Microsphere-based injectable semaglutide formulation

Abstract

This invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 μm to 500 μm; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, releases semaglutide for at least four weeks. This invention also provides related microsphere compositions, injectable formulations, therapeutic methods, and articles of manufacture.

Description

[0001] Dkt. Avidence-8PCT MICROSPHERE-BASED INJECTABLE SEMAGLUTIDE FORMULATION This application claims the benefit of U.S. Provisional Application No.63 / 655,697, filed June 4, 2024, and U.S. Provisional Application No.63 / 704,614, filed October 8, 2024, the contents of both of which are incorporated herein by reference. Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Field of the Invention The present invention relates to methods for treating glucacon-like-peptide-1-receptor (GLP-1R)-related disorders via injection of semaglutide-containing biodegradable microspheres. Background of the Invention GLP-1 Receptor Agonists Type 2 diabetes is a disorder characterized by high blood glucose levels. Despite advances in the treatment of type 2 diabetes, optimal glycemic control is often not achieved. Glucagon-like peptide-1 (GLP-1) is a natural peptide of 30 amino acid residues secreted by intestinal cells after meals. It stimulates glucose-dependent insulin release and suppresses postprandial glucagon secretion. To mimic the biological function of GLP-1, GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, were developed for glycemic control in type 2 diabetes, risk reduction of major adverse cardiovascular events, weight loss, management of obesity-related indications (e.g., metabolic dysfunction-associated steatohepatitis, obstructive sleep apnea, osteoarthritis, chronic kidney disease, heart failure, and alcoholic fatty liver disease), treatment of neurodegenerative disorders (e.g., Alzheimer’s disease), and treatment of addictive disorders (e.g., alcohol use disorder, substance use disorder). Semaglutide (commercially known as Wegovy®and Ozempic®) and tirzepatide (commercially known as Mounjaro®and Zepbound®) are administered as once weekly subcutaneous injections. For chronic conditions such as diabetes and obesity, a lower injection frequency is associated with higher patient compliance and better disease control. To achieve sustained release of peptide drugs such as semaglutide and tirzepatide in a long-acting injectable formulation, encapsulation by biodegradable polymers is typically used. PLGA Microspheres Generally An important biodegradable material commonly used for extended-release drug delivery is polylactic co-glycolic acid copolymer (PLGA). PLGA is made of polylactic acid (PLA) units, polyglycolic acid (PGA) units, and typically both. As an FDA-approved polymer, it has been extensively investigated in many medical and pharmaceutical fields due to its biodegradability and biocompatibility. PLGA-containing microspheres have shown sustained release characteristics due to degradation and diffusion mechanisms. The drug release profile of a PLGA microsphere preparation is dependent on certain factors, such as the specific properties of the drug, the ratio of PLA to PGA, the type of end cap of the polymer (i.e., ester or acid), the molecular weight and inherent viscosity of the polymer, the loading ratio of drug to the polymer, and the size of the microspheres. Known Challenge of PLGA Microspheres One major challenge for developing PLGA microspheres is achieving a high drug loading ratio that reduces the total injection burden to the patient. A microsphere drug with high drug loading is associated with fewer injection site reactions and less injection site pain. As discussed by Park et al., 2019, “[t]he important properties of microparticles for clinical applications…include…high drug loading….” However, “[t]he obstacles hindering more widespread use of PLGA for producing sustained-release formulations for clinical use include low drug loading…” (Han et al., 2016). In particular, PLGA microspheres with encapsulated peptide drugs especially suffer from this problem of low drug loading. For example, Bydureon BCise has about 5% drug loading (calculated from the FDA label of Bydureon BCise). One-Month Lupron Depot has an 8.3% drug loading (Zhou et al., 2018). Sandostatin LAR has about 5% drug loading (Song et al., 2022), and Trelstar has drug loading in the range of 2.65%- 10.95% (calculated from the FDA label of Trelstar). Increasing drug loading in PLGA microspheres is highly challenging. As discussed by Park et al.2019, “[t]he interactions among drug, PLGA, and solvent affect the microparticle properties in unpredictable ways, as their impacts are not linear… Due to each drug’s unique physicochemical properties, each drug formulation requires an ideal combination of PLGA type, solvent type, and microparticle formation conditions.” Thus, to increase drug loading in PLGA microspheres requires repeated experimentation, especially for peptide drugs such as semaglutide and tirzepatide. Prior Art Pertaining to Semaglutide-Loaded PLGA Microspheres U.S. Patent No.11,865,213 discloses long-acting microparticles comprising semaglutide or a pharmaceutically acceptable salt and a biodegradable carrier at a ratio of about 1:10 to about 1:15 (w / w), which were made from a water-in-oil-in-water (w / o / w) double emulsion method. This range equates to a semaglutide loading of 6.25% to 9.09%. Published examples include PLGA microspheres containing semaglutide sodium salt and free base. International Publication No. WO 2024 / 010379 discloses sustained-release microspheres consisting of semaglutide or a pharmaceutically acceptable salt, a bioavailability improver, and a biodegradable polymer, in which the bioavailability- improving agent is contained in an amount of 2.5% to 250% by weight based on the weight of semaglutide. Published examples include microspheres containing PLGA semaglutide sodium salt and free base. U.S. Publication No. US 2023 / 0096928 discloses sustained-release microspheres consisting of semaglutide or a pharmaceutically acceptable salt and a biodegradable polymer, wherein the semaglutide or pharmaceutically acceptable salt is 3% by weight or more. Published examples include PLGA microspheres containing semaglutide sodium salt, pamoate salt, and free base. The example with the highest semaglutide loading was 13.7% (semaglutide pamoate salt encapsulated in a PLGA microsphere). International Publication No. WO 2022 / 270956 claims a sustained-release microsphere formulation wherein the semaglutide or the pharmaceutically acceptable salt is included in an amount of 3% by weight or more and less than 9% by weight of the sustained release microsphere. Published examples include PLGA microspheres containing semaglutide sodium salt and free base. The example with the highest semaglutide loading was 15%, but this formulation released 90.4% of the semaglutide within one day. There remains a need for an injectable formulation of semaglutide microspheres that are long-lasting and that have a high loading ratio. Summary of the Invention This invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 μm to 500 μm; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, releases semaglutide for at least four weeks. This invention also provides a plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. This invention further provides an injectable formulation comprising (a) a pharmaceutically acceptable carrier and (b) a plurality of biodegradable microspheres wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. This invention still further provides a method for treating a subject afflicted with a GLP- 1R-related disorder comprising administering biodegradable microspheres to the subject, wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. Finally, this invention provides an article of manufacture (kit) comprising, in separate compartments, (a) (i) a diluent and (ii) optionally, a label instructing the user to administer the biodegradable microspheres subcutaneously or intramuscularly and (b) a plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 μm and a d90 value of 500 μm or less; (ii) comprise a polylactic-co- glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. Brief Description of the Figures Figure 1 This figure shows a mixer (Model L5MA, Silverson, Massachusetts, US) with an in-line mixing chamber and general-purpose disintegrating head that was used to continuously create oil-in-water emulsions and generate microspheres. Detailed Description of the Invention This invention provides semaglutide-containing biodegradable microspheres and methods for using them to treat GLP-1R-related disorders. Definitions In this application, certain terms are used which shall have the meanings set forth as follows. As used herein, “administering”, with respect to biodegradable microspheres, means delivering to a specified part of the body, such as subcutaneous tissue (e.g., in the abdomen, thigh, or upper arm) or intramuscular tissue (e.g., in the deltoid or buttocks). Methods of administering biodegradable microspheres to subcutaneous tissue are known and include, for example, injection with an auto-injector. See, e.g., the Bydureon BCise®label. As used herein, a “biodegradable microsphere” comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix, which matrix can include solely polylactic acid (PLA), solely polyglycolic acid (PGA), or a polymeric combination of lactic acid and glycolic acid units. In general, for certain lactic acid to glycolic acid ratios (e.g., 50:50 to 100:0), the higher a microsphere’s lactic acid content, the slower it degrades and, thus, the more stable it is. Conversely, for such ratios, the higher a microsphere’s glycolic acid content, the faster it degrades and the less stable it is. In one embodiment, the biodegradable microsphere contains a combination of lactic acid and glycolic acid units wherein the molar ratio of lactic acid to glycolic acid units (i.e., the “lactic acid to glycolic acid ratio”, or “L:G ratio”) is 0:100, 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 46:54, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 60:40, 61:39, 62:38, 63:37, 64:46, 65:35, 66:34, 67:33, 68:32, 69:31, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 85:15, 90:10, 95:5, or 100:0. In another embodiment, the biodegradable microsphere contains a combination of lactic acid and glycolic acid units wherein the molar ratio of lactic acid to glycolic acid is from 5:95 to 20:80, from 20:80 to 40:60, from 40:60 to 50:50, from 40:60 to 60:40, from 50:50 to 60:40, from 60:40 to 70:30, from 70:30 to 80:20, from 80:20 to 90:10, from 90:10 to 100:0, from 50:50 to 70:30, from 60:40 to 80:20, from 70:30 to 90:10, from 80:20 to 100:0, from 40:60 to 70:30, from 50:50 to 80:20, from 60:40 tom 90:10, from 70:30 to 100:0, from 40:60 to 80:20, from 50:50 to 90:10, from 60:40 to 100:0, from 50:50 to 100:0, from 45:55 to 55:45, from 45:55 to 65:35, from 45:55 to 75:25, from 45:55 to 85:15, from 45:55 to 95:5, from 55:45 to 65:35, from 55:45 to 75:25, from 55:45 to 85:15, from 55:45 to 95:5, from 65:35 to 75:25, from 65:35 to 85:15, from 65:35 to 95:5, from 75:25 to 85:15, from 75:25 to 95:5, from 85:15 to 95:5, from 47:53 to 53:47, from 63:37 to 67:33, from 73:27 to 77:23, from 47:53 to 77:23, from 47:53 to 67:33, or from 63:37 to 77:23. The population of biodegradable microspheres used in this invention can be homogeneous or heterogeneous with respect to the microspheres’ molar ratio of lactic acid to glycolic acid. In one embodiment, the population of biodegradable microspheres is homogeneous with respect to the microspheres’ molar ratio of lactic acid to glycolic acid (e.g., the population includes only microspheres wherein the molar ratio of lactic acid to glycolic acid is 50:50 or 65:35). In another embodiment, the population of biodegradable microspheres is heterogeneous (e.g., the population includes both (i) microspheres wherein the molar ratio of lactic acid to glycolic acid is 65:35, and (ii) microspheres wherein the molar ratio of lactic acid to glycolic acid is 75:25). In a preferred embodiment, the instant microspheres contain PLGA having an inherent viscosity of 0.1 to 2.4 dl / g (e.g., 0.16 to 1.7 dl / g), and a molecular weight from 1,000 to 600,000 (e.g., from 7,000 to 240,000). In one embodiment, the biodegradable microsphere has a viscosity of 0.1 dl / g, 0.2 dl / g, 0.3 dl / g, 0.4 dl / g, 0.5 dl / g, 0.6 dl / g, 0.7 dl / g, 0.8 dl / g, 0.9 dl / g, 1.0 dl / g, 1.1 dl / g, 1.2 dl / g, 1.3 dl / g, 1.4 dl / g, 1.5 dl / g, 1.6 dl / g, 1.7 dl / g, 1.8 dl / g, 1.9 dl / g, 2.0 dl / g, 2.1 dl / g, 2.2 dl / g, 2.3 dl / g, or 2.4 dl / g. In another embodiment, the biodegradable microsphere has a viscosity of from 0.1 dl / g to 0.2 dl / g, from 0.2 dl / g to 0.3 dl / g, from 0.3 dl / g to 0.4 dl / g, from 0.4 dl / g to 0.5 dl / g, from 0.5 dl / g to 0.6 dl / g, from 0.6 dl / g to 0.7 dl / g, from 0.7 dl / g to 0.8 dl / g, from 0.8 dl / g to 0.9 dl / g, from 0.9 dl / g to 1.0 dl / g, from 1.0 dl / g to 1.1 dl / g, from 1.1 dl / g to 1.2 dl / g, from 1.2 dl / g to 1.3 dl / g, from 1.3 dl / g to 1.4 dl / g, from 1.4 dl / g to 1.5 dl / g, from 1.5 dl / g to 1.6 dl / g, from 1.6 dl / g to 1.7 dl / g, from 1.7 dl / g to 1.8 dl / g, from 1.8 dl / g to 1.9 dl / g, from 1.9 dl / g to 2.0 dl / g, from 2.0 dl / g to 2.1 dl / g, from 2.1 dl / g to 2.2 dl / g, from 2.2 dl / g to 2.3 dl / g, or from 2.3 dl / g to 2.4 dl / g. In a further embodiment, the biodegradable microsphere has a viscosity of from 0.1 dl / g to 0.6 dl / g, from 0.2 dl / g to 0.6 dl / g, from 0.3 dl / g to 0.6 dl / g, from 0.6 dl / g to 1.0 dl / g, from 1.0 dl / g to 1.5 dl / g, from 1.5 dl / g to 2.0 dl / g, or from 2.0 dl / g to 2.4 dl / g. The inherent viscosity of PLGA used in the present invention is measured at a concentration of 0.1% (w / v) in chloroform at 25°C using an Ubbelohde viscometer. Preferred embodiments of the present microspheres are (i) PLGA with L:G ratio from 47:53 to 53:47, viscosity of 0.3- 0.6 dl / g, acid-terminated; (ii) PLGA with L:G ratio from 63:37 to 67:33, viscosity of 0.3- 0.5 dl / g, acid-terminated; and (iii) PLGA with L:G ratio from 73:27 to 77:23, viscosity 0.3-0.5 dl / g, acid-terminated. In a further embodiment, the drug loading ratio for the present biodegradable microsphere is (i) 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, 50%, 50.5%, 51%, 51.5%, 52%, 52.5%, 53%, 53.5%, 54%, 54.5%, 55%, 55.5%, 56%, 56.5%, 57%, 57.5%, 58%, 58.5%, 59%, 59.5%, or 60%; (ii) from 14% to 14.5%, from 14.5% to 15%, from 15% to 15.5%, from 15.5% to 16%, from 16% to 16.5%, from 16.5% to 17%, from 17% to 17.5%, from 17.5% to 18%, from 18% to 18.5%, from 18.5% to 19%, from 19% to 19.5%, from 19.5% to 20%, from 20% to 20.5%, from 20.5% to 21%, from 21% to 21.5%, from 21.5% to 22%, from 22% to 22.5%, from 22.5% to 23%, from 