days, 10 days, 14 days, 17 days, 21 days, 24 days, 28 days, 31 days, 35 days, and 42 days, remove the samples. Use a microsampler to take 1 mL of the supernatant (add an equal amount of preheated fresh medium after sampling) and centrifuge it in a 2 mL centrifuge tube (5000 rpm, 10 minutes). After centrifugation, take an appropriate amount of supernatant. Prepare 3 copies in parallel.

[0276] Chromatographic conditions:

[0277] Chromatographic column: Waters CSH C18 3.5μm, 4.6×150mm

[0278] Column temperature: 45°C

[0279] Mobile phase: 0.05 mol / L ammonium dihydrogen phosphate (pH 9.50)-acetonitrile (2:1)

[0280] Flow rate: 1.0 mL / min

[0281] Detection wavelength: 215nm

[0282] Sample tray temperature: 10°C

[0283] Injection volume: 10 μL

[0284] Elution method: isocratic elution

[0285] Run time: 10 minutes

[0286] The release rates of the microspheres of Examples 1 to 6 of the present disclosure are shown in Tables 1 to 6.

[0287] Table 1. Note: d is day

[0288] Table 2. Note: d is day

[0289] Table 3. Note: d is day

[0290] Table 4. Note: d is day

[0291] Table 5. Note: d is day

[0292] Table 6. Note: d is day

[0293] 6 to 11 show the release curves of the microspheres of Examples 1 to 6 of the present disclosure.

[0294] Example 8

[0295] Determination of drug loading of semaglutide microspheres

[0296] Sample to be tested:

[0297] Semaglutide microspheres prepared in Examples 1 to 6;

[0298] Three parallel samples were set up for each sample.

[0299] Detection method:

[0300] 1. Dissolve the PLGA in the microspheres with acetonitrile to release semaglutide. Then add phosphate buffer to dissolve the semaglutide and precipitate most of the PLGA. Finally, centrifuge to remove the PLGA.

[0301] 2. Detect the content of semaglutide by HPLC.

[0302] Example 9

[0303] Determination of pore size distribution of microspheres

[0304] About 200 mg of semaglutide microspheres were weighed in a dilatometer, sealed, and weighed to obtain the weight of the dilatometer assembly. The dilatometer assembly was then put on a machine for low-pressure and high-pressure tests, with the pressure increasing from 0.50 psia to 60,000 psia.

[0305] Test sample: Semaglutide microspheres prepared in Examples 1 to 5.

[0306] The pore volume and pore size distribution of the sample were calculated from the mercury intrusion curve obtained using the Washburn equation.

[0307] 1 to 5 show the pore volume / pore size distribution curves of the microspheres of Examples 1 to 5 of the present disclosure.

[0308] Example 10

[0309] In vivo pk of semaglutide microspheres in rats

[0310] Healthy SD rats aged 7 to 8 weeks were selected as research subjects, with a body weight of 200 to 250 g, and the drug was administered by subcutaneous injection at the back of the neck. The dosage was 18 mg / kg, and about 0.2 mL of blood was collected from the jugular vein at a specific time after administration. After blood collection, the blood collection tube containing the anticoagulant (K2EDTA) was repeatedly inverted several times to fully mix it. Centrifuge to obtain a plasma sample. The LC-MS / MS method was used to determine the blood concentration (ng / mL) of semaglutide in the plasma sample at each time point, and the drug concentration-time curves of the microspheres of Examples 1 to 5 were drawn, and the AUC of the microspheres of Examples 1 to 5 were calculated. inf .

[0311] 11 to 15 show the drug concentration-time curves of the microspheres of Examples 1 to 5 of the present disclosure.

[0312] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0313] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. 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 voids of the microspheres is 0.013 to 0.15 mL / g.

2. 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 0.013 to 0.20 mL / g.

3. The microspheres according to claim 1 or 2, further comprising sucrose, preferably in an amount of 1% to 3% by weight based on the weight of the microspheres.

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

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

6. A pharmaceutical composition comprising the microspheres according to 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; and removing the solvent from 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; and removing the solvent from 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. The method according to claim 7 or 8, wherein the microspheres further comprise sucrose, preferably in an amount of 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), preferably, the content of poly(lactide-co-glycolide) (PLGA) is 75% to 85% by weight based on the weight of the microspheres.

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), preferably, the content of poly(lactide-co-glycolide) (PLGA) is 80% to 85% by weight based on the weight of the microspheres.

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

13. 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 voids of the microspheres is 0.013 to 0.15 mL / g, wherein the microspheres are prepared by a method comprising the following steps: 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; and The solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion is removed to obtain the microspheres.

14. 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 0.013 to 0.20 mL / g, wherein the microspheres are prepared by a method comprising the following steps: 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; and The solvent in the oil phase of the water-in-oil-in-water (W / O / W) emulsion is removed to obtain the microspheres.

15. The method according to claim 13 or 14, wherein the microspheres further comprise sucrose, preferably in an amount of 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), preferably, the content of poly(lactide-co-glycolide) (PLGA) is 75% to 85% by weight based on the weight of the microspheres.

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), preferably, the content of poly(lactide-co-glycolide) (PLGA) is 80% to 85% by weight based on the weight of the microspheres.

18. A method for treating diabetes comprising administering a therapeutically effective amount of the microspheres of any one of claims 1 to 6 and 13 to 17 to a subject in need thereof.

19. A method for reducing body weight comprising administering to a subject in need thereof a therapeutically effective amount of the microspheres of any one of claims 1 to 6, 13 to 17.

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