Injectable formulations comprising therapeutic compounds and methods of using thereof

Abstract

The present invention relates to improved injectable pharmaceutical compositions comprising one or more therapeutic compounds, or pharmaceutically acceptable salts thereof, that have been developed to significantly reduce both gastrointestinal adverse events (GI AEs) and any accompanying serious adverse events (SAEs) relative to the high rates of GI AEs and SAEs that presently accompany administration of existing pharmaceutical compositions (whether as oral or injectable formulations) of the same therapeutic compounds. Also provided are processes of manufacture and methods of administering the improved injectable pharmaceutical compositions to patients for the treatment of a disease or disorder, such as obesity or overweightedness.

Description

WSGR Ref. No.: 56017-743.601INJECTABLE FORMULATIONS COMPRISING THERAPEUTIC COMPOUNDS AND METHODS OF USING THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 744,755 filed on January 13, 2025, U. S. Provisional Application No. 63 / 775,854 filed on March 21, 2025, U. S. Provisional Application No. 63 / 744,757 filed on January' 13, 2025, U. S. Provisional Application No. 63 / 775,952 filed on March 21, 2025, and U. S. Provisional Application No. 63 / 823,607 filed on June 13, 2025, the entirety of each is incorporated herein by reference.TECHNICAL FIELD

[0002] The present invention relates to injectable pharmaceutical compositions comprising one or more therapeutic compounds, or pharmaceutically acceptable salts thereof, that have been developed to significantly reduce both gastrointestinal adverse events (GI AEs) and related serious adverse events (SAEs) relative to the high rates of occurrence of GI AEs and accompanying SAEs upon administration of existing formulations, whether oral or injectable, of the same therapeutic compounds.BACKGROUND

[0003] The notoriously high occurrence of GI AEs and any related SAEs that presently accompanies otherwise beneficial treatments for obesity, overweightedness, and other cardiometabolic diseases and disorders represents the most significant obstacle and shortcoming to safe and effective treatment. Such GI AE-inducing therapies include peptides and small molecules that are analogs of endogenous human gut hormones such as glucagon-like peptide- 1 receptor agonists (GLP-1 RAs), amylin receptor agonists (amylin RAs, including selective amylin receptor agonists (SARAs) and dual amylin & calcitonin receptor agonists (DACRAs), glucose¬ dependent in sul inotropic polypeptide receptor agonists (GIP RAs), GIP receptor antagonists, glucagon receptor agonists (GCG RAs), and peptide YY receptor agonists (PYY RAs).

[0004] Each of these gut hormone analogs, whether peptides (e.g., semaglutide GLP-1 RA or tirzepatide GLP-l / GIP RA) or small molecules (e.g., orfoglipron GLP-1 RA) is generally administered at relatively low and more tolerable initial doses that are suboptimal with respect to efficacy in order to mitigate and manage the inevitable onset of GI AEs. Nonetheless, even dosing at low strength fails to prevent occurrence of GI AEs that invariably accompany the initial onset of administration (whether oral or injectable) and re-emerge upon each dose escalation to higher and more efficacious dose strengths.

[0005] Accordingly, to mitigate and manage the presently inevitable onset of GI AEs, such. i.WSGR Ref. No.: 56017-743.601peptides and small molecules are administered at higher doses only upon completion of cumbersome, complex and prolonged step-wise “dose titrations” that begin with a lowest and most tolerable “initiation dose” having relatively minimal efficacy, followed by a dose titration (i.e., dose escalation) through intermediate dose strengths. Such dose titrations culminate, only if tolerable to the subject, in a highest “maintenance dose” with greater efficacy despite also being the most difficult for patients to withstand accompanying GI AEs.

[0006] F or example, Novo Nordisk’s high-dose strength injectable Wegovy® (2.4 mg semaglutide GLP-I RA peptide) for the treatment of obesity, is administered subcutaneously via weekly self-injections only after completion of a “starting dosage” of 0.25 mg semaglutide for four weeks, followed by “escalation dosages." i.e., titration through intermediate dosage levels (0.5 mg, 1.0 mg, and 1.7 mg semaglutide, each for four more weeks), before attaining, only if tolerated by the patient, the highest US FDA & EMA approved “maintenance dosage” of either 1.7 mg or 2.4 mg semaglutide, sixteen weeks after the starting dose of 0.25 mg. As used herein the terms “dose” and “dosage” are used interchangeable. In the case of injectable Wegovy, two optional maintenance doses are provided for patients who cannot tolerate the highest maintenance dose of 2.4 nig and can only tolerate the lower maintenance dose of 1.7 mg, particularly those who cannot manage associated GI AEs, including nausea, vomiting, diarrhea, and constipation at the highest maintenance dose of 2.4 mg. Some patients cannot even tolerate the starting dose (0.25 mg) or either of the escalation dosages (0.5, or 1.0 mg semaglutide).

[0007] Intolerability of these medicines is not merely an issue of inconvenience and discomfort, as GI AEs can cause severe dehydration with potentially life-threatening safety concerns. In some cases, particularly for patients with pre-existing kidney-related impairment, GI AEs and accompanying dehydration can lead to dangerous SAEs such as acute kidney injury, dialysis, amputation and even death. For patients so afflicted with GI AEs, they often must either immediately cease treatment or drop back and suffice with administration of more tolerable but lower and less efficacious doses of Wegovy. Still other patients choose to discontinue altogether their treatment, whether with Wegovy or any other GLP-1 RA or gut hormone analog therapy, for which similar dose escalations are likewise employed for the treatment of obesity and other cardiometabolic indications.

[0008] Cumbersome and potentially ineffective dose titrations are likewise required for administration of all approved and investigational treatments for obesity: Zepbound® (tirzepatide peptide for subcutaneous self-injection) is slowly titrated for four weeks per dose, from a starting dosage of 2.5 mg / week, followed by a dose titration of 5 mg / week, 7.5 mg / week, 10 mg / week, 12.5 mg / week, and up to a highest maintenance dosage of 15 mg / week. Zepbound provides threeWSGR Ref. No.: 56017-743.601maintenance dosages of 5 mg, 10 mg, and 15 mg / week for those patients who cannot tolerate the highest prescribed maintenance dose of 15 mg / week tirzepatide. Orforglipron (small molecule for oral administration) is likewise titrated from a starting dosage of 1 mg / day, through a dose titration of 3 mg / day, 6 mg / day, and 12 mg / day, and up to a highest maintenance dosage of 36 mg / day, and recently FDA approved oral Wegovy® (semaglutide GLP-1 RA peptide for oral administration) is similarly titrated from a starting dosage of 1.5 mg / day, through escalation dosages of 4 mg / day and 9 mg / day, each for 30 days, and up to a highest orally administered maintenance dosage of 25 mg / day semaglutide.

[0009] Two underlying issues exacerbate high occurrence of GI AEs and any related SAEs for this entire drug class: (i) rapid absorption of this class of drugs and (ii) the relatively high doses required for the treatment of obesity, and even greater combined doses required for combination therapies for the treatment of obesity, relative to lower doses that were previously found sufficient for the effective treatment of diabetes with GLP-1 RAs.

[0010] Regarding rapid absorption, small molecule gut-derived metabolic hormone analogs (e.g., orfoglipron GLP-1 RA) attain Tmax within one to twelve hours of oral administration, and peptide gut-derived metabolic hormone analogs, (e.g., semaglutide or MET-097i GLP-1 RAs or tirzepatide GLP-1 / G1P R / V) attain Tmax within one to four days of subcutaneous injectable administration. Patients often suffer their most pronounced occurrence GI AEs immediately following initial dosing at the onset of absorption of these drugs, and upon each increase in dose strength during titration, whether orally administered small molecules or subcutaneously injected peptides.

[0011] Newer and significantly higher doses are required for the effective treatment of obesity, relative to those previously developed for the treatment of diabetes with GLP-1 RAs. As such, patients being treated for obesity necessarily absorb much higher concentrations of drug and suffer substantially higher GI AEs at higher “obesity doses” than they would otherwise suffer on relatively lower “diabetes doses” of the same drug (e.g., GLP-1 or GLP-1 / GIP RA) for the treatment of diabetes.

[0012] Further, the notoriously high occurrence of GI AEs that accompanies administration of each of these gut hormone analogs as monotherapies for obesity (e.g., semaglutide monotherapy) becomes even worse upon attempts at co-administration of “combo” therapies of two or more of any such gut hormone analogs (e.g., “CagriSema®” combo therapy) for improved efficacy. Consequently, although developers of obesity treatments strive to attain increased efficacy by co¬ administration of two or more gut hormone analogs, unmanageably high GI AEs represent the most significant challenge and roadblock to clinical development of these much needed comboWSGR Ref. No.: 56017-743.601treatments - despite universal utilization of dose titrations. In December of 2024, Novo Nordisk announced top line data from its Phase 3 human clinical trial of CagriSema® (weekly subcutaneous injectable co-administration of the DACRA, cagrilintide, with the GLP-1 RA, semaglutide). These data revealed that, despite multi-month dose titration, GI AEs were intolerable to such an extent that only 57% of patients on the study could withstand the highest weekly maintenance dose, which is co-administration of 2.4 mg cagrilintide and 2.4 mg semaglutide. On average, 22.7% weight loss was achieved, despite 43% of patients failing to ever reach that highest maintenance dose. Indeed, high occurrence of GI. Es not only hampered the effectiveness of CagriSema during clinical trials, but these safety concerns place certain patients (for example those with any preexisting renal impairment) at increased risk for serious SAEs, including acute kidney injury, dialysis, and even death in the most extreme cases.