23% to 23.5%, from 23.5% to 24%, from 24% to 24.5%, from 24.5% to 25%, from 25% to 25.5%, from 25.5% to 26%, from 26% to 26.5%, from 26.5% to 27%, from 27% to 27.5%, from 27.5% to 28%, from 28% to 28.5%, from 28.5% to 29%, from 29% to 29.5%, from 29.5% to 30%, from 30% to 30.5%, from 30.5% to 31%, from 31% to 31.5%, from 31.5% to 32%, from 32% to 32.5%, from 32.5% to 33%, from 33% to 33.5%, from 33.5% to 34%, from 34% to 34.5%, from 34.5% to 35%, from 35% to 35.5%, from 35.5% to 36%, from 36% to 36.5%, from 36.5% to 37%, from 37% to 37.5%, from 37.5% to 38%, from 38% to 38.5%, from 38.5% to 39%, from 39% to 39.5%, from 39.5% to 40%, from 40% to 40.5%, from 40.5% to 41%, from 41% to 41.5%, from 41.5% to 42%, from 42% to 42.5%, from 42.5% to 43%, from 43% to 43.5%, from 43.5% to 44%, from 44% to 44.5%, from 44.5% to 45%, from 45% to 45.5%, from 45.5% to 46%, from 46% to 46.5%, from 46.5% to 47%, from 47% to 47.5%, from 47.5% to 48%, from 48% to 48.5%, from 48.5% to 49%, from 49% to 49.5%, from 49.5% to 50%, from 50% to 50.5%, from 50.5% to 51%, from 51% to 51.5%, from 51.5% to 52%, from 52% to 52.5%, from 52.5% to 53%, from 53% to 53.5%, from 53.5% to 54%, from 54% to 54.5%, from 54.5% to 55%, from 55% to 55.5%, from 55.5% to 56%, from 56% to 56.5%, from 56.5% to 57%, from 57% to 57.5%, from 57.5% to 58%, from 58% to 58.5%, from 58.5% to 59%, from 59% to 59.5%, or from 59.5% to 60%; (iii) from 14% to 15%, from 15% to 16%, from 16% to 17%, from 17% to 18%, from 18% to 19%, from 19% to 20%, from 20% to 21%, from 21% to 22%, from 22% to 23%, from 23% to 24%, from 24% to 25%, from 25% to 26%, from 26% to 27%, from 27% to 28%, from 28% to 29%, from 29% to 30%, from 30% to 31%, from 31% to 32%, from 32% to 33%, from 33% to 34%, from 34% to 35%, from 35% to 36%, from 36% to 37%, from 37% to 38%, from 38% to 39%, from 39% to 40%, from 40% to 41%, from 41% to 42%, from 42% to 43%, from 43% to 44%, from 44% to 45%, from 45% to 46%, from 46% to 47%, from 47% to 48%, from 48% to 49%, from 49% to 50%, from 50% to 51%, from 51% to 52%, from 52% to 53%, from 53% to 54%, from 54% to 55%, from 55% to 56%, from 56% to 57%, from 57% to 58%, from 58% to 59%, or from 59% to 60%; (iv) from 14% to 16%, from 16% to 18%, from 18% to 20%, from 20% to 22%, from 22% to 24%, from 24% to 26%, from 26% to 28%, from 28% to 30%, from 30% to 32%, from 32% to 34%, from 34% to 36%, from 36% to 38%, from 38% to 40%, from 40% to 42%, from 42% to 44%, from 44% to 46%, from 46% to 48%, from 48% to 50%, from 50% to 52%, from 52% to 54%, from 54% to 56%, from 56% to 58%, or from 58% to 60%; or (v) from 14% to 20%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, from 45% to 50%, from 50% to 55%, from 55% to 60%, from 15% to 25%, from 15% to 30%, from 15% to 35%, from 15% to 40%, from 15% to 45%, from 15% to 50%, from 15% to 55%, from 15% to 60%, from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from 20% to 60%, from 25% to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 25% to 55%, from 25% to 60%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 55%, from 45% to 60%, or from 50% to 60%. The subject biodegradable microsphere (i) has a diameter from 1 μm to 500 μm, (ii) can carry a therapeutic agent (e.g., semaglutide), and (iii) depending on its polymeric composition, degrades over a period lasting, for example, from four weeks to over six months when placed subcutaneously or intramuscularly. Microsphere diameters, set forth as ranges from d10 to d90 (as defined herein), include, for example, the following: from 1 μm to 20 μm, from 20 μm to 40 μm, from 40 μm to 60 μm, from 60 μm to 80 μm, from 80 μm to 100 μm, from 100 μm to 120 μm, from 120 μm to 140 μm, from 140 μm to 160 μm, from 160 μm to 180 μm, from 180 μm to 200 μm, from 200 μm to 250 μm, from 250 μm to 300 μm, from 300 μm to 350 μm, from 350 μm to 400 μm, from 400 μm to 450 μm, and from 450 μm to 500 μm. Microsphere diameters also include, for example, the following: 20 μm, 40 μm, 60 μm, 80 μm, 100 μm, 120 μm, 140 μm, 160 μm, 180 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, and 500 μm. Microsphere diameters, set forth as ranges from d10 to d90 (as defined herein), also include, for example, the following: from 20 μm to 100 μm, from 20 μm to 150 μm, from 50 μm to 100 μm, and from 50 μm to 150 μm. In a further embodiment, the d10 values for the present microsphere diameters include the following: (i) 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, and 40 μm; (ii) from 5 μm to 10 μm, from 10 μm to 15 μm, from 15 μm to 20 μm, from 20 μm to 25 μm, from 25 μm to 30 μm, from 30 μm to 35 μm, and from 35 μm to 40 μm; (iii) from 5 μm to 15 μm, from 15 μm to 25 μm, and from 25 μm to 35 μm; and (iv) from 5 μm to 25 μm, from 25 μm to 40 μm, and from 5 μm to 40 μm. In a further embodiment, the d90 values for the present microsphere diameters include the following: (i) 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, and 120 μm; (ii) from 20 μm to 30 μm, from 30 μm to 40 μm, from 40 μm to 50 μm, from 50 μm to 60 μm, from 60 μm to 70 μm, from 70 μm to 80 μm, from 80 μm to 90 μm, from 90 μm to 100 μm, from 100 μm to 110 μm, and from 110 μm to 120 μm; (iii) from 20 μm to 40 μm, from 40 μm to 60 μm, from 60 μm to 80 μm, from 80 μm to 100 μm, or from 100 μm to 120 μm; and (iv) from 20 μm to 60 μm, from 60 μm to 100 μm, and from 20 μm to 120 μm. The subject biodegradable microspheres can further comprise polyethylene glycol (PEG). Biodegradable PLGA microspheres (including homogeneous and heterogeneous populations thereof having defined molar ratios of lactic acid to glycolic acid units) are commercially available from, among other sources, Millipore-Sigma in the form of Degradex®products (Burlington, MA) and Evonik Industries in the form of Resomer®products (Essen, Germany). The subject biodegradable microspheres can be prepared by an “oil-in-water” single emulsion process, which consists of (a) preparing an “oil phase” by dispersing or dissolving semaglutide or a pharmaceutically acceptable salt and biocompatible polymers (e.g., PLGA) in one or more organic solvents (e.g., dichloromethane, DMSO, or acetic acid); (b) adding the “oil phase” into a aqueous solution containing surfactants (e.g., polyvinyl alcohol); (c) emulsification by mixing, stirring, or sonication; and (d) drying to remove the organic solvents and aqueous solvents. Alternatively, the subject biodegradable microspheres can be prepared by a “water-in- oil-in-water” double emulsion process, which consists of (a) preparing an aqueous dispersion or solution containing semaglutide or a pharmaceutically acceptable salt; (b) adding the aqueous phase into an organic solution containing biocompatible polymers (e.g., dichloromethane solution containing PLGA); (c) primary emulsification by mixing, stirring, or sonication; (d) Adding this emulsion into another aqueous solution containing surfactants (e.g., polyvinyl alcohol); (e) secondary emulsification by mixing, stirring, or sonication; and (f) drying to remove the organic solvents and aqueous solvents. As used herein, the term “carry”, with respect to pharmaceutical semaglutide and a biodegradable microsphere, means that the pharmaceutical semaglutide is bound to, or otherwise contained in or on, the biodegradable microsphere in a manner permitting release from the microsphere during its biodegradation. As used herein, the phrase “causing weight loss” in a subject includes, without limitation, (i) causing a loss of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, or at least 60% of the subject’s body weight; (ii) causing a loss of from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 50%, or from 50% to 60% of the subject’s body weight; and (iii) causing a loss of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55% or 60% of the subject’s body weight. Preferably, weight loss as exemplified above is measured over a time period of from one to six months (e.g., after one month, after two months, after three months, after four months, after five months, or after six months). In a further embodiment of this invention, the subject method, rather than causing weight loss, either stops weight gain or reduces its rate (e.g., by limiting weight gain over the above time period to below 1%, 2%, 3%, 4% or 5% of the subject’s body weight). As used herein, the term “diluent” includes, without limitation, sodium chloride, carboxymethylcellulose sodium, polysorbate 80, mannitol (which can optionally be incorporated on and / or into the microspheres to improve suspendability), water, and medium chain fatty acids. As used herein, the term “d90value”, with respect to the present microspheres, means the 90thpercentile diameter in the microsphere population on a volume-weighted basis. The term “d50 value” means the 50thpercentile diameter in the microsphere population on a volume-weighted basis. The term “d10value” means the 10thpercentile diameter in the microsphere population on a volume-weighted basis. A “GLP-1R-related disorder” includes, without limitation, obesity, diabetes (e.g., type 1 diabetes and type 2 diabetes), poor glycemic control (e.g., in type 2 diabetes), cardiovascular disease, heart failure, metabolic associated steatohepatitis, obstructive sleep apnea, osteoarthritis, chronic kidney disease, alcoholic fatty liver disease, neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lou Gehrig’s disease, Creutzfeldt-Jakob disease, stroke, and multiple sclerosis) and addictive disorders (e.g., alcohol use disorder, substance use disorder). As used herein, the term “pharmaceutical semaglutide” includes, without limitation, semaglutide free base, semaglutide acetate salt, and other pharmaceutical salts and esters of semaglutide. Among the pharmaceutically acceptable salts of semaglutide, acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, genticinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, 2-hydroxyethanesulfonate, isethionate, nicotinate, 2- naphthalenesulfonate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, thiocyanate, glutamate, or bicarbonate of semaglutide. Among the pharmaceutically acceptable salts of semaglutide, base addition salts include, for example, alkali metal salts, alkaline earth metal salts, and quaternary ammonium salts of semaglutide. “Pharmaceutically acceptable carriers” are well known and include, without limitation, the diluents described herein. As used herein, a biodegradable microsphere “releases” semaglutide when some or all of the semaglutide contained by the microsphere is freed into the microsphere’s surrounding milieu. In one embodiment, the semaglutide release profile of the present plurality of semaglutide-containing microspheres includes an extended period of semaglutide release, which extended period is preferably continuous. In another embodiment, the semaglutide release profile of the present plurality of semaglutide- containing microspheres includes an initial semaglutide “burst release” period followed by an extended period of semaglutide release, which extended period is preferably continuous. By way of example, in one scenario, the semaglutide release profile includes a five-day “burst release” period followed by a three-month continuous semaglutide release period. In another scenario, the semaglutide release profile includes only a three-month continuous semaglutide release period. With respect to the subject plurality of biodegradable microspheres, the term “burst release” means the portion (e.g., 10%) of semaglutide released from the microspheres into a surrounding milieu (e.g., PBS solution or subcutaneous environment in an animal or a human) within the first several days after the microspheres are introduced into this milieu. In one embodiment, burst release means the portion of semaglutide released from the microspheres into a surrounding milieu within the first one, two, three, four, five, six, or seven days after the microspheres are introduced into this milieu. In vitro, burst release can be measured, for example, by the amount of semaglutide released and dissolved in the surrounding medium during a period of time divided by the total amount of encapsulated semaglutide in the microspheres, or, alternatively, by the difference in amount of encapsulated semaglutide in the microspheres at the beginning versus at the end of a measurement period. In vivo, burst release can be measured, for example, by the area-under-the-curve (AUC) of semaglutide during the measurement period divided by the AUC from time 0 to time of complete semaglutide release. The period of time to monitor the burst release can be, for example, within one day, within two days or within three days after the microspheres are introduced to the milieu for drug release. The burst release within one day includes the following, for example: less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 7%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%. The burst release within two days includes the following, for example: less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 7%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%. The burst release within three days includes the following, for example: less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 7%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%. As an example of continuous semaglutide release, in a plurality of semaglutide-carrying biodegradable microspheres having an average release per day of X mg (after the optional burst release), the semaglutide released per day (after the optional burst release) is, e.g., from 0.1X mg to 10X mg, from 0.2X mg to 10X mg, from 0.3X mg to 10X mg, from 0.4X mg to 10X mg, from 0.5X mg to 10X mg, from 0.1X mg to 9X mg, from 0.2X mg to 9X mg, from 0.3X mg to 9X mg, from 0.4X mg to 9X mg, from 0.5X mg to 9X mg, from 0.1X mg to 8X mg, from 0.2X mg to 8X mg, from 0.3X mg to 8X mg, from 0.4X mg to 8X mg, from 0.5X mg to 8X mg, from 0.1X mg to 7X mg, from 0.2X mg to 7X mg, from 0.3X mg to 7X mg, from 0.4X mg to 7X mg, from 0.5X mg to 7X mg, from 0.1X mg to 6X mg, from 0.2X mg to 6X mg, from 0.3X mg to 6X mg, from 0.4X mg to 6X mg, from 0.5X mg to 6X mg; from 0.1X mg to 5X mg, from 0.2X mg to 5X mg, from 0.3X mg to 5X mg, from 0.4X mg to 5X mg, from 0.5X mg to 5X mg, from 0.1X mg to 4X mg, from 0.2X mg to 4X mg, from 0.3X mg to 4X mg, from 0.4X mg to 4X mg, from 0.5X mg to 4X mg, from 0.1X mg to 3X mg, from 0.2X mg to 3X mg, from 0.3X mg to 3X mg, from 0.4X mg to 3X mg, from 0.5X mg to 3X mg, from 0.1X mg to 2X mg, from 0.2X mg to 2X mg, from 0.3X mg to 2X mg, from 0.4X mg to 2X mg, or from 0.5X mg to 2X mg. In another example, in a plurality of semaglutide-carrying biodegradable microspheres having an average release per week of X mg (after the optional burst release), the semaglutide released per week (after the optional burst release) is, e.g., from 0.1X mg to 10X mg, from 0.2X mg to 10X mg, from 0.3X mg to 10X mg, from 0.4X mg to 10X mg, from 0.5X mg to 10X mg, from 0.1X mg to 9X mg, from 0.2X mg to 9X mg, from 0.3X mg to 9X mg, from 0.4X mg to 9X mg, from 0.5X mg to 9X mg, from 0.1X mg to 8X mg, from 0.2X mg to 8X mg, from 0.3X mg to 8X mg, from 0.4X mg to 8X mg, from 0.5X mg to 8X mg, from 0.1X mg to 7X mg, from 0.2X mg to 7X mg, from 0.3X mg to 7X mg, from 0.4X mg to 7X mg, from 0.5X mg to 7X mg, from 0.1X mg to 6X mg, from 0.2X mg to 6X mg, from 0.3X mg to 6X mg, from 0.4X mg to 6X mg, from 0.5X mg to 6X mg; from 0.1X mg to 5X mg, from 0.2X mg to 5X mg, from 0.3X mg to 5X mg, from 0.4X mg to 5X mg, from 0.5X mg to 5X mg, from 0.1X mg to 4X mg, from 0.2X mg to 4X mg, from 0.3X mg to 4X mg, from 0.4X mg to 4X mg, from 0.5X mg to 4X mg, from 0.1X mg to 3X mg, from 0.2X mg to 3X mg, from 0.3X mg to 3X mg, from 0.4X mg to 3X mg, from 0.5X mg to 3X mg, from 0.1X mg to 2X mg, from 0.2X mg to 2X mg, from 0.3X mg to 2X mg, from 0.4X mg to 2X mg, or from 0.5X mg to 2X mg. For example, the amount of semaglutide released per day or per week can be indicated by the plasma concentration of semaglutide in an animal (such as a mouse, a rat, a rabbit, or a dog) or a human after the semaglutide-containing microspheres are injected into the animal or human. In another example, the amount of semaglutide released per day or per week can be indicated by the concentration of semaglutide in an appropriate medium that dissolves the released semaglutide after the semaglutide-containing microspheres are introduced into the medium. In yet another example, the amount of semaglutide released per day or per week can be calculated as the difference in the amount of semaglutide present in the microspheres before and after a period of time when the microspheres are present in an appropriate medium. The duration of continuous semaglutide release characterized by an average release per day or per week within an abovementioned quantitative range is at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. As used herein, the term “semaglutide” encompasses the structure below (with CAS number 910463-68-2) as well as its free base form and acetate salt. Semaglutide is a GLP-1 receptor agonist. It is commercially known and is sold by Novo Nordisk under the trade name Ozempic®and Wegovy®. or and adult or child). In one embodiment, the human subject has a body mass index (BMI) of 25 or higher, 27 or higher, 30 or higher, 35 or higher, 40 or higher, 45 or higher, 50 or higher, 55 or higher, 60 or higher, 65 or higher, or 70 or higher. In another embodiment, the human subject has a BMI from 25 to 27, from 25 to 30, from 27 to 30, from 30 to 35, from 30 to 40, from 30 to 45, from 30 to 50, from 30 to 55, from 30 to 60, from 30 to 65, from 30 to 70, from 40 to 45, from 40 to 50, from 40 to 55, from 40 to 60, from 40 to 65, from 40 to 70, from 45 to 50, from 45 to 55, from 45 to 60, from 45 to 65, from 45 to 70, from 50 to 55, from 50 to 60, from 50 to 65, from 50 to 70, from 55 to 60, from 55 to 65, from 55 to 70, from 60 to 65, from 60 to 70, or from 65 to 70. As used herein, the term “therapeutically effective amount”, with respect to pharmaceutical semaglutide carried in biodegradable microspheres, refers to the amount of pharmaceutical semaglutide collectively carried by the total dose of biodegradable microspheres administered subcutaneously or intramuscularly. In one embodiment, the effective amount is 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 550 μg, 600 μg, 650 μg, 700 μg, 750 μg, 800 μg, 850 μg, 900 μg, 950 μg, 1mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, 1,200 mg, 1,250 mg, 1,300 mg, 1,350 mg, 1,400 mg, 1,450 mg, 1,500 mg, 1,550 mg, 1,600 mg, 1,650 mg, 1,700 mg, 1,750 mg, 1,800 mg, 1,850 mg, 1,900 mg, 1,950 mg, or 2,000 mg. In another embodiment, the effective amount is from 1 μg to 10 μg, from 10 μg to 50 μg, from 50 μg to 100 μg, from 100 μg to 150 μg, from 150 μg to 200 μg, from 200 μg to 250 μg, from 250 μg to 300 μg, from 300 μg to 350 μg, from 350 μg to 400 μg, from 400 μg to 450 μg, from 450 μg to 500 μg, from 500 μg to 550 μg, from 550 μg to 600 μg, from 600 μg to 650 μg, from 650 μg to 700 μg, from 700 μg to 750 μg, from 750 μg to 800 μg, from 800 μg to 850 μg, from 850 μg to 900 μg, from 900 μg to 950 μg, from 950 μg to 1 mg, 1 mg to 10 mg, from 10 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 150 mg, from 150 mg to 200 mg, from 200 mg to 250 mg, from 250 mg to 300 mg, from 300 mg to 350 mg, from 350 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1,000 mg, from 1,000 mg to 1,050 mg, from 1,050 mg to 1,100 mg, from 1,100 mg to 1,150 mg, from 1,150 mg to 1,200 mg, from 1,200 mg to 1,250 mg, from 1,250 mg to 1,300 mg, from 1,300 mg to 1,350 mg, from 1,350 mg to 1,400 mg, from 1,400 mg to 1,450 mg, from 1,450 mg to 1,500 mg, from 1,500 mg to 1,550 mg, from 1,550 mg to 1,600 mg, from 1,600 mg to 1,650 mg, from 1,650 mg to 1,700 mg, from 1,700 mg to 1,750 mg, from 1,750 mg to 1,800 mg, from 1,800 mg to 1,850 mg, from 1,850 mg to 1,900 mg, from 1,900 mg to 1,950 mg, or from 1,950 mg to 2,000 mg. In a further embodiment, the effective amount is from 1 μg to 250 μg, from 250 μg to 500 μg, from 500 μg to 750 μg, from 750 μg to 1 mg, 1 mg to 250 mg, from 250 mg to 500 mg, from 500 mg to 750 mg, from 750 mg to 1,000 mg, from 1,000 mg to 1,250 mg, from 1,250 mg to 1,500 mg, from 1,500 mg to 1,750 mg, or from 1,750 mg to 2,000 mg. In yet a further embodiment, the effective amount is from 1 μg to 500 μg, from 500 μg to 1 mg, 1 mg to 500 mg, from 10 mg to 500 mg, from 500 mg to 1,000 mg, from 1,000 mg to 1,500 mg, or from 1,500 mg to 2,000 mg. As used herein, “treating” a subject afflicted with a disorder shall include, without limitation, (i) slowing, stopping or reversing the disorder's progression, (ii) slowing, stopping or reversing the progression of the disorder’s symptoms, (iii) reducing the likelihood of the disorder’s recurrence, and / or (iv) reducing the likelihood that the disorder’s symptoms will recur. In the preferred embodiment, treating a subject afflicted with a disorder means (i) reversing the disorder's progression, ideally to the point of eliminating the disorder, and / or (ii) reversing the progression of the disorder’s symptoms, ideally to the point of eliminating the symptoms. Embodiments of the Invention This invention solves an unmet need in the art by providing an unexpectedly superior way to treat GLP-1R-related disorders using semaglutide. The invention does this via semaglutide-carrying microspheres that can be administered to a subject subcutaneously or intramuscularly and release semaglutide over time. Specifically, this invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 μm to 500 μm (e.g., from 5 μm to 100 μm); (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, releases semaglutide for at least four weeks. In one embodiment of the present biodegradable microsphere, the microsphere has a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50. In another embodiment, the microsphere (i) has a diameter of from 5 μm to 100 μm; and (ii) has a lactic acid to glycolic acid molar ratio of 50:50, 65:35, 75:25, from 47:53 to 53:47, from 63:37 to 67:33, from 73:27 or 77:23, from 50:50 to 75:25, from 50:50 to 65:35, from 65:35 to 75:25, from 47:53 to 77:23, from 47:53 to 67:33, or from 63:37 to 77:23. In another embodiment, the microsphere further comprises polyethylene glycol (PEG). In another embodiment, the microsphere, when present subcutaneously, releases semaglutide for longer than four weeks. In another embodiment, the microsphere, when present intramuscularly, releases semaglutide for longer than four weeks. Preferably, the microsphere, when present subcutaneously, releases semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. Also preferably, the microsphere, when present intramuscularly, releases semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In a further preferred embodiment of the present biodegradable microsphere, the microsphere has a pharmaceutical semaglutide loading ratio of at least 14%. Preferably, the microsphere has a pharmaceutical semaglutide loading ratio of from 14% to 16%, from 16% to 18%, from 18% to 20%, from 20% to 22%, from 22% to 24%, from 24% to 26%, from 26% to 28%, from 28% to 30%, from 30% to 32%, from 32% to 34%, from 34% to 36%, from 36% to 38%, from 38% to 40%, from 40% to 42%, from 42% to 44%, from 44% to 46%, from 46% to 48%, from 48% to 50%, from 50% to 52%, from 52% to 54%, from 54% to 56%, from 56% to 58%, from 58% to 60%, from 14% to 20%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, from 45% to 50%, from 50% to 55%, from 55% to 60%, from 15% to 25%, from 15% to 30%, from 15% to 35%, from 15% to 40%, from 15% to 45%, from 15% to 50%, from 15% to 55%, from 15% to 60%, from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from 20% to 60%, from 25% to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 25% to 55%, from 25% to 60%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 55%, from 45% to 60%, or from 50% to 60%. This invention also provides a plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 μm and a d90 value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. In an embodiment of the instant plurality of biodegradable microspheres, the microspheres further comprise polyethylene glycol (PEG). The PEG can be any type suitable for use in forming biodegradable microspheres (e.g., PEG1450 (Polysciences, Inc., Warrington, PA)). Moreover, the ratio of PEG to PLGA can be any ratio suitable for use in forming biodegradable microspheres (e.g., 25:100, 50:100, 75:100 or 100:100). In another embodiment of the instant plurality of biodegradable microspheres, the microspheres, when present subcutaneously, release semaglutide for longer than four weeks. In a further embodiment of the instant plurality of biodegradable microspheres, the microspheres, when present intramuscularly, release semaglutide for longer than four weeks. Preferably, the microspheres, when present subcutaneously, release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. Also preferably, the microspheres, when present intramuscularly, release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In a further embodiment of the instant plurality of biodegradable microspheres, the microspheres (i) have a d10 value of at least 5 μm and a d90 value of 100 μm or less; (ii) have a lactic acid to glycolic acid molar ratio of from 50:50 to 75:25; and (iii) carry from 1 μg to 2,000 mg of pharmaceutical semaglutide. In a further preferred embodiment of the instant plurality of biodegradable microspheres, the microspheres have a pharmaceutical semaglutide loading ratio of at least 14%. Preferably, the microspheres have a pharmaceutical semaglutide loading ratio of from 14% to 16%, from 16% to 18%, from 18% to 20%, from 20% to 22%, from 22% to 24%, from 24% to 26%, from 26% to 28%, or from 28% to 30%, from 30% to 32%, from 32% to 34%, from 34% to 36%, from 36% to 38%, from 38% to 40%, from 40% to 42%, from 42% to 44%, from 44% to 46%, from 46% to 48%, from 48% to 50%, from 50% to 52%, from 52% to 54%, from 54% to 56%, from 56% to 58%, from 58% to 60%, from 14% to 20%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, from 45% to 50%, from 50% to 55%, from 55% to 60%, from 15% to 25%, from 15% to 30%, from 15% to 35%, from 15% to 40%, from 15% to 45%, from 15% to 50%, from 15% to 55%, from 15% to 60%, from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from 20% to 60%, from 25% to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 25% to 55%, from 25% to 60%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 55%, from 45% to 60%, or from 50% to 60%. This invention further provides an injectable formulation comprising (a) a pharmaceutically acceptable carrier and (b) a plurality of biodegradable microspheres wherein the microspheres (i) have a d10 value of at least 1 μm and a d90 value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. In an embodiment of the instant injectable formulation, the microspheres further comprise polyethylene glycol (PEG). In another embodiment of the instant injectable formulation, the microspheres, when present subcutaneously, release semaglutide for longer than four weeks. In a further embodiment of the instant injectable formulation, the microspheres, when present intramuscularly, release semaglutide for longer than four weeks. Preferably, the microspheres, when present subcutaneously, release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. Also preferably, the microspheres, when present intramuscularly, release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In a further preferred embodiment of the instant injectable formulation, the microspheres have a pharmaceutical semaglutide loading ratio of at least 14%. Preferably, the microspheres have a pharmaceutical semaglutide loading ratio of from 14% to 16%, from 16% to 18%, from 18% to 20%, from 20% to 22%, from 22% to 24%, from 24% to 26%, from 26% to 28%, or from 28% to 30%, from 30% to 32%, from 32% to 34%, from 34% to 36%, from 36% to 38%, from 38% to 40%, from 40% to 42%, from 42% to 44%, from 44% to 46%, from 46% to 48%, from 48% to 50%, from 50% to 52%, from 52% to 54%, from 54% to 56%, from 56% to 58%, from 58% to 60%, from 14% to 20%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, from 45% to 50%, from 50% to 55%, from 55% to 60%, from 15% to 25%, from 15% to 30%, from 15% to 35%, from 15% to 40%, from 15% to 45%, from 15% to 50%, from 15% to 55%, from 15% to 60%, from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from 20% to 60%, from 25% to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 25% to 55%, from 25% to 60%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 55%, from 45% to 60%, or from 50% to 60%. This invention still further provides a method for treating a subject afflicted with a GLP- 1R-related disorder comprising administering biodegradable microspheres to the subject, wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. In an embodiment of the instant therapeutic method, the microspheres further comprise polyethylene glycol (PEG). In the preferred embodiment of the instant therapeutic method, the subject is human (e.g., male or female). In another embodiment of the instant therapeutic method, the microspheres (i) have a d10value of at least 5 μm and a d90value of 100 μm or less; (ii) have a lactic acid to glycolic acid molar ratio of from 50:50 to 75:25; and (iii) carry from 1 μg to 2,000 mg of pharmaceutical semaglutide. Preferably, the microspheres have an average lactic acid to glycolic acid molar ratio of 50:50, 65:35, 75:25, from 47:53 to 53:47, from 63:37 to 67:33, from 73:27 to 77:23, from 47:53 to 77:23, from 47:53 to 67:33, from 63:37 to 77:23, or from 50:50 to 75:25. In another embodiment of the instant therapeutic method, the microspheres, when present subcutaneously, release semaglutide for longer than four weeks. In a further embodiment of the instant therapeutic method, the microspheres, when present intramuscularly, release semaglutide for longer than four weeks. Preferably, the microspheres, when present subcutaneously, release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. Also preferably, the microspheres, when present intramuscularly, release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In a further preferred embodiment of the instant method, the microspheres have a pharmaceutical semaglutide loading ratio of at least 14%. Preferably, the microspheres have a pharmaceutical semaglutide loading ratio of from 14% to 16%, from 16% to 18%, from 18% to 20%, from 20% to 22%, from 22% to 24%, from 24% to 26%, from 26% to 28%, or from 28% to 30%, from 30% to 32%, from 32% to 34%, from 34% to 36%, from 36% to 38%, from 38% to 40%, from 40% to 42%, from 42% to 44%, from 44% to 46%, from 46% to 48%, from 48% to 50%, from 50% to 52%, from 52% to 54%, from 54% to 56%, from 56% to 58%, from 58% to 60%, from 14% to 20%, from 15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, from 45% to 50%, from 50% to 55%, from 55% to 60%, from 15% to 25%, from 15% to 30%, from 15% to 35%, from 15% to 40%, from 15% to 45%, from 15% to 50%, from 15% to 55%, from 15% to 60%, from 20% to 30%, from 20% to 35%, from 20% to 40%, from 20% to 45%, from 20% to 50%, from 20% to 55%, from 20% to 60%, from 25% to 35%, from 25% to 40%, from 25% to 45%, from 25% to 50%, from 25% to 55%, from 25% to 60%, from 30% to 40%, from 30% to 45%, from 30% to 50%, from 30% to 55%, from 30% to 60%, from 35% to 45%, from 35% to 50%, from 35% to 55%, from 35% to 60%, from 40% to 50%, from 40% to 55%, from 40% to 60%, from 45% to 55%, from 45% to 60%, or from 50% to 60%. In this invention, the biodegradable microspheres can be administered to the subject using any known method (e.g., injection) appropriate for administering agents subcutaneously or intramuscularly. In one embodiment, the instant method is performed only once. In another embodiment, the instant method is performed a plurality of times (e.g., two times, three times, four times, five times, or more). In that embodiment, each subsequent time the method is performed, it is performed after a suitable period has lapsed since the preceding time the method was performed. This suitable time can be, for example, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or longer. Microsphere-based drug products and methods of delivering them are known, at least generally (e.g., Lupron®(leuprolide acetate microspheres for depot suspension (Abbvie)); and Sandostatin LAR®Depot (octreotide acetate for injectable suspension) (Novartis)). In the present method for treating a subject afflicted with a GLP-1R-related disorder, the GLP-1R-related disorder can be, for example, obesity, diabetes (e.g., type 1 diabetes and type 2 diabetes), poor glycemic control (e.g., in type 2 diabetes), cardiovascular disease, heart failure, metabolic associated steatohepatitis, obstructive sleep apnea, osteoarthritis, chronic kidney disease, alcoholic fatty liver disease, a neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lou Gehrig’s disease, Creutzfeldt-Jakob disease, stroke, or multiple sclerosis) and an addictive disorder (e.g., alcohol use disorder, substance use disorder). As such, the following are exemplary embodiments of the present therapeutic method. In a first embodiment, this invention provides a method for treating a human subject afflicted with obesity (i.e., a method for causing weight loss in the subject) comprising administering the present biodegradable microspheres to the subject. The human subject treated in the present method can have any BMI above normal, such as a BMI of 25 or higher, 27 or higher, 30 or higher, 40 or higher, or 50 or higher. Preferably, the subject has a BMI of 27 or higher. In a second embodiment, this invention provides a method for treating a human subject (e.g., an adult human subject) afflicted with diabetes (e.g., type 1 diabetes or type 2 diabetes) comprising administering the present biodegradable microspheres to the subject. Preferably, this invention provides a method for treating a human subject afflicted with type 2 diabetes comprising administering the present biodegradable microspheres to the subject. In a third embodiment, this invention provides a method for treating a human subject (e.g., an adult human subject) afflicted with poor glycemic control (e.g., in type 2 diabetes) comprising administering the present biodegradable microspheres to the subject. That is, in this embodiment, the method improves glycemic control in the subject (e.g., lowering fasting and post-prandial glucagon levels in subjects afflicted with type 2 diabetes). In a fourth embodiment, this invention provides a method for treating a human subject afflicted with cardiovascular disease comprising administering the present biodegradable microspheres to the subject. In a preferred embodiment, the cardiovascular disease is stroke, myocardial infarction, cardiovascular death, angina, or heart failure. In a fifth embodiment, this invention provides a method for treating a human subject afflicted with metabolic associated steatohepatitis comprising administering the present biodegradable microspheres to the subject. In a sixth embodiment, this invention provides a method for treating a human subject afflicted with obstructive sleep apnea comprising administering the present biodegradable microspheres to the subject. In a seventh embodiment, this invention provides a method for treating a human subject afflicted with osteoarthritis comprising administering the present biodegradable microspheres to the subject. In an eighth embodiment, this invention provides a method for treating a human subject afflicted with chronic kidney disease comprising administering the present biodegradable microspheres to the subject. In a ninth embodiment, this invention provides a method for treating a human subject afflicted with alcoholic fatty liver disease comprising administering the present biodegradable microspheres to the subject. In a tenth embodiment, this invention provides a method for treating a human subject afflicted with a neurodegenerative disease comprising administering the present biodegradable microspheres to the subject. In a preferred embodiment, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lou Gehrig’s disease, Creutzfeldt-Jakob disease, stroke, or multiple sclerosis. Finally, in an eleventh embodiment, this invention provides a method for treating a human subject afflicted with an addictive disorder comprising administering the present biodegradable microspheres to the subject. In a preferred embodiment, the addictive disorder is alcohol use disorder, or substance use disorder. This invention also provides an article of manufacture (kit) comprising, in separate compartments, (a) (i) a diluent and (ii) optionally, a label instructing the user to subcutaneously or intramuscularly administer the present biodegradable microspheres to a subject, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less (e.g., a d10value of least 5 μm and a d90 value of 100 μm or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix (preferably having a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50 (e.g., 50:50, 65:35, 75:25, from 47:53 to 53:47, from 63:37 to 67:33, from 73:27 to 77:23, from 47:53 to 77:23, from 47:53 to 67:33, 63:37 to 77:23, or from 50:50 to 75:25)); (iii) carry a therapeutically effective amount of pharmaceutical semaglutide (e.g., from 1 μg to 2,000 mg of pharmaceutical semaglutide); and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks (and optionally release semaglutide for at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months). In one embodiment of the instant kit, the microspheres further comprise polyethylene glycol (PEG). Where applicable, the embodiments described above for the instant method are also envisioned for this article of manufacture. In a preferred embodiment, the instant kit is supplied as a single-dose kit and contains (i) a single dose vial of semaglutide-carrying biodegradable microspheres, and (ii) a single dose vial of diluent (e.g., sterile, clear liquid solution of 0.9% w / w sodium chloride, 0.5% - 1% w / w sodium carboxymethylcellulose, and 0.1% w / w polysorbate-80, or sterile liquid of medium-chain fatty acids). This invention further provides an article of manufacture comprising a syringe having therein the instant injectable formulation. Ideally, this article of manufacture is ready for use without further manipulation. This invention still further provides an article of manufacture comprising a dual chamber syringe having therein, in separate compartments, (a) a diluent, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 μm and a d90value of 500 μm or less (e.g., a d10value of least 5 μm and a d90value of 100 μm or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks, wherein the diluent and microspheres can be admixed within the syringe to form an injectable formulation immediately prior to use (e.g., within 30 minutes, 20 minutes, 10 minutes, five minutes, or one minute of use). Where applicable, the embodiments described above for the instant method and instant kit are also envisioned for the above two syringe-based articles of manufacture. This invention will be better understood by reference to the examples which follow, but those skilled in the art will readily appreciate that the specific examples detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Examples Example 1. Screening for conditions to prepare semaglutide microspheres in a beaker PLGA refers to poly-lactic-co-glycolic acid; PDLA refers to poly-D-lactic acid, which is one kind of poly-lactic acid (PLA); DMSO refers to dimethyl sulfoxide; PVA refers to polyvinyl alcohol; PBS refers to phosphate buffered saline, pH 7.4; and MW refers to molecular weight. (i)_PLGA50:50, 0.2 dl / g, acid-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.16-0.24 dl / g. MW:7,000-17,000; (ii) PLGA50:50, L:G ratio = 47:53 to 53:47, 0.2 dl / g, ester-terminated: Inherent viscosity = 0.16-0.24 dl / g. MW:7,000-17,000; (iii) PLGA50:50, 0.4 dl / g, acid-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.32-0.44 dl / g. MW:24,000-38,000; (iv) PLGA50:50, 0.4 dl / g, ester-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.32-0.44 dl / g. MW:24,000-38,000; (v) PLGA50:50, 0.5 dl / g, acid-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.45-0.6 dl / g. MW:38,000-54,000; (vi) PLGA50:50, 0.5 dl / g, ester-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.45-0.6 dl / g. MW:38,000-54,000; (vii) PLGA50:50, 0.6 dl / g, ester-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.50-0.65 dl / g; (viii) PLGA50:50, 0.7 dl / g, ester-terminated: L:G ratio = 47:53 to 53:47, Inherent viscosity = 0.61-0.74 dl / g. MW:54,000-69,000; (ix) PLGA65:35, 0.4 dl / g, acid- terminated: L:G ratio = 63:37 to 67:33, Inherent viscosity = 0.32-0.44 dl / g. MW:24,000- 38,000; (x) PLGA75:25, 0.2 dl / g, acid-terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.14-0.22 dl / g. MW: 4,000-15,000; (xi) PLGA75:25, 0.2 dl / g, ester- terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.16-0.24 dl / g. MW: 4,000- 15,000; (xii) PLGA75:25, 0.4 dl / g, acid-terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.32-0.44 dl / g. MW: 15,000-35,000; (xiii) PLGA75:25, 0.4 dl / g, ester- terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.32-0.44 dl / g. MW: 15,000- 35,000; (xiv) PLGA75:25, 0.6 dl / g, ester-terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.5-0.7 dl / g. MW: 35,000-76,000 with average about 61,100; (xv) PLGA75:25, 0.65 dl / g, ester-terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.55-0.75 dl / g. MW: about 97,000; (xvi) PLGA75:25, 0.9 dl / g, ester-terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.71-1.0 dl / g. MW:76,000-115,000; (xvii) PLGA75:25, 1.1 dl / g, ester-terminated: L:G ratio = 73:27 to 77:23, Inherent viscosity = 0.9-1.3 dl / g. MW: 115,000-190,000; (xviii) PLGA85:15, 1.5 dl / g, ester-terminated: L:G ratio = 83:17 to 87:13, Inherent viscosity = 1.3-1.7 dl / g. MW: 190,000-240,000. In experiments described herein, one type of PVA (i.e., of one molecular weight and degree of hydrolysis) at one concentration (i.e., 1%) is used to produce microspheres. However, in this invention, other types of PVA and other PVA concentrations are also envisioned to yield the same microspheres. For example, where 0.11% PVA4-88, 200 μl DCM and 1,400 rpm stirring is used to produce a certain population of microspheres, 0.05% PVA4-88, 300 μl DCM and 1,000 rpm stirring may also be used to produce essentially the same population of microspheres. Surfactants other than PVA can also be used in this invention to produce microspheres. These other surfactants include, for example, the commonly known surfactants vitamin E, Tween-20, Tween-80, poloxamers, poloxamines, pluronic polymers (such as F68 and F127), and sodium cholate. Similarly, in experiments described herein, DCM, in combination with DMSO or acetic acid, is used to produce microspheres. However, in this invention, other types of organic solvents (e.g., ethyl acetate, chloroform, acetone, propylene carbonate, and tetrahydrofuran) may be used instead of DCM to yield essentially the same microspheres, assuming other experimental parameters are adjusted accordingly. Moreover, in this invention, any of a plurality of physical methods for preparing PLGA microspheres (e.g., spinning disk, spray drying, and microfluidics) may be used to yield the subject microspheres. Semaglutide free base (Thinheal Pharmaceutical, China) or semaglutide acetate (Xingcan Pharmaceutical, China) was dissolved in co-solvent #1 with sonication and shaking, and mixed with co-solvent #2, into which PLGA was added and dissolved to form the oil phase. The oil phase was injected into different volumes of PVA4-88 solution in a 50 ml beaker and emulsified with a stir bar for 30 minutes to form microspheres in an oil-in-water single emulsion. The microspheres were observed under light microscopy for morphology. In general, semaglutide free base and semaglutide acetate were soluble in acetic acid or DMSO. Additional DCM could be mixed in without causing precipitation of semaglutide, up to a limit. From the emulsification process, there were three types of outcomes, including formation of opaque microspheres under light microscopy, formation of transparent microspheres, and poor microsphere formation with few microspheres and mostly debris (Table 1). The result from the emulsification process depended on the amount of semaglutide, amount of PLGA, type of PLGA, amounts of co-solvents and amount of PVA, among others. The outcome was highly sensitive to the reaction condition and highly unpredictable. Table 1. Screening for conditions to prepare semaglutide microspheres

[0002] Example 2. Preparing semaglutide acetate microspheres on and mixed to 50 ml 1% r single 1 minute, lyophilized. rospheres NaOH, and ed the n Agilent TFA in water e: 30 °C; i res, about 4 haken at 60 r d with the the amount ncapsulated elease ( from 63:37 to indicates a r 4 dl / g; maglutide 50 µl DCM and 88 with a stir bar The shed with PBS, microspheres d in Example 2 is very high The particle analyzer te loading o from 73:27 to eres glutide acetate was dissolved in 200 µl DMSO with sonication and mixed with 350 µl DCM and 8 mg PLGA (Table 4). The oil phase was injected into 50 ml 1% PVA4-88 with a stir bar at 1,400 rpm for 30 minutes in an oil-in-water single emulsion. The microspheres were collected by centrifugation at 500 g for 1 minute, washed with PBS, filtered with a 100 µm strainer, washed with water, and lyophilized. ing e o :G f 50 d. s e 2 d iffraction particle size analyzer (LS13320, Beckman Coulter, US). Table 5. Characteristics of semaglutide acetate microspheres injected to rats (PLGA50:50 has L:G ratio from 47:53 to 53:47; PLGA65:35 has L:G ratio from 63:37 to 67:33; PLGA75:25 has L:G ratio from 73:27 to 77:23; Viscosity of 0.2 dl / g indicates a l / g; d injected periodically th Triple maglutide tide wed (hour). Example 6. In vivo release of semaglutide acetate microspheres in rats 4-8 mg of semaglutide acetate was dissolved in 400 µl DMSO with sonication and mixed with 650 µl DCM and 8-16 mg PLGA (Table 7). Half of the oil phase was injected into 50 ml 1% or 5% PVA4-88 with a stir bar at 1,500 rpm for 15 minutes in an oil-in- water single emulsion. The microspheres were collected by centrifugation at 500 g for iner, washed with ple beakers in parallel ovide a higher dose. method in Example 2 alyzed with a laser- ). ected to rats L:G ratio from 73:27 to scosity of 0.5 dl / g ml saline and injected were taken periodically System with Triple showed semaglutide 1J and 2F-2J showed semaglutide release over at least 63 days (= 1512 hours). ent sampling timepoints 5

[0003] Example 7. Effects of Washing on Semaglutide Acetate Microspheres 6-8 mg of semaglutide acetate was dissolved in 400 µl DMSO with sonication and mixed with 650 µl DCM and 12 mg PLGA50:50 (with L:G ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated (Table 9). The oil phase was injected into 50 ml 1% PVA4-88 with a stir bar at 1,400 rpm for 15 minutes in an oil-in-water single emulsion. The microspheres were collected by centrifugation at 300 g for 1 minute, washed with PBS, filtered with an 85 µm strainer, washed with water. These reactions were conducted in multiple beakers in parallel and the microspheres from the same group were combined. Half of the microspheres were lyophilized directly. The other half were washed in 10 mM PBS at 36 °C for one day with continuous rotation before a final wash in water on the second day and lyophilization. Semaglutide acetate loading before and after one day of PBS washing was analyzed with the same HPLC method in Example 2 and shown in Table 9. The particle size of microspheres was analyzed with a laser-diffraction particle size analyzer (LS13320, Beckman Coulter, US). One day washing in PBS at 36 °C did not result in significant changes in drug loading. By calculating the amount of semaglutide acetate in microspheres before and after one day washing in PBS, burst release within one day was determined to be 1.4% and 0% for the 8 mg and 7 mg semaglutide acetate groups, respectively. Table 9. Effects of one day of PBS washing on semaglutide microspheres ts and dogs onication and 7:53 to 53:47), 0.5 the oil phase ( a e ). e o p ase was njece no m - w a stir bar at 1,400 rpm for 15 minutes in an oil-in-water single emulsion. The microspheres were collected by centrifugation at 500 g for 1 minute, washed with PBS, filtered with an 85 µm strainer, washed with water, and lyophilized. These reactions were conducted in multiple beakers in parallel and the microspheres from the same group were combined to provide a higher dose. Semaglutide acetate loading was analyzed with the same HPLC method in Example 2 and shown in Table 10. The particle size of microspheres was analyzed with a laser- diffraction particle size analyzer (LS13320, Beckman Coulter, US). 10 mg or 100 mg of microspheres from each group were resuspended in 1 ml saline and injected subcutaneously to male Sprague Dawley rats or male Beagle dogs, respectively. Plasma samples were taken periodically to analyze semaglutide concentrations (SCIEX Exion LC-MS / MS System with Triple Quad 6500+ and Analyst 1.7.1 AB Sciex). In Table 11, the 8 mg semaglutide acetate group showed 7 weeks of continuous drug release in dogs, and the 7 mg and 6 mg semaglutide acetate groups showed 9 weeks of continuous drug release in dogs. Table 10. Characteristics of semaglutide acetate microspheres injected to rats and dogs Table 11. Plasma semaglutide concentration in rats and dogs at different sampling timepoints (day) Example 9. Preparing semaglutide acetate microspheres in a Silverson inline mixer with acetic acid as co-solvent Figure 1 shows an inline mixing chamber (Silverson Machines, Massachusetts, USA) where the oil phase (organic solution with dissolved PLGA and semaglutide acetate) and the water phase (PVA4-88 solution) can be mixed to prepare microspheres. To prepare the oil phase, acetic acid was optionally used as a co-solvent to increase solubility of semaglutide acetate, and its effect on drug release in vivo was studied. Specifically, 30-60 mg semaglutide acetate was dissolved in 100 µl acetic acid with sonication in a sonicator bath, and 2 ml DMSO was added and mixed. This DMSO- acetic acid solution was warmed to 85 °C and 3.25 ml DCM was injected into this warmed solution and mixed by vortex. Then, 60 mg PLGA50:50 (with L:G ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated was dissolved into the solution. Five batches of this DCM-DMSO-acetic acid solution were combined and pumped into the inline mixing chamber at 8 ml / min, and the water phase (0.11% PVA4-88) was pumped into the inline mixing chamber at 800 ml / min. The mixer was set at 800 rpm to prepare an oil-in-water single emulsion, which was solidified in a beaker for 5 minutes under stirring and collected on a 10 µm sieve. The microspheres were filtered through a 90 µm strainer, washed in PBS (pH=7.4) twice, then washed in water once, and lyophilized. For microspheres prepared without acetic acid co-solvent, 30-60 mg semaglutide acetate was dissolved in 2 ml DMSO with sonication in a sonicator bath, and another 2 ml DMSO was added and mixed. This DMSO solution was warmed to 85 °C and 6.5 ml DCM was injected into this warmed solution and mixed by vortex. Then, 60 mg PLGA50:50 (with L:G ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated was dissolved into the solution. Five batches of this 800 ml / min. The mixer was set at 900 rpm to prepare an oil-in-water single emulsion, 5 minutes under collected on a 10 µm were through a 90 µm washed in PBS (pH=7.4) twice, then washed in water once, and lyophilized. Semaglutide acetate loading was analyzed with the same HPLC method in Example 2 and shown in Table 12. The particle size of microspheres was analyzed with a laser- diffraction particle size analyzer (LS13320, Beckman Coulter, US). Table 12. Characteristics of semaglutide acetate microspheres. Using acetic acid as a co-solvent increases semaglutide acetate loading in microspheres. 100 mg of microspheres from each group were resuspended in 1 ml saline and injected subcutaneously to male Beagle dogs. Plasma samples were taken periodically to analyze semaglutide concentrations (SCIEX Exion LC-MS / MS System with Triple Quad 6500+ and Analyst 1.7.1 AB Sciex). In Table 13 formulations 9A-9D and 9F-9H ormulations 9A-9H ions 9A, 9B, 9C, and wing continuous after microsphere injection. Example 10. Preparing semaglutide acetate microspheres in a Silverson inline mixer with acetic acid as co-solvent and PLGA75:25 20-60 mg semaglutide acetate was dissolved in 100 µl acetic acid with sonication in a sonicator bath, and 2 ml DMSO was added and mixed. This DMSO-acetic acid solution was warmed to 85 °C and 3.25 ml DCM was injected into this warmed solution and mixed by vortex. Then, 60 mg PLGA75:25 (with L:G ratio from 73:27 to 77:23), 0.4 dl / g ( ih i i f 2 44 l i i i l i h l ion. line l- i g 90 l 2 - ns Table 14. Characteristics of semaglutide acetate microspheres made from acetic acid co-solvent and PLGA75:25 (with L:G ratio from 73:27 to 77:23), 0.4 dl / g (with viscosity range of 0.32-0.44 dl / g), acid-terminated

[0004] mulation alt thereof. omprising ceutically rosphere lt thereof and preparation method therefor. use thereof. nalyzing PLGA and Release.304:125-134. producing sustained- oading. Frontiers in sphere formulation, Depot. The AAPS Journal. 20 mg of microspheres from each group were resuspended in 1 ml saline and injected subcutaneously to male Sprague Dawley rats. Plasma samples were taken periodically to analyze semaglutide concentrations (SCIEX Exion LC-MS / MS System with Triple Quad 6500+ and Analyst 1 .7.1 AB Sciex). In Table 8, all groups showed semaglutide release over at least 35 days (= 840 hours) and formulations 1 F-1 J and 2F-2J showed semaglutide release over at least 63 days (= 1512 hours).

[0005] Table 8. Plasma semaglutide concentration in rats at different sampling timepoints (hour).

[0006] Example 7. Effects of Washing on Semaglutide Acetate Microspheres

[0007] 6-8 mg of semaglutide acetate was dissolved in 400 pl DMSO with sonication and mixed with 650 pl DCM and 12 mg PLGA50:50 (with L:G ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated (Table 9). The oil phase was injected into 50 ml 1 % PVA4-88 with a stir bar at 1 ,400 rpm for 15 minutes in an oil-in-water single emulsion. The microspheres were collected by centrifugation at 300 g for 1 minute, washed with PBS, filtered with an 85 pm strainer, washed with water.

[0008] These reactions were conducted in multiple beakers in parallel and the microspheres from the same group were combined. Half of the microspheres were lyophilized directly. The other half were washed in 10 mM PBS at 36 °C for one day with continuous rotation before a final wash in water on the second day and lyophilization.

[0009] Semaglutide acetate loading before and after one day of PBS washing was analyzed with the same HPLC method in Example 2 and shown in Table 9. The particle size of microspheres was analyzed with a laser-diffraction particle size analyzer (LS13320, Beckman Coulter, US). One day washing in PBS at 36 °C did not result in significant changes in drug loading. By calculating the amount of semaglutide acetate in microspheres before and after one day washing in PBS, burst release within one day was determined to be 1 .4% and 0% for the 8 mg and 7 mg semaglutide acetate groups, respectively.

[0010] Table 9. Effects of one day of PBS washing on semaglutide microspheres

[0011] Example 8. In vivo release of semaglutide acetate microspheres in rats and dogs

[0012] 6-8 mg of semaglutide acetate was dissolved in 400 pl DMSO with sonication and mixed with 650 pl DCM and 12 mg PLGA50:50 (with L:G ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated to form the oil phase (Table 10). The oil phase was injected into 50 ml 1 % PVA4-88 with a stir bar at 1 ,400 rpm for 15 minutes in an oil-in-water single emulsion. The microspheres were collected by centrifugation at 500 g for 1 minute, washed with PBS, filtered with an 85 pm strainer, washed with water, and lyophilized. These reactions were conducted in multiple beakers in parallel and the microspheres from the same group were combined to provide a higher dose.

[0013] Semaglutide acetate loading was analyzed with the same HPLC method in Example 2 and shown in Table 10. The particle size of microspheres was analyzed with a laserdiffraction particle size analyzer (LS13320, Beckman Coulter, US). 10 mg or 100 mg of microspheres from each group were resuspended in 1 ml saline and injected subcutaneously to male Sprague Dawley rats or male Beagle dogs, respectively. Plasma samples were taken periodically to analyze semaglutide concentrations (SC EX Exion LC-MS / MS System with Triple Quad 6500+ and Analyst 1 .7.1 AB Sciex). In Table 11 , the 8 mg semaglutide acetate group showed 7 weeks of continuous drug release in dogs, and the 7 mg and 6 mg semaglutide acetate groups showed 9 weeks of continuous drug release in dogs.

[0014] Table 10. Characteristics of semaglutide acetate microspheres injected to rats and dogs

[0015] Table 11. Plasma semaglutide concentration in rats and dogs at different sampling timepoints (day) acetic acid as co-solvent

[0016] Figure 1 shows an inline mixing chamber (Silverson Machines, Massachusetts, USA) where the oil phase (organic solution with dissolved PLGA and semaglutide acetate) and the water phase (PVA4-88 solution) can be mixed to prepare microspheres. To prepare the oil phase, acetic acid was optionally used as a co-solvent to increase solubility of semaglutide acetate, and its effect on drug release in vivo was studied.

[0017] Specifically, 30-60 mg semaglutide acetate was dissolved in 100 pl acetic acid with sonication in a sonicator bath, and 2 ml DMSO was added and mixed. This DMSO- acetic acid solution was warmed to 85 °C and 3.25 ml DCM was injected into this warmed solution and mixed by vortex. Then, 60 mg PLGA50:50 (with L:G ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated was dissolved into the solution. Five batches of this DCM-DMSO-acetic acid solution were combined and pumped into the inline mixing chamber at 8 ml / min, and the water phase (0.11 % PVA4-88) was pumped into the inline mixing chamber at 800 ml / min. The mixer was set at 800 rpm to prepare an oil-in-water single emulsion, which was solidified in a beaker for 5 minutes under stirring and collected on a 10 pm sieve. The microspheres were filtered through a 90 pm strainer, washed in PBS (pH=7.4) twice, then washed in water once, and lyophilized.

[0018] For microspheres prepared without acetic acid co-solvent, 30-60 mg semaglutide acetate was dissolved in 2 ml DMSO with sonication in a sonicator bath, and another 2 ml DMSO was added and mixed. This DMSO solution was warmed to 85 °C and 6.5 ml DCM was injected into this warmed solution and mixed by vortex. Then, 60 mg PLGA50:50 (with LG ratio from 47:53 to 53:47), 0.5 dl / g (with viscosity range from 0.45-0.6 dl / g), acid-terminated was dissolved into the solution. Five batches of this DCM-DMSO solution were combined and pumped into the inline mixing chamber at 16 ml / min, and the water phase (0.11 % PVA4-88) was pumped into the mixing chamber at 800 ml / min. The mixer was set at 900 rpm to prepare an oil-in-water single emulsion, which was solidified in a beaker for 5 minutes under stirring and collected on a 10 pm sieve. The microspheres were filtered through a 90 pm strainer, washed in PBS (pH=7.4) twice, then washed in water once, and lyophilized.

[0019] Semaglutide acetate loading was analyzed with the same HPLC method in Example 2 and shown in Table 12. The particle size of microspheres was analyzed with a laserdiffraction particle size analyzer (LS13320, Beckman Coulter, US).

[0020] Table 12. Characteristics of semaglutide acetate microspheres. Using acetic acid as a co-solvent increases semaglutide acetate loading in microspheres. 100 mg of microspheres from each group were resuspended in 1 mi saline and injected subcutaneously to male Beagle dogs. Plasma samples were taken periodically to analyze semaglutide concentrations (SCIEX Exion LC-MS / MS System with Triple Quad 6500+ and Analyst 1.7.1 AB Sciex). In Table 13, formulations 9A-9D and 9F-9H showed continuous semaglutide release over 8 weeks. Notably, formulations 9A-9H showed unexpectedly high drug loading above 20%, and formulations 9A, 9B, 9C, and 9F showed unexpectedly high drug loading above 30% while showing continuous semaglutide release over 8 weeks.

[0021] Table 13. Plasma semaglutide concentration in dogs after microsphere injection.

[0022] Dog Plasma Semaglutlde Concentration (ng / ml) le 10. semaqlutide acetate mi in a Silverson inline mixer with acetic acid as co-solvent and PLGA75:25

[0023] 20-60 mg semaglutide acetate was dissolved in 100 l acetic acid with sonication in a sonicator bath, and 2 ml DMSO was added and mixed. This DMSO-acetic acid solution was warmed to 85 °C and 3.25 ml DOM was injected into this warmed solution and mixed by vortex. Then, 60 mg PLGA75:25 (with LG ratio from 73:27 to 77:23), 0.4 dl / g (with viscosity range of 0.32-0.44 dl / g), acid-terminated was dissolved into the solution. This DCM-DMSO-acetic acid solution was pumped into the Silverson inline mixing chamber at 8 ml / min, and the water phase (0.11 % PVA4-88) was pumped into the inline ixing chamber at 800 ml / min. The ixer was set at 800-2000 rpm to prepare an oil- in-water single emulsion, which was solidified in a beaker for 5 minutes under stirring and collected on a 10 pm sieve. The microspheres were filtered through a 75 pm or 90 pm strainer, washed in PBS (pH=7.4) twice, then washed in water once, and lyophilized.

[0024] Semaglutide acetate loading was analyzed with the same HPLC method in Example 2 and shown in Table 14. The particle size of microspheres was analyzed with a laserdiffraction particle size analyzer (LS13320, Beckman Coulter, US). Some formulations showed unexpectedly high drug loading above 20% or above 30%. Table 14. Characteristics of semaglutide acetate microspheres made from acetic acid co-solvent and PLGA75:25 (with L:G ratio from 73:27 to 77:23), 0.4 dl / g (with viscosity range of 0.32-0.44 dl / g), acid-terminated.

[0025] References

[0026] FDA label for Bydureon BCise.

[0027] FDA label for Trelstar.

[0028] FDA label for Semaglutide.

[0029] International Publication No. WO 2022 / 270956. Sustained release formulation composition comprising semaglutide or pharmaceutically acceptable salt thereof.

[0030] U.S. Publication No. US 2023 / 0096928. Pharmaceutical composition comprising sustained-release microspheres including GLP-1 analogue or pharmaceutically acceptable salt thereof.

[0031] International Publication No. WO 2024 / 010379. Sustained release-mlcrosphere formulation comprising semaglutide or pharmaceutically acceptable salt thereof and preparation method therefor.

[0032] U.S. Patent No. 11 ,865,213. Semaglutide depot systems and use thereof.

[0033] Park et al. (2019) Injectable, long-acting PLGA formulation: Analyzing PLGA and understanding microparticle formation. Journal of Controlled Release. 304:125-134.

[0034] Han et al. (2016) Bioerodable PLGA-based microparticles for producing sustained- release drug formulations and strategies for improving drug loading. Frontiers in Pharmacology. 7: 185.

[0035] Song et al. (2022) IVIVC of octreotide in PLGA-glucose microsphere formulation, Sandostatin LAR. AAPS PharmSciTech. 23:258.

[0036] Zhou et al. (2018) Reverse engineering the 1 -month Lupron Depot. The AAPS Jou nal. 20:105.

Claims

What is claimed is:

1. A biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 μm to 500 μm; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, releases semaglutide for at least four weeks.

2. The biodegradable microsphere of claim 1, wherein the microsphere has a lactic acid to glycolic acid molar ratio of from 100:0 to 50:

50.

3. The biodegradable microsphere of claim 1 or 2, wherein the microsphere (i) has a diameter of from 5 μm to 100 μm; and (ii) has a lactic acid to glycolic acid molar ratio of 50:50, 65:35, 75:25, from 47:53 to 53:47, from 63:37 to 67:33, from 73:27 to 77:23, from 47:53 to 77:23, from 47:53 to 67:33, from 63:37 to 77:23, or from 50:50 to 75:

25.

4. The biodegradable microsphere of any of claims 1-3, wherein the microsphere further comprises polyethylene glycol (PEG).

5. The biodegradable microsphere of any of claims 1-4, wherein the microsphere, when present subcutaneously or intramuscularly, releases semaglutide for longer than four weeks.

6. The biodegradable microsphere of any of claims 1-5, wherein the microsphere has a pharmaceutical semaglutide loading ratio of at least 14%.

7. A plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 μm and a d90 value of 500 μm or less; (ii) comprise a polylactic- co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks.

8. The plurality of biodegradable microspheres of claim 7, wherein the microspheres further comprise polyethylene glycol (PEG).

439. The plurality of biodegradable microspheres of claim 7 or 8, wherein the microspheres, when present subcutaneously or intramuscularly, release semaglutide for at least eight weeks.

10. The plurality of biodegradable microspheres of any of claims 7-9, wherein the microspheres (i) have a d10 value of at least 5 μm and a d90 value of 100 μm or less; (ii) have a lactic acid to glycolic acid molar ratio of from 50:50 to 75:25; and (iii) carry from 1 μg to 2,000 mg of pharmaceutical semaglutide.

11. The plurality of biodegradable microspheres of any of claims 7-10, wherein the microspheres have a pharmaceutical semaglutide loading ratio of at least 14%.

12. An injectable formulation comprising (a) a pharmaceutically acceptable carrier and (b) a plurality of biodegradable microspheres wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less; (ii) comprise a polylactic- co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks.

13. The formulation of claim 12, wherein the microspheres further comprise polyethylene glycol (PEG).

14. The formulation of claim 12 or 13, wherein the microspheres, when present subcutaneously or intramuscularly, release semaglutide for at least eight weeks.

15. A method for treating a subject afflicted with a GLP-1R-related disorder comprising administering biodegradable microspheres to the subject, wherein the microspheres (i) have a d10value of at least 1 μm and a d90value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks.

16. The method of claim 15, wherein the microspheres further comprise polyethylene glycol (PEG). 4417. The method of claim 15 or 16, wherein the subject is human.

18. The method of any of claims 15-17, wherein the microspheres (i) have a d10 value of at least 5 μm and a d90 value of 100 μm or less; (ii) have a lactic acid to glycolic acid molar ratio of from 50:50 to 75:25; and (iii) carry from 1 μg to 2,000 mg of pharmaceutical semaglutide.

19. The method of any of claims 15-18, wherein the microspheres have an average lactic acid to glycolic acid molar ratio of 50:50, 65:35, 75:25, from 47:53 to 53:47, from 63:37 to 67:33, from 73:27 to 77:23, from 47:53 to 77:23, from 47:53 to 67:33, from 63:37 to 77:23, or from 50:50 to 75:

25.

20. The method of any of claims 15-19, wherein the microspheres release semaglutide for at least eight weeks.

21. The method of any of claims 15-20, wherein the microspheres release semaglutide for at least three months.

22. The method of any of claims 15-21, wherein the microspheres release semaglutide for at least six months.

23. The method of any of claims 15-22, wherein the microspheres have a pharmaceutical semaglutide loading ratio of at least 14%.

24. A kit comprising, in separate compartments, (a) a diluent, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 μm and a d90 value of 500 μm or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical semaglutide; and (iv) when present subcutaneously or intramuscularly, release semaglutide for at least four weeks. 45

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