[0013] Accordingly, there remains a high unmet need to fundamentally redesign safer and more effective formulations of analogs of endogenous human gut hormones and methods for patient administration that yield superior dosing strategies for obesity treatments. Improved formulations and methods of administration could provide access to higher doses of therapeutic compounds that can be administered safely and comfortably to patients and attain greater efficacy with reduced risk of unwanted GI AEs and potentially life-threatening S / XEs.SUMMARY

[0014] The present invention relates to injectable pharmaceutical compositions comprising one or more therapeutic compounds, or pharmaceutically acceptable salts thereof, that have been developed to significantly reduce GI AEs and related SAEs relative to the high rates of occurrence of GI AEs upon administration of presently utilized oral or injectable formulations of the same therapeutic compounds. Also provided are processes of manufacture and methods of administering the same to patients for the treatment of a disease or disorder, such as overweightedness, obesity and other cardiometabolic indications. The formulations and dosing strategies described herein provide dramatically improved safety and tolerability upon injectable administration, which in turn permits safe and tolerable access to higher and more efficacious doses of drug that, in the case of obesity and related disorders, achieve greater weight loss. In some embodiments, the injectable pharmaceutical compositions as provided herein have improved properties or characteristics compared with the conventionally known pharmaceutical compositions.

[0015] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer; wherein the therapeutic compound is selected from the group consisting of the compounds asWSGR Ref. No.: 56017-743.601described in Table 1, or a pharmaceutically acceptable salt thereof; andthe biodegradable polymer is a co-polymer that derives from first monomers of (i) one or both of glycolide and lactide (L, D or DL), and (ii) one or more additional monomers other than glycolide and lactide.

[0016] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound and a biodegradable polymer;wherein:the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof; andthe biodegradable polymer is a co-polymer that derives from:(i) first monomers of glycolide, lactide, or a combination of glycolide and lactide,wherein the lactide is L-lactide, D-lactide or DL-lactide, and(ii) one or more additional monomers other than glycolide and lactide,

[0017] In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), and co-polymers thereof.

[0018] In some embodiments, the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, 8-caprolactone, 1,4-butane diol, 1,4-butanediisocyanate, -CONHCH2CH2CH2CH2NHCO-, 1,6-hexane diol, 1,6-hexanediisocyanate, substituted lactide, substituted glycolide, 6-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, cyclic anhydride, hydroxymethyl -glycolide, succinic acid, butyric acid, valeric acid, 3-hydroxybutyric acid (3-HB), 3 -hydroxy valeric acid (3-HV), glucose, fructose, glucosamine, oxalic acid, diketene acetal, sebacic acid, adipic acid, terephthalic acid, N-vinylpyrrolidone, N-vinylcaprolactam, 2- hydroxyethyl methacrylate, alkyl cyanoacrylate, a diisocyanate, an a-amino acid, a dicarboxylic acid, and a diol.

[0019] In some embodiments, the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, e-caprolactone, 1,4-butane diol, CONHCH2CH2CH2CH2NHCO-, 6-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, and cyclic anhydride.

[0020] In some embodiments, the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PEG-PPG), polytetramethylene ether glycol (PTMG), polycaprolactone (PCL), polydioxanoneWSGR Ref. No.: 56017-743.601(PDO), polyhydroxyalkanoates (PHAs), polyphosphazenes, polylactide-co-glycolide-co-caprolactone, (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polycarbonate, polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylene carbonate (polylactide-co-trimethylenecarbonate, PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester polysaccharide, poly(butylene succinate lactide) (PBSLA), polyesteramide, poly alkylene oxalates, biodegradable polyurethanes, polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly-(HEMA)), polycyanoacrylate, galactose, polyol, cellulose, starch, chitosan, silk, collagen, polybutylene succinate (PBS), hyaluronic acid, alginate, gelatin, and copolymers thereof.

[0021] In some embodiments, the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polycaprolactone (PCL), polydioxanone (PDO), and copolymers thereof.

[0022] In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PEA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polycaprolactone (PCL), polydioxanone (PDO), and copolymers thereof.

[0023] In some embodiments, the microparticle further comprises an excipient.

[0024] In some embodiments, the excipient is selected from the group consisting of a buffer, a pharmaceutically acceptable salt, a solvent, an amino acid, a poly(amino acid), a cyclodextrin, a viscosity modifier, a polysaccharide, a surfactant, a hydrogel, or any combination thereof.

[0025] In some embodiments,(i) the buffer comprises TRIS (Tris(hydroxymethyl)aminomethane), sodium phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, choline bicarbonate, EDTA, or any combination thereof;(ii) the pharmaceutically acceptable salt comprises sodium chloride, choline chloride, betaine HC1, carnitine HO, or any combination thereof;(iii) the solvent comprises methylene chloride, methanol, ethanol, acetic acid, formic acid, trifluoroacetic acid, polyvinyl alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DM SO), N-methyl-2-pyrrolidone (NMP), benzyl alcohol, or any combination thereof;WSGR Ref. No.: 56017-743.601(iv) the amino acid comprises arginine, histidine, lysine, aspartic acid, glutamic acid, or any combination thereof;(v) the poly(amino acid comprises poly(glutamic acid), poly(aspartic acid), or any combination thereof;(vi) the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin (HPBCD), sulfobutyl ether beta¬ cyclodextrin (SBE-P-CD), carboxymethyl cyclodextrin (CMCD), sulfated cyclodextrin, or any combination thereof;(vii) the viscosity modifier comprises carboxymethyl cellulose (CMC), hyaluronic acid, or any combination thereof;(viii) the polysaccharide comprises carrageenan, alginate, dextran sulfate, trehalose, or any combination thereof;(ix) the surfactant comprises a pluronic;(x) the hydrogel comprises a thermogelling aliphatically modified block copolymer; or(xi) any combination thereof.

[0026] In some embodiments,(a) the sulfobutyl ether beta-cyclodextrin is Captisol®);(b) the pluronic comprises pluronic F 127; or(c) a combination thereof.

[0027] In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 5% (wt / wt %) to about 50% (wt / wt %).

[0028] In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 5% (wt / wt %) to about 25% (wt / wt %).

[0029] In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 10% (wt / wt %) to about 20% (wt / wt %).

[0030] In some embodiments, the microparticle comprises a weight % of the biodegradable polymer of from about 50% (wt / wt %) to about 95% (wt / wt %).

[0031] In some embodiments, the microparticle comprises a weight % of the biodegradable polymer of from about 50% (wt / wt %) to about 95% (wt / wt %) and further comprises a loading % of the therapeutic compound of from about 10% (wt / wt %) to about 25% (wt / wt %).

[0032] In some embodiments, the microparticle has a mean diameter of from about 20 pm to about 80 pm.

[0033] In some embodiments, the therapeutic compound is selected from the group consisting of a GLP-1 (glucagon-like peptide-1) Receptor Agonist (RA), GIP (glucose-dependent insulinotropic polypeptide) RA, Amylin RA, Selective Amylin Receptor / Xgonist (SARA), DualWSGR Ref. No.: 56017-743.601Amylin & Calcitonin Receptor Agonist (DACRA), Glucagon RA, PYY RA, GIP Receptor Antagonist, an oxyntomodulin analogue, and any combination thereof.

[0034] In some embodiments, the therapeutic compound is a peptide of from about 20 to about 50 amino acids.

[0035] In some embodiments, the therapeutic compound is a peptide of from about 20 to about 50 amino acids, and the peptide further comprises a fatty diacid moiety' covalently attached to the peptide via a linker moiety.

[0036] In some embodiments, the therapeutic compound comprises an antibody or antibody conjugate.

[0037] In some embodiments, the therapeutic compound is a small molecule.

[0038] In some embodiments, the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the therapeutic compound is any one compound selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, and A8, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the therapeutic compound is seniaglutide (compound Al) or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the therapeutic compound is seniaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the therapeutic compound is i2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the therapeutic compound is i2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the therapeutic compound is pramlintide (compound A6) or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the therapeutic compound is pramlintide acetate (compound A7) or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of an acetate salt, a choline salt, a sodium salt, and a chloride salt.

[0047] In some embodiments, the pharmaceutically acceptable salt is a choline salt.

[0048] In another aspect, provided herein is a pharmaceutical composition comprising the microparticle as described herein suspended in a diluent.

[0049] In some embodiments, the diluent is an aqueous diluent.WSGR Ref. No.: 56017-743.601

[0050] In some embodiments, the diluent is a non-aqueous diluent.

[0051] In some embodiments, the non-aqueous diluent is a Miglyol®.

[0052] In some embodiments, the non-aqueous diluent is Miglyol 812,

[0053] In some embodiments, the pharmaceutical composition is formulated for injection through an injection needle having a needle gauge of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.

[0054] In another aspect, provided herein is an injection device comprising a chamber and an injection needle, wherein the chamber contains the microparticle as described herein or the pharmaceutical composition as described herein.

[0055] In some embodiments, the injector is an autoinjector,

[0056] In some embodiments, the injector is an autoinjector for subcutaneous self-administration by a patient.

[0057] In some embodiments, the injection needle has a needle gauge of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.

[0058] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject the microparticle as described herein or the pharmaceutical composition as described herein via injectable administration, wherein the microparticle or the phar aceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein administration of the maintenance dose is in the absence of a prior dose titration comprising one or more prior doses less than the maintenance dose, and further in the absence of a subsequent dose titration comprising one or more subsequent doses greater than the maintenance dose.

[0059] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject a pharmaceutical composition via injectable administration, wherein the pharmaceutical composition comprises a suspension of microparticles in a diluent, wherein the microparticles comprise a therapeutic compound, and a biodegradable polymer, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof;wherein the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein administration of the maintenance dose is in the absence of a prior dose titrationWSGR Ref. No.: 56017-743.601comprising one or more prior doses less than the maintenance dose, and further in the absence of a subsequent dose titration comprising one or more subsequent doses greater than the maintenance dose.

[0060] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject a pharmaceutical composition via injectable administration, wherein the pharmaceutical composition comprises a suspension of microparticles in a diluent, wherein the microparticles comprise a therapeutic compound, and a biodegradable polymer; the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof;wherein the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein a Tmax of the therapeutic compound in the subject is reached from about 10 days to about 60 days following a first administration of the pharmaceutical composition.

[0061] In some embodiments, the Tmax of the therapeutic compound is attained in the subject as a substantially single bell-shaped peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound, following the first administration.

[0062] In some embodiments, the Tmax of the therapeutic compound is attained in the subject as a substantially unimodal peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound following the first administration.

[0063] In some embodiments, the Tmax of the therapeutic compound is attained in the subject as a substantially single bell-shaped peak, in the absence of prior burst release in plasma absorption of the therapeutic compound of up to 20% of the Tmax following the first administration.

[0064] In some embodiments, the Tmax of the therapeutic compound is attained in the subject as a substantially unimodal peak, in the absence of prior burst release in plasma absorption of the therapeutic compound of up to 20% of the Tmax following the first administration.

[0065] In some embodiments, a plasma concentration of the therapeutic compound in the subject is not more than 10% of the Tmax within about 2 days following the first administration.

[0066] In some embodiments, a plasma concentration of the therapeutic compound in the subject is not more than 25% of the Tmax within about 7 days following the first administration.

[0067] In some embodiments, a plasma concentration of the therapeutic compound in the subject is not more than 50% of the Tmax within about 10 days following the first administration.

[0068] In some embodiments, a plasma concentration of therapeutic compound in the subject is not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,WSGR Ref. No.: 56017-743.60117%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the Ttnax within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 days following the first administration.

[0069] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject a pharmaceutical composition via injectable administration, wherein the pharmaceutical composition comprises a suspension of microparticles in a diluent; wherein the microparticles comprise a therapeutic compound, and a biodegradable polymer; wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof;wherein the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein the pharmaceutical composition is administered such that the ratio between the plasma half-life of the therapeutic compound in days in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:100 to about 1:2,

[0070] In some embodiments, the ratio between the plasma half-life of the therapeutic compound in days in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:50 to about 1:2.

[0071] In some embodiments, the ratio between the plasma half-life of the therapeutic compound in days in in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:25 to about 1:2.

[0072] In some embodiments, the ratio between the plasma half-life of the therapeutic compound in days in in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:10 to about 1:2.

[0073] In some embodiments, the therapeutic compound is semaglutide (compound Al), having a plasma half-life of about 7 days in the subject and a dosing interval of about 30 days, wherein the ratio between the plasma half-life of the therapeutic compound in days in the subject and theWSGR Ref. No.: 56017-743.601dosing interval of the pharmaceutical composition in days is about 1:4.3.

[0074] In some embodiments, the maintenance dose is from about 5 mg to about 50 mg of the therapeutic compound per administration.

[0075] In some embodiments, the maintenance dose is from about 10 mg to about 25 mg of the therapeutic compound per administration.

[0076] In some embodiments, the therapeutic compound is semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg semaglutide for administration once per month.

[0077] In some embodiments, the therapeutic compound is semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg semaglutide choline for administration once per month.

[0078] In some embodiments, the therapeutic compound is cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg cagrilintide for administration once per month.

[0079] In some embodiments, the therapeutic compound is i2o-1061 (compound A4) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg i2o-1061 for administration once per month.

[0080] In some embodiments, the therapeutic compound is i2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg i2o-2248 for administration once per month.

[0081] In some embodiments, the therapeutic compound is i2o-2248 choline (compound A8) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg i2o-2248 choline for administration once per month.

[0082] In some embodiments, the therapeutic compound is pramlintide (compound A6) or pramlintide acetate (compound A7 ) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg pramlintide or pramlintide acetate, for administration once per month.

[0083] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 10% to about 30% weight reduction in the population of subjects.

[0084] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 15% to about 35% weight reduction in the population of subjects.

[0085] In some embodiments, the maintenance dose of the therapeutic compound, uponWSGR Ref. No.: 56017-743.601administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 20% gastrointestinal adverse events (GI AEs) in the population of subjects.

[0086] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 10% GI AEs in the population of subjects.

[0087] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 15% incidence of nausea in the population of subjects.

[0088] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 10% incidence of nausea in the population of subjects.

[0089] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 15% incidence of vomiting in the population of subjects.

[0090] In some embodiments, the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 10% incidence of vomiting in the population of subjects.

[0091] In some embodiments, the microparticle or the pharmaceutical composition is administered to the subject or a population of subjects at the maintenance dose of the therapeutic compound for a period of time from about four (4) weeks to about one hundred (100) weeks.

[0092] In some embodiments, the population of subjects comprises from about twenty (20) to about twenty thousand (20,000) subjects.

[0093] In some embodiments, the microparticle or the pharmaceutical composition is administered via subcutaneous injection.

[0094] In some embodiments, the microparticle or the pharmaceutical composition is administered via self-administered subcutaneous injection.

[0095] In some embodiments, the microparticle or the pharmaceutical composition is administered once per week, once per two weeks, once per month, once per two months, once per three months, once per a quarter year, once per four months, once per five months, once per six months, or once per year.

[0096] In some embodiments, the microparticle or the pharmaceutical composition is administered once per week, once per two weeks, once per three weeks, once per four weeks, once per month, once per two months, once per three months, once per four months, once per fiveWSGR Ref. No.: 56017-743.601months, once per six months, once per seven months, once per eight months, once per nine months, once per ten months, once per eleven months, once per twelve month, once per a quarter year, or once per year.

[0097] In some embodiments, the microparticle or the pharmaceutical composition is administered once per month.

[0098] In some embodiments, the microparticle or the pharmaceutical composition is administered once per a quarter year.

[0099] In some embodiments, the disease or disorder is selected from the group consisting of a metabolic disease or disorder, a cardiometabolic disease or disorder, a cardiovascular disease or disorder, kidney related disease, and a neurological disease or disorder.

[0100] In some embodiments, the disease or disorder is selected from the group consisting of type 1 diabetes, type 2 diabetes, a pre-diabetic condition, obesity, overweight, need for weight loss, metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH, i.e., nonalcoholic steatohepatitis NASH), arrhythmia, coronary artery disease, heart failure, valve disease, aortic disease, congenital heart disease, heart attack, angina, cardiomyopathy, peripheral arterial disease, atherosclerosis, cardiac dysrhythmias, pericarditis, pulmonary hypertension, stroke, cerebrovascular disease, rheumatic heart disease, atrial fibrillation, Brugada syndrome, aortic stenosis, bradycardia, endocarditis, high cholesterol, long QT syndrome, chronic kidney disease, epilepsy, Alzheimer disease, dementias, stroke, multiple sclerosis, Parkinson’s disease, neuroinfections, brain tumors, amyotrophic lateral sclerosis (ALS), tauopathies, age-related macular degeneration, sleep apnea, arthritis, infertility, alcohol addiction and drug addiction.

[0101] In some embodiments, the disease or disorder is a cardiometabolic indication.

[0102] In some embodiments, the disease or disorder is overweightedness or obesity.

[0103] In some embodiments, the subject is a human.

[0104] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining the ratio between the plasma half-life of the therapeutic compound in days in a subject and the dosing interval of the microparticle in days that is from about 1:100 to about 1:2, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0105] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for administering a therapeutic compound to a subject inWSGR Ref. No.: 56017-743.601the absence of a prior dose titration comprising one or more prior doses less than a maintenance dose of from about 4 mg to about 100 mg, and further in the absence of a subsequent dose titration comprising one or more subsequent doses greater than the maintenance dose of from about 4 mg to about 100 mg,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0106] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound in a subject that is reached from about 10 days to about 60 days following a first administration of the therapeutic compound, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound that is attained in a subject as a substantially single bell-shaped peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0108] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound that is attained in a subject as a substantially unimodal peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound following the first administration, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0109] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound that is attained in a subject as a substantially unimodal peak, in the absence of prior burst release in plasma absorption of the therapeutic compound not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%,WSGR Ref. No.: 56017-743.60142%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the Tmax within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 days following the first administration, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0110] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for inducing from about 10% to about 30% weight reduction in a population of subjects, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the population of subjects, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table I, or a pharmaceutically acceptable salt thereof.

[0111] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for inducing from about 1% to about 20% gastrointestinal adverse events (GI AEs) in a population of subjects, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the population of subjects, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0112] In another aspect, provided herein is a microparticle comprising a therapeutic compound and a biodegradable polymer for administering the therapeutic compound to a subject once per week, once per two weeks, once per three weeks, once per four weeks, once per month, once per two months, once per three months, once per four months, once per five months, once per six months, once per seven months, once per eight months, once per nine months, once per ten months, once per eleven months, once per twelve month, once per a quarter year, or once per year,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the biodegradable polymer is a co-polymer that derives from:WSGR Ref. No.: 56017-743.601(i) first monomers of, glycolide, lactide, or a combination of glycolide and lactide,wherein the lactide is L-lactide, D-lactide or DL-lactide, and(ii) one or more additional monomers other than glycolide and lactide.BRIEF DESCRIPTION OF THE DRAWINGS

[0114] FIG. 1A shows experimentally determined rat plasma concentration of semaglutide administered via subcutaneous injection of a single dose of (a) aqueous semaglutide (Wegovy, left-hand peak at day 1) and (b) non-aqueous semaglutide choline (Formulation A, right-hand peak at day 14).

[0115] FIG. IB shows (a) experimentally determined human plasma concentration of semaglutide administered via subcutaneous injection of a single dose of aqueous semaglutide (Wegovy®) and (b) projected human plasma concentration of semaglutide from subcutaneous injection of a single dose of non-aqueous semaglutide choline (Formulation A).

[0116] FIG. 2 shows experimentally determined human plasma concentrations of a single dose of (a) orforglipron administered orally, (b) aqueous MET-097i administered via subcutaneous injection, (c) aqueous tirzepatide (Zepbound®) administered via subcutaneous injection, (d) aqueous semaglutide (Wegovy®) administered via subcutaneous injection, and (e) projected human plasma concentration of semaglutide from subcutaneous injection of a single dose of non-aqueous semaglutide choline (Formulation A).

[0117] FIG. 3 shows (a) projected human plasma concentration of semaglutide from six months of six successive monthly subcutaneous injections, without titration, of non-aqueous semaglutide choline (Formulation A), and (b) experimentally determined human plasma concentrations from six months of successive weekly subcutaneous injections, via 5-stage dose titration (0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg / week) of aqueous semaglutide (Wegovy®).

[0118] FIG. 4 shows experimentally determined percentage (%) change in rat body weight from baseline upon subcutaneous injections of a single dose of non-aqueous semaglutide choline (Formulation A).

[0119] FIG. 5 shows experimentally determined cumulative in vitro release (IVR.) of semaglutide from biodegradable polymer microparticles of semaglutide choline (Formulation A).

[0120] FIG. 6 shows experimentally determined cumulative in vitro release (IVR) of semaglutide from multiple biodegradable polymer microparticle formulations of semaglutide choline as (a) Formulation A; (b) Formulation B; (c) Formulation C; and (d) Formulation D.

[0121] FIG. 7 shows experimentally determined cumulative in vitro release (IVR) of semaglutide from multiple biodegradable polymer microparticle formulations of semaglutide choline as (e) Formulation E; (f) Formulation F; (g) Formulation G; and (h) Formulation H.WSGR Ref. No.: 56017-743.601

[0122] FIG. 8A and FIG. 8B show biodegradable microspheres of semaglutide choline having 5.6% loading of semaglutide choline (97% encapsulation efficiency) and 42 pm average particle size.

[0123] FIG. 9 shows results of Example 15, specifically cumulative food intake over 87 hours for each of 7 dose groups. Feeding cycles, represented as the steeper upward slopes, were interspersed with 3 “lights-on” periods of little or no feeding, represented as near-horizontal segments.

[0124] FIG. 10 shows additional results of Example 15, specifically cumulative food intake as a percentage of the vehicle-treated group’s intake measured at the same time.

[0125] FIG. HA is a graph illustrating changes in blood concentration of semaglutide over time after administering prior art PLGA microspheres containing semaglutide to rats, as described in WO 2024 / 010379. Changes include burst release and multiple peaks in semaglutide concentration.

[0126] FIG. 11B is a graph illustrating changes in blood concentration of semaglutide over time after administering prior art PLGA microspheres containing semaglutide to rats, as described in WO 2022 / 270956. Lines (a), (b) and (c) each has 6%, 4% and 3% loading of semaglutide, respectively. Changes include burst release and multiple peaks in semaglutide concentration.

[0127] FIG. 11C is a graph illustrating changes in blood concentration of semaglutide over time after administering prior art AdoGel® crosslinked degradable polymer hydrogel containing semaglutide to rats, as described in Diabetes. 2024;73 (Supplement_l). Changes include burst release in semaglutide concentration.

[0128] FIG. I ID is a graph illustrating changes in blood concentration of small molecule GLP-1 agonist D4 over time after administering three prior art PLGA-based in situ forming depots formulations (a), (b) and (c) of D4 to rats, as described in WO 2025 / 011664. Changes include burst release in semaglutide concentration.

[0129] FIG. HE is a graph illustrating changes in blood concentration of semaglutide over time after administering prior art semaglutide prodrug (i.e., semaglutide connected via cleavable linker to 50 p hydrogel microspheres) to mice, as described in PNAS 2024 Vol. 121 No. 47 e2415815121. Changes include burst release and multiple peaks in semaglutide concentration.

[0130] FIG. HF is a graph illustrating changes in blood concentration of semaglutide over time after administering prior art semaglutide prodrug (i.e., semaglutide connected via cleavable linker to TransCon™ Carrier Platform) to rats, as described in Ascendis Pharma corporate presentation “New TransCon™ Carrier Platform” of September 5, 2023. Changes include burst release in semaglutide concentration.WSGR Ref. No.: 56017-743.601

[0131] FIG. 12 shows aqueous solubility of choline semaglutide at all tested concentrations of 1 mg / mL, 5 mg / mL and 10 mg / mL in water that resulted in clear solutions at 25°C. By contrast, the base form of semaglutide (i.e., semaglutide free acid) was insoluble in water at all tested concentrations of 1 mg / mL, 5 mg / mL and 10 mg / mL in water that resulted in precipitation at 25°C.

[0132] FIG. 13 shows aqueous solubility of choline semaglutide at a concentration of 200 mg / mL in TRIS buffer stored at 37°C for eight (8) days. By contrast, the base form of semaglutide (i.e., semaglutide free acid) at a concentration of 200 mg / mL in TRIS buffer stored at 37°C gelled irreversibly at day three (3).

[0133] FIG. 14 illustrates the tendency of the base form of semaglutide (i.e., semaglutide free acid) and semaglutide sodium to aggregate in water as 1 mg / mL solutions at 40°C, where data were obtained on an hourly basis for one week (n = 5). By contrast, 1 mg / mL semaglutide choline in water showed complete resistance to aggregation at 40°C, where data were obtained on an hourly basis for one week (n = 5).DETAILED DESCRIPTION

[0134] The present invention relates to injectable pharmaceutical compositions comprising one or more therapeutic compounds, or pharmaceutically acceptable salts thereof, that have been developed to significantly reduce GI AEs and related SAEs relative to the high rates of occurrence of GI AEs upon administration of presently utilized oral or injectable formulations of the same therapeutic compounds. Also provided are processes of manufacture and methods of administering the same to patients for the treatment of a disease or disorder, such as overweightedness, obesity and other cardiometabolic indications. In some embodiments, the subject is treated to obtain weight loss or weight reduction. In some embodiments, the subject is treated for weight loss or weight reduction. The improved formulations and dosing strategies described herein provide dramatically improved safety and tolerability upon injectable administration, which in turn permits safe and tolerable access to higher and more efficacious doses of drug that, in the case of obesity and related disorders, achieve greater weight loss. In some embodiments, the injectable pharmaceutical compositions as provided herein have improved properties or characteristics compared with the conventionally known pharmaceutical compositions. In some embodiments, the injectable pharmaceutical compositions as provided herein exhibit significantly reduce both gastrointestinal adverse events (GI AEs) and related serious adverse events (SAEs) relative to the high rates of occurrence of GI AEs and accompanying SAEs upon administration of existing formulations, whether oral or injectable, of the same therapeutic compounds.WSGR Ref. No.: 56017-743.601

[0135] Surprisingly, after significant trial, error, and optimization, Applicant discovered and developed much improved long-acting pharmaceutical compositions and dosing strategies that achieve significantly improved administration of GI AE-inducing therapeutic compounds, including therapeutic peptides and small molecules described herein. In preferred embodiments, the long-acting pharmaceutical compositions of the invention are formulated into precisely tuned biodegradable microparticles comprising the therapeutic compound and certain biodegradable polymers for administration via subcutaneous self-injection. Notably, the biodegradable microparticle-based pharmaceutical compositions described herein permit administration of a therapeutic compound (i) at higher and more efficacious dosing, that counterintuitively (ii) provides lower incidence of GI AEs in subjects than the incidence of GI AEs from administration of conventional oral or injectable formulations of the same therapeutic compound that are presently in use. Further, the biodegradable microparticle-based pharmaceutical compositions described herein further permit (iii) direct maintenance dosing in the absence of a prior dose titration, i.e., in the absence of one or more prior doses of the therapeutic compound at lower dose strengths (i.e., having fewer milligrams of therapeutic compound) than the maintenance dose. A further advantage of the present invention is (iv) infrequent dosing via self-administered periodic injections such as once per month or once per quarter of a year or according to other convenient dosing intervals described herein. Representative non-limiting therapeutic compounds (e.g., peptides and small molecules), and non-limiting biodegradable polymers are described herein.

[0136] Applicants discovered how to precisely tune certain injectable suspensions of biodegradable microparticles upon careful pairing of each therapeutic compound with an appropriate biodegradable polymer, addition of certain additives in some instances, and selection of appropriate diluent, in which the microparticles are suspended, upon injection. The innovative formulations and improved dosing strategies described herein were designed to dramatically minimize the onset of GI AEs for greater safety, despite surprisingly and significantly increasing the dose of therapeutic peptide that can be well tolerated, for greater efficacy, such as weight loss. Accordingly, the improved formulations and dosing strategies described herein permit access to higher, more efficacious, and more safely tolerable doses of therapeutic compounds described herein, relative to administration of known conventional oral formulations of GI AE-inducing small molecules, and relative to known aqueous injectable formulations of GI AE-inducing peptides, particularly for the treatment of overweightedness, obesity and other cardiometabolic indications.

[0137] The following is a non-limiting summary of certain embodiments of the invention. More detailed descriptions of additional embodiments of the invention are also provided below.WSGR Ref. No.: 56017-743.601

[0138] In another aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound (such as pramlintide), or a pharmaceutically acceptable salt thereof, and a biodegradable polymer; whereinthe therapeutic compound is selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof; andthe biodegradable polymer is a co-polymer that derives from monomers of one or both of glycolide and lactide (L, D or DL), wherein the monomers of one or both of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) copolymers.

[0139] In some embodiments, the therapeutic compound is pramlintide, or a pharmaceutically acceptable salt thereof. In some embodiments, the microparticle further comprises any of the excipients described herein.

[0140] In some embodiments, microparticles are prepared from an emulsification process selected from the group consisting of an oil-in-water (O / W) emulsification process, a water-in- oil-in-water (W / O / W) emulsification process, a solid-in-oil-in-water (S / O / W) emulsification process, and a solid-in-oil-in-oil (S / O / O) emulsification process.

[0141] In some embodiments, microparticles are prepared from an oil-in-water (O / W) emulsification process. In some embodiments, microparticles are prepared from a water-in-oil-in- water (W / O / W) emulsification process. In some embodiments, microparticles are prepared from a solid-in-oil-in-water (S / O / W) emulsification process. In some embodiments, microparticles are prepared from a solid-in-oil-in-oil (S / O / O) emulsification process.Microparticles

[0142] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer; wherein the therapeutic compound is selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof; andthe biodegradable polymer is a co-polymer that derives from first monomers of (i) one or both of glycolide and lactide (L, D or DL), and (ii) one or more additional monomers other than glycolide and lactide.

[0143] In some embodiments, the pharmaceutical compositions described herein comprise microparticles (also described herein as microspheres) comprising one or more therapeutic compounds and a biodegradable polymer. The term "microparticle(s)" as used herein refers toWSGR Ref. No.: 56017-743.601intradermally, transdermally, intramuscularly, or subcutaneously injectable particles comprising a biodegradable polymer, and a therapeutic compound, or pharmaceutically acceptable salts thereof. Microparticles have certain physical properties useful for biodegradable drug delivery systems, including desirable degradability and porosity for sustained delivery of active ingredients in a relatively constant manner over an extended period of time. In some embodiments, as used herein, either of the terms “microparticles” or “microspheres” is used interchangeably to include particles, spheres, microspheres, microparticles nanoparticles, and the like.

[0144] A microparticle can have a spherical, non- spherical, regular or irregular shape. In some embodiments, the microparticle is substantially spherical.

[0145] Size distribution of microparticles can be described using a mean diameter of the volume. Mean diameter of the volume distribution represents the center of gravity of the distribution and is a type of “average particle size.” In some embodiments, microparticles have a mean diameter of the volume distribution of between about 20 microns to about 100 microns, such as about 20, 30, 40, 50, 60, 7080, 90 or 100 microns, or an average particle size between any two of these values. Microparticles of the present disclosure may have an average diameter, e.g., average particle size, of about 1 pm to about 100 pm. In some embodiments, the microparticles have an average diameter of about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 55 pm, about 60 pm, about 65 pm, about 70 pm, about 75 pm, about 80 pm, about 85 pm, about 90 pm, about 95 pm, about 100 pm, or an average diameter between any two of these values. In some embodiments, the microparticle has a mean diameter of from about 20 pm to about 80 pm.

[0146] In some embodiments, microspheres or microparticles will be of a size and diameter (e.g., from about 1 to 100 pm (microns) suitable for administration via injection by passage through a 25-35 gauge needle, such as through a 25 gauge needle, 27 gauge needle, 30 gauge needle, 31 gauge needle, 32 gauge needle, 33 gauge needle, 34 gauge needle, or 35 gauge needle.

[0147] In some embodiments, “drug loading” of the microparticles, meaning the weight percentage of any one or more of the therapeutic compounds (e.g., of Table 1), or pharmaceutically acceptable salts thereof, relative to the weight percentage of the microparticles is a (wt. %) selected from the group consisting of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2,WSGR Ref. No.: 56017-743.60114.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, 50.0, 50.1, 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9, 51.0, 51.1, 51.2, 51.3, 51.4, 51.5, 51.6, 51.7, 51.8, 51.9, 52.0, 52.1, 52.2, 52.3, 52.4, 52.5, 52.6, 52.7, 52.8, 52.9, 53.0, 53.1, 53.2, 53.3, 53.4, 53.5, 53.6, 53.7, 53.8, 53.9, 54.0, 54.1, 54.2, 54.3, 54.4, 54.5, 54.6, 54.7, 54.8, 54.9, 55.0, 55.1, 55.2, 55.3, 55.4, 55.5, 55.6, 55.7, 55.8, 55.9, 56.0, 56.1, 56.2, 56.3, 56.4, 56.5, 56.6, 56.7, 56.8, 56.9, 57.0, 57.1, 57.2, 57.3, 57.4, 57.5, 57.6, 57.7, 57.8, 57.9, 58.0, 58.1, 58.2, 58.3, 58.4, 58.5, 58.6, 58.7, 58.8, 58.9, 59.0, 59.1, 59.2, 59.3, 59.4, 59.5, 59.6, 59.7, 59.8, 59.9, 60.0, 60.1, 60.2, 60.3, 60.4, 60.5, 60.6, 60.7, 60.8, 60.9, 61.0, 61.1, 61.2, 61.3, 61.4, 61.5, 61.6, 61.7, 61.8, 61.9, 62.0, 62.1, 62.2, 62.3, 62.4, 62.5, 62.6, 62.7, 62.8, 62.9, 63.0, 63.1, 63.2, 63.3, 63.4, 63.5, 63.6, 63.7, 63.8, 63.9, 64.0, 64.1, 64.2, 64.3, 64.4, 64.5, 64.6, 64.7, 64.8, 64.9, 65.0, 65.1, 65.2, 65.3, 65.4, 65.5, 65.6, 65.7, 65.8, 65.9, 66.0, 66.1, 66.2, 66.3, 66.4, 66.5, 66.6, 66,7, 66.8, 66,9, 67.0, 67.1, 67.2, 67.3, 67.4, 67.5, 67.6, 67.7, 67.8, 67.9, 68.0, 68.1, 68.2, 68.3, 68.4, 68.5, 68.6, 68.7, 68.8, 68.9, 69.0, 69.1, 69.2, 69.3, 69.4, 69.5, 69.6, 69.7, 69.8, 69.9, 70.0, 70.1, 70.2, 70.3, 70.4, 70.5, 70.6, 70.7, 70.8, 70.9, 71.0, 71.1. 71.2, 71.3, 71.4, 71.5, 71.6, 71.7, 71.8, 71.9. 72.0,WSGR Ref. No.: 56017-743.60172.1, 72.2, 72.3, 72.4, 72.5, 72.6, 72.7, 72.8, 72.9, 73.0, 73.1, 73.2, 73.3, 73.4, 73.5, 73.6, 73.7, 73.8, 73.9, 74.0, 74.1, 74.2, 74.3, 74.4, 74.5, 74.6, 74.7, 74.8, 74.9, 75.0, 75.1, 75.2, 75.3, 75.4, 75.5, 75.6, 75.7, 75.8, 75.9, 76.0, 76.1, 76.2, 76.3, 76.4, 76.5, 76.6, 76.7, 76.8, 76.9, 77.0, 77.1, 77.2, 77.3, 77.4, 77.5, 77.6, 77.7, 77.8, 77.9, 78.0, 78.1, 78.2, 78.3, 78.4, 78.5, 78.6, 78.7, 78.8, 78.9, 79.0, 79.1, 79.2, 79.3, 79.4, 79.5, 79.6, 79.7, 79.8, 79.9, 80.0, 80.1, 80.2, 80.3, 80.4, 80.5, 80.6, 80.7, 80.8, 80.9, 81.0, 81.1, 81.2, 81.3, 81.4, 81.5, 81.6, 81.7, 81.8, 81.9, 82.0, 82.1, 82.2, 82.3, 82.4, 82.5, 82.6, 82.7, 82.8, 82.9, 83.0, 83.1, 83.2, 83.3, 83.4, 83.5, 83.6, 83.7, 83.8, 83.9, 84.0, 84.1, 84.2, 84.3, 84.4, 84.5, 84.6, 84.7, 84.8, 84.9, 85.0, 85.1, 85.2, 85.3, 85.4, 85.5, 85.6, 85.7, 85.8, 85.9, 86.0, 86.1, 86.2, 86.3, 86.4, 86.5, 86.6, 86.7, 86.8, 86.9, 87.0, 87.1, 87.2, 87.3, 87.4, 87.5, 87.6, 87.7, 87.8, 87.9, 88.0, 88.1, 88.2, 88.3, 88.4, 88.5, 88.6, 88.7, 88.8, 88.9, 89.0, 89.1, 89.2, 89.3, 89.4, 89.5, 89.6, 89.7, 89.8, 89.9, and 90.0, or within a range of any two of the above values. In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 5 to about 50%, 5 to about 25%, or 10 to about 20% (wt / wt %). In some embodiments, the microparticle comprises a weight % of polymer of from about 50% to about 95% (wt / wt %).Excipients

[0148] In some embodiments, the microparticle further comprising an excipient. In some embodiments, the excipient is selected from the group consisting of a buffer (such as TRIS, sodium phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, choline bicarbonate and EDTA), a pharmaceutically acceptable salt (such as any of those described herein including sodium chloride, choline chloride, betaine HC1 and carnitine HO), a solvent (such as methylene chloride, methanol, ethanol, acetic acid, formic acid, trifluoroacetic acid, polyvinyl alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP) and benzyl alcohol), amino acid (such as arginine, histidine, lysine, aspartic acid and glutamic acid), poly(amino acid) (such as (poly(glutamic acid) and poly(aspartic acid)), cyclodextrin (such as hydroxypropyl-beta-cyclodextrin (HPBCD), sulfobutyl ether beta-cyclodextrin (SBE-p-CD, Captisol®), carboxymethyl cyclodextrin (CMCD) and sulfated cyclodextrin), viscosity modifier (such as carboxymethyl cellulose (CMC) and hyaluronic acid), polysaccharide (such as carrageenan, alginate, dextran sulfate and trehalose), surfactant (such as a pluronic, e.g., pluronic F127) and thermogelling aliphatically modified block copolymers as disclosed such as for example poly(lactide-co-£-caprolactone)-poly(ethylene glycol)-poly(lactide-co-s-caprolactone) acetate (e g. Ingell Gamma PEG1500(Cap50Lac50)2.2-C2), poly(lactide-co-s-caprolactone)-poly(ethylene glycol)-poly(lactide-co-£-caprolactone) propionate (e.g. Ingell GammaWSGR Ref. No.: 56017-743.601PEG1500(Cap50-Lac50)2.2-C3) or poly(lactide-co-s-caprolactone)-poly(ethylene glycol)-poly(lactide-co-£-caprolactone) hexanoate (e.g. Ingell Gamma PEG1500(Cap50-Lac50)2.2-C6).

[0149] In some embodiments, the excipient is selected from the group consisting of a buffer, antimicrobial agent, a surfactant, a sugar, an amino acid (such as histidine, proline, arginine, glycine, or guanidine), betaine, or a choline salt (such as choline chloride, choline phosphate, choline carbonate, choline bicarbonate, or choline sulfate, etc.), an organic acid (such as butyric acid, valeric acid, caproic acid, enanthic acid, decanoic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxynaphthoic acid, naphadicylic acid, pamoic acid or a sulfonic acid), or pharmaceutically acceptable salts thereof, or an additive selected from the group consisting of disodium phosphate, dipotassium phosphate, diammonium phosphate, meglumine, aluminum carbonate, dihydroxyalumium sodium carbonate, ammonium phosphate, HEPES, HEPPS, spermine, spermidine, putrescine, methylene blue, glycerol, hydrochloride, urea, sodium chloride, potassium chloride, triethylamine, ethanolamine, triethanolamine, ethylenediamine, poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivaca phosphorus (ropivacaine), oxytetracycline, sunitinib, rhizolutin, benzofuran, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, aluminum phosphate, dihydrxy aluminum aminoacetate, calcium phosphate, calcium hydroxide, magaldrate, phosphate salt, phosphide salt, phosphide salt, carbonate salt, chromate salt, dichromate salt, oxalate salt, silicate salt, sulfate salt, sulfide salt, alkaline earth metals or ammonium, tartrate salt, tetraborate salt, thiosulfate salt, and a citrate salt.

[0150] In some embodiments, the microparticles may comprise one or more choline salts, including choline chloride, choline sulphate, choline acetate, choline phosphate and the like. The amount of choline salt present in the microparticles can range from about 0.01% (w / w) to about 20% (w / w), such as from about 0.01% (w / w) to about 10% (w / w), such as from about 0.1% (w / w) to about 5% (w / w) of the total weight of the composition.

[0151] In some embodiments, the microparticles may comprise one or more sugars. The sugar is a monosaccharide, disaccharide or oligosaccharide or a derivative thereof. Sugar alcohols of monosaccharides are suitable derivatives of sugar. Monosaccharides include, but are not limited to, glucose, fructose and mannose. A disaccharide, as further defined herein, is a compound which upon hydrolysis yields two molecules of a monosaccharide. Suitable disaccharides include, but are not limited to, sucrose, lactose and trehalose. Suitable oligosaccharides include, but are notWSGR Ref. No.: 56017-743.601limited to, raffinose and acarbose. The microparticles may further comprise glucose, dextrose, galactose, maltose, fructose, mannose, sucrose, lactose, trehalose, raffinose, acarbose, glycol, glycerol, erythritol, threitol, arabitol, ribitol, sorbitol, dulcitol, iditol, isomalt, nialtitol, lactitol, mannitol, xylitol, or a combination of two or more thereof. In one embodiment, the sugar is sucrose, glucose, mannose, or fructose. In one embodiment, the sugar is sucrose. The amount of sugar present in the microparticles can range from about 0.01% (w / w) to about 20% (w / w), such as from about 0.01% (w / w) to about 10% (w / w), such as from about 0.1% (w / w) to about 5% (w / w) of the total weight of the composition. In one embodiment, about 2% (w / w) sucrose is used.

[0152] In some embodiments, the microparticles comprising a therapeutic compound and biodegradable polymer are prepared according to one or more steps at pH 3.0 to 9.0, or at a pH of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, or within a range of any two of those values.

[0153] In some embodiments, the microparticles comprising a therapeutic compound and biodegradable polymer are prepared according to one or more steps with a buffer selected from the group consisting of phosphate, citrate, choline, acetate, Tris, borate, carbonate / bicarbonate, histidine, succinate, glycine, and lactate buffer.

[0154] In another aspect, provided is a method for producing sustained-release microparticles containing a therapeutic compound, or pharmaceutically acceptable salts thereof, and optionally one or more excipients, via, for example, a solvent extraction and / or evaporation method comprising the following steps:(i ) a therapeutic compound, or pharmaceutically acceptable salts thereof, optionally one or more excipients, and one or more biodegradable polymers are dissolved in one or more organic solvents to produce a “dispersed phase”;(ii) preparing an emulsion by adding the dispersed phase in step (i) to an aqueous solution phase “continuous phase,” optionally containing a surfactant;(iii) forming microparticles by extracting and / or evaporating the organic solvent from the emulsion in step (ii); and(iv) recovering microparticles from the remaining continuous phase of step (iii).

[0155] In some embodiments, the pH of the continuous phase of step (ii) is adjusted with buffer to a value of from 3.0 to 4.0, from 4.0 to 5.0, from 5.0 to 6.0, from 6.0 to 7.0, from 7.0 to 8.0, from 8.0 to 9.0, or from 9.0 to 10.0.

[0156] Microparticles may be prepared by processes known in the art and described, e.g., inWSGR Ref. No.: 56017-743.601U. S. Pat. Nos. 7,563,871, 7,456,254, 7,223,440, 6,824,822, 6,667,061, 6,495,164, and 6,479,065, and U. S, Publication No. 2023 / 0096928, and international PCT publications W02005 / 068533 Al, WO2013 / 015685A1, W02021 / 066650A1, WO2023177300 and W02024010379, the disclosures of each of which are incorporated by reference herein.Therapeutic Compounds

[0157] In some embodiments, when referring to the invention, the terms “compound,” “compound of the invention,” “therapeutic compound” and “therapeutic agent” are used interchangeably.

[0158] In some embodiments, the compound (i.e., therapeutic compound) of the invention is a therapeutic peptide, or pharmaceutically acceptable salts thereof, selected from the group consisting of any of therapeutic peptide compounds in Table 1:Table 1. Representative Therapeutic Peptide Compounds of the InventionCompound Mode of Sequen ce / Structure# ActionAl GLP-1 H(Aib)EGTFTSDVSSYLEGQAAK*EFIAWLVRGRG* wherein the following linker and acyl group is covalently attached to the g-amino side chain of lysine at position 20:-[CO(CH2)O(CH2)2O(CH2)2NH]2-(yGlu)-CO(CH2)i6CO2HA2 GLP-1 [His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-GIu-GIy- GIn-AIa-Ala-Lys*-Glu-Phe-IIe-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly]( i t0 -7)[choline(+i)]i-7,In some embodiments, the peptide is: [His-Aib-Glu-Gly-llir-Phe-Thr-Ser- Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys*-Glu-Phe-Ile-Ala- Trp-Leu-V al-Arg-GIy-Arg-Gly]1'4to [choline'^’1'Us,where *, in each instance, is covalently bound to side chain amino group of lysine, and * is - COCH2O(CH2)2O(CH2)2NHCOCH2O(CH2)2O(CH2)2NHCO(CH2)2NHCH( CO2)NHCO(CH2)I6CO2A3 Amylin [Eicosanedioic acid-(y- Glu)JKC+NTATC+ATQRLAEFLRHSSNNFGPILPPTNVGSNTP-NH2with a disulfide bond between C2+& C7+and wherein the y-Glu is covalently attached to the N-terminal amino group at KI. In some embodiments, the y-Glu is covalently attached to the s-amino sidechain at KI.A4 Amylin [HO2C(CH2)18CO)-(yGlu)2J- KCNTSTCATQRLANELHKSSNNFGPILPPTKVGSE1Y-NH2A.5 PYY PKPEAPGK* (yGlu-yGlu-CO(CH2),sCO2H)DASPEE WDRYYKDLRHYLNWLTRQRF-NH2A6 Amyl in KCNTATCATQRLANFLVHSSNNFGPILPPTN\'GSNTY-NH2A7 Amylin KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-NIL ■ CHsCOO- A8 PYY PKPEAPGK* (yGlu-yGlu-CO(CH2)i8CO2H)DASPEEWDRYYKDLRHYLN^'LTRQRF-NH2■ [choline(+1)]WSGR Ref. No.: 56017-743.601

[0159] In Table 1: “yGlu” and “gamma glutamic acid” are used interchangeably to represent a bivalent gamma glutamic acid -NHCH(CO2H)(CH2)2C(O)- group.

[0160] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is any one the peptides, or pharmaceutically acceptable salts thereof, as described herein (e.g., in Table 1). In some embodiments, the compound (e.g., the therapeutic compound) of the invention is any combination of two or more peptides, or pharmaceutically acceptable salts thereof, as described herein (e.g., in Table 1), or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is selected from the group consisting of semaglutide, semaglutide choline, cagrilintide, i2o-1061, i2o-24 (i2o-2248), or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments of the microparticle, the therapeutic compound is selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound (e.g., the therapeutic compound) of the invention is any one compound selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, and A8, or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments of the microparticle, the therapeutic compound is semaglutide (compound Al), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is semaglutide choline (compound A2), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is cagrilintide (compound A3), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is i2o-1061 (compound A4), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is i2o-2248 (compound A5), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is i2o-2248 choline (compound A8), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is pramlintide (compound A6), or a pharmaceutically acceptable salt thereof. In some embodiments of the microparticle, the therapeutic compound is pramlintide acetate (compound A7), or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is semaglutide (compound Al or A2) or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a cationic salt of one or more anions of semaglutide. In some embodiments, the compound is a cationic salt of one or more anions of semaglutide, having a ratio of cation to semaglutide of from about 1:1 to about 7:1. In some embodiments, the compound isWSGR Ref. No.: 56017-743.601a cationic salt of one or more anions of semaglutide, having a ratio of cation to semaglutide of from about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or a value between any two of those ratios. In some embodiments, the compound is a cationic salt of one or more anions of semaglutide, having a ratio of cation to semaglutide of from about 1:1 to about 5:1. In some embodiments, the compound is a cationic salt of one or more anions of semaglutide, having a ratio of cation to semaglutide of from about 3: 1 to about 5: 1. In some embodiments, the compound is a cationic salt of one or more anions of semaglutide, having a ratio of cation to semaglutide of from about 4:1 to about 5:1. In some embodiments, the cationic salt is choline.

[0165] In some embodiments, the compound (e.g,, the therapeutic compound) of the invention is pramlintide (compound A6) or pharmaceutically acceptable salts thereof. In some embodiments, the compound is an anionic salt of one or more cations of pramlintide. In some embodiments, the compound is an anionic salt of one or more cations of pramlintide, having a ratio of anion to pramlintide of from about 1:1 to about 6:1. In some embodiments, the compound is an anionic salt of one or more cations of pramlintide, having a ratio of anion to pramlintide of from about 2: 1 to about 5: 1. In some embodiments, the compound is an anionic salt of one or more cations of pramlintide, having a ratio of anion to pramlintide of from about 2:1 to about 4:1. In some embodiments, the compound is an acetate salt of pramlintide. In some embodiments, the compound is a chloride salt of pramlintide.

[0166] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is i2o-1061 (compound A4) or pharmaceutically acceptable salts thereof. In some embodiments, the compound is an anionic salt of one or more cations of i2o-1061. In some embodiments, the therapeutic agent is an anionic salt of one or more cations of i2o-1061, having a ratio of anion to i2o-1061 of from about 1: 1 to about 6: 1. In some embodiments, the therapeutic agent is an anionic salt of one or more cations of i2o-1061, having a ratio of anion to i2o-1061 of from about 3:1 to about 5:1. In some embodiments, the therapeutic agent is an acetate or chloride salt of one or more cations of i2o-1061. In some embodiments, the therapeutic agent is an acetate or chloride salt of one or more cations of i2o-1061, having a ratio of anion to i2o-1061 of from about 3:1 to about 5:1.

[0167] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is cagrilintide (compound A3) or pharmaceutically acceptable salts thereof In some embodiments, the compound is an anionic salt of one or more cations of cagrilintide. In some embodiments, the therapeutic agent is an anionic salt of one or more cations of cagrilintide, having a ratio of anion to cagrilintide of from about 1:1 to about 6:1. In some embodiments, the therapeutic agent is an anionic salt of one or more cations of cagrilintide, having a ratio of anion to cagrilintide of fromWSGR Ref. No.: 56017-743.601about 3:1 to about 5:1. In some embodiments, the therapeutic agent is an acetate or chloride salt of one or more cations of cagrilintide, In some embodiments, the therapeutic agent is an acetate or chloride salt of one or more cations of cagrilintide, having a ratio of anion to cagrilintide of from about 3: 1 to about 5:1.

[0168] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is i2o-2248 (also designated i2o-24, A5) or pharmaceutically acceptable salts thereof. In some embodiments, the compound is an anionic salt of one or more cations of i2o-2248. In some embodiments, the compound is a cationic salt of one or more anions of i2o-2248. In some embodiments, the compound is a choline salt of one or more anions of i2o-2248. In some embodiments, the compound is a choline salt of one or more anions of i2o-2248, having a ratio of choline to i2o-2248 of from about 1:1 to about 5:1. In some embodiments, the therapeutic agent is a choline salt of one or more anions of i2o-2248, having a ratio of choline to i2o-2248 of from about 1: 1 to about 3:1.

[0169] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound and a biodegradable polymer;wherein:the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof; andthe biodegradable polymer is a co-polymer that derives from:(i) first monomers of, glycolide, lactide, or a combination of glycolide and lactide, wherein the lactide is L-lactide, D-lactide or DL-lactide, and(ii) one or more additional monomers other than glycolide and lactide,

[0170] In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), and co-polymers thereof.

[0171] In some embodiments, the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, 8-caprolactone, 1,4-butane diol, 1,4-butanediisocyanate, -CONHCH2CH2CH2CH2NHCO-, 1,6-hexane diol, 1,6-hexanediisocyanate, substituted lactide, substituted glycolide, 5-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, cyclic anhydride, hydroxymethyl -glycolide, succinic acid, butyric acid, valeric acid, 3-hydroxybutyric acid (3-HB), 3 -hydroxy valeric acid (3-HV), glucose, fructose, glucosamine, oxalic acid, diketene acetal, sebacic acid, adipic acid, terephthalic acid, N-vinylpyrrolidone, N-vinyl caprolactam, 2-WSGR Ref. No.: 56017-743.601hydroxyethyl methacrylate, alkyl cyanoacrylate, a diisocyanate, an a-amino acid, a dicarboxylic acid, and a diol.

[0172] In some embodiments, the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, s-caprolactone, 1,4-butane diol, -CONHCH2CH2CH2CH2NHCO-, 8-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, and cyclic anhydride.

[0173] In some embodiments, the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PEG-PPG), polytetramethylene ether glycol (PTMG), polycaprolactone (PCL), polydioxanone (PDO), polyhydroxyalkanoates (PHAs), polyphosphazenes, polylactide-co-glycolide-co-caprolactone, (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polycarbonate, polyalkyl carbonate, polytrimethyl enecarbonate (PTMC), polylacti de-co-trimethylene carbonate (polylactide-co-trimethylenecarbonate, PLTMC), polyhydroxybutyric acid (PUB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), poly orthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester polysaccharide, poly(butylene succinate lactide) (PBSLA), polyesteramide, polyalkylene oxalates, biodegradable polyurethanes, polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinyl caprolactam, poly(hydroxyethylmethacrylate) (poly-(HEMA)), polycyanoacrylate, galactose, polyol, cellulose, starch, chitosan, silk, collagen, polybutylene succinate (PBS), hyaluronic acid, alginate, gelatin, and copolymers thereof

[0174] In some embodiments, the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polycaprolactone (PCL), polydioxanone (PDO), and copolymers thereof

[0175] In some embodiments, the first monomers of glycolide, lactide, or a combination of glycoiide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polycaprolactone (PCL), polydioxanone (PDO), and copolymers thereof.

[0176] In some embodiments, the microparticle further comprises an excipient.

[0177] In some embodiments, the excipient is selected from the group consisting of a buffer, a pharmaceutically acceptable salt, a solvent, an amino acid, a poly(amino acid), a cyclodextrin, a viscosity modifier, a polysaccharide, a surfactant, a hydrogel, or any combination thereofWSGR Ref. No.: 56017-743.601

[0178] In some embodiments,(i) the buffer comprises TRIS (Tris(hydroxymethyl)aminomethane), sodium phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, choline bicarbonate, EDTA, or any combination thereof;(ii) the pharmaceutically acceptable salt comprises sodium chloride, choline chloride, betaine HC1, carnitine HC1, or anv combination thereof;(iii) the solvent comprises methylene chloride, methanol, ethanol, acetic acid, formic acid, trifluoroacetic acid, polyvinyl alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), benzyl alcohol, or any combination thereof;(iv) the amino acid comprises arginine, histidine, lysine, aspartic acid, glutamic acid, or any combination thereof;(v) the poly(amino acid comprises poly(glutamic acid), poly(aspartic acid), or any combination thereof;(vi) the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin (HPBCD), sulfobutyl ether betacyclodextrin (SBE-P-CD), carboxymethyl cyclodextrin (CMCD), sulfated cyclodextrin, or any combination thereof;(vii) the viscosity modifier comprises carboxymethyl cellulose (CMC), hyaluronic acid, or any combination thereof;(viii) the polysaccharide comprises carrageenan, alginate, dextran sulfate, trehalose, or any combination thereof;(ix) the surfactant comprises a pluronic;(x) the thermogelling aliphatically modified block copolymer; or(xi) any combination thereof.

[0179] In some embodiments,(a) the sulfobutyl ether beta-cyclodextrin is Captisol®);(b) the pluronic comprises pluronic F127; or(c) a combination thereof

[0180] In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 5% (wt / wt %) to about 50% (wt / wt %).

[0181] In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 5% (wt / wt %) to about 25% (wt / wt %).

[0182] In some embodiments, the microparticle comprises a loading % of the therapeutic compound of from about 10% (wt / wt %) to about 20% (wt / wt %).

[0183] In some embodiments, the microparticle comprises a weight % of the biodegradableWSGR Ref. No.: 56017-743.601polymer of from about 75% (wt / wt %) to about 95% (wt / wt %).

[0184] In some embodiments, the microparticle is substantially spherical,

[0185] In some embodiments, the microparticle has a mean diameter of from about 20 pm to about 80 pm.

[0186] In some embodiments, the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the therapeutic compound is any one compound selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, and A8, or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the therapeutic compound is semaglutide (compound Al) or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the therapeutic compound is semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the therapeutic compound is cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, the therapeutic compound is i2o-1061 (compound A4) or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the therapeutic compound is i2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the therapeutic compound is i2o-2248 choline (compound A8) or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the therapeutic compound is pramlintide (compound A6) or a pharmaceutically acceptable salt thereof.

[0195] T In some embodiments, the therapeutic compound is pramlintide acetate (compound A7) or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of an acetate salt, a choline salt, a sodium salt, and a chloride salt.

[0197] In some embodiments, the pharmaceutically acceptable salt is a choline salt.

[0198] In another aspect, provided herein is a pharmaceutical composition comprising the microparticle as described herein suspended in a diluent.

[0199] In some embodiments, the diluent is an aqueous diluent.

[0200] In some embodiments, the diluent is a non-aqueous diluent.

[0201] In some embodiments, the non-aqueous diluent is a Miglyol®.WSGR Ref. No.: 56017-743.601

[0202] In some embodiments, the non-aqueous diluent is Miglyol 812.

[0203] In some embodiments, the pharmaceutical composition is formulated for injection through an injection needle having a needle gauge of 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.Pharmaceutically Acceptable Salts

[0204] As used herein, the terms “salt,” “salt form,” “ionic salt form” and “pharmaceutically acceptable salt,” as used herein, refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1—19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds as provided herein include those derived from suitable inorganic and organic acids and bases. Further pharmaceutically acceptable salts are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Saits. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry' (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D C on their website). These disclosures are incorporated herein by reference.

[0205] As used herein, the term “pharmaceutically acceptable salt” refers to any of the cationic components or anionic components described herein, in any of the molar ratios described herein.

[0206] In some embodiments, the compound (e g., the therapeutic compound) of the invention is provided in its base form (i.e., free acid form or free base form). In some embodiments, the therapeutic compound is any one of the therapeutic compounds of Table 1 in its base form.

[0207] In some embodiments, the compound (e g., the therapeutic compound) of the invention is provided as pharmaceutically acceptable salts thereof. In some embodiments, the therapeutic compound is any one of the therapeutic compounds of Table 1 provided as a pharmaceutically acceptable anionic salt thereof. In some embodiments, the therapeutic compound is any one of the therapeutic compounds of Table 1 provided as a pharmaceutically acceptable cationic salt thereof.

[0208] In an aspect, provided herein is, inter alia, a compound consisting, or consisting essentially, of the structure of Formula I:WSGR Ref. No.: 56017-743.601oJj e ©R1O R2Formula I,wherein:ORurepresents one or more anions of any of the compounds of Table 1;OA® one or more carboxyl groups of any of the compounds of Table 1 are in the form of; andR2is one or more catanionic components,O

[0209] In some embodiments,R1O represents one or more anions of any of the compounds of Table 1 with the proviso that the compound is not semaglutide (Al or A2), or cagrilintide (A20).

[0210] In some embodiments, the cationic component of R2derives from appropriate bases and is selected from the group consisting of alkali metal, alkaline earth metal, a metal ion such as aluminum, sodium, lithium, potassium, magnesium, calcium, and zinc, ammonium (NH ), a protonated or positively (+) charged ion from an aliphatic primary amine, secondary' amine or tertiary amine such as 2-aminoethanol, tromethamine, dimethylamine, diethylamine, N-ethyl-glucamine, hydrabamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, (2,2',2"-nitrilotris(ethanol)), 2-diethylaminoethanol, procaine or substituted procaine (e.g., chloroprocaine), meglumine, betaine, carnitine, ethylenediamine, choline, acetylcholine, aralkyl amine such as N, N- dibenzylethylenediamine, benzathine, benethamine; heterocyclic aromatic amine such as pyridine, pyrimidine, picoline, quinoline or isoquinoline, quaternary ammonium (e.g., NH ) such as betaine, nontoxic quaternary ammonium (e.g., NMe4', N+(Ct-4alkyl)4,), tetramethylammonium, tetraethylammonium, benzyltrimethylanimonium, b enzy 1 tri ethy 1 am m on ium, b enzy Itri butyl ammonium, meth y 1 tri octyl ammonium or tetrabutylammonium; IH-imidazole, substituted-imidazole (e.g., N-alkyl imidazole, N-methyl imidazole), pyrrolidine, substituted pyrrolidine (e.g., 1 -alkyl pyrrolidine, 1 -methyl pyrrolidine, 1-(2-hydroxy-ethyl)-pyrrolidine), piperidine or substituted piperidine (e.g., 1 -alkyl piperidine, 1-methyl piperidine), piperazine or substituted piperazine (e.g., 1-alkyl piperazine, 1-methyl piperazine, 1,4-dialkyl piperazine, 1,4-dimethyl piperazine), morpholine, substituted morpholine (e.g., N-substituted morpholine, N-methyl morpholine or 4-(2-hydroxyethyl)-morpholine), basicWSGR Ref. No.: 56017-743.601amino acid such as arginine, lysine, or histidine, aminoguanidine, guanidine derivatives and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0211] In some embodiments, the cationic component of R2is betaine, carnitine, choline, or acetylcholine. In some embodiments, the cationic component of R2is selected from the group consisting of acetate, sodium and chloride. In some embodiments the component of R2is choline.

[0212] In some embodiments, the anion of any of the compounds of Table 1 and cationic component are provided in a ratio (aniomcationic component) that is selected from the group consisting of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1: 18, 1: 19, 1:20 or within a range of any two of these ratios. In some embodiments, the compound is not semaglutide or cagrilintide.

[0213] In some embodiments, the anion of any of the compounds of Table 1 and choline are provided in a ratio (anion: choline) that is selected from the group consisting of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20 or within a range of any two of these ratios. In some embodiments, the compound is not semaglutide or cagrilintide.

[0214] In another aspect, provided herein is a compound comprising an ionic salt form of a having the structure of Formula II:R3® R4©Formula II,wherein:R3represents one or more cations of any of the compounds of Table 1; andwherein one or more amino groups of any of the compounds of Table 1 are in the form of R3; andR4© is one or more anionic components. In some embodiments, the compound is not semaglutide or cagrilintide.

[0215] In some embodiments, R " represents one or more cations of any of the compounds of Table 1, with the proviso that the compound is not semaglutide or cagrilintide.

[0216] In some embodiments, the anionic component of R4© is selected from the group consisting of besylate, mesylate, tosylate, sulfonate, sulfate, ethyl sulfate, camsylate, isethionate, edisylate, 1 -hydroxy-2-naphthoate, 2,2-dichloroacetate, 2 -hydroxyethanesulfonate, 2-oxoglutarate, 4-acetamidobenzoate, 4-aminosalicylate, acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, bromide, chloride, camphorate, camphor- 10-sulfonate, caprateWSGR Ref. No.: 56017-743.601(decanoate), caproate (hexanoate), caprylate (octanoate), carbonate, cinnamate, citrate, cyclamate, dodecyl sulfate, dodecylsulfurate, ethanesulfonate, ethane-l,2-disulfonate, ethanesulfonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluconate, glutantate, glucuronate, glutamate, glutarate, glycerophosphorate, glycine, glycolate, hippurate, hydrobromate, hydroiodide, hydrochlorate, isobutyrate, lactate, lactobionate, laurate, lysine, maleate, malate, malonate, mandelate, methanesulfonate, naphthalene-!, 5 -di sulfonate, naphthalene-2-sulfonate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, phosphorate, proprionate, pyroglutamate, salicylate, sebacate, stearate, succinate, sulfurate, tannate, tartarate, thiocyanate, toluenesulfonate, undecylenate, a-lipoate, 12-hydroxystearate, 2-(4-isobutylphenyl)propionate, 2-(4,4-dimethyl-2-pentanyl)-5,7,7-trimethyloctanoate, 2-aminoethanesulfonate, 2-hexyldecanoate, 2-hy dr oxy hippurate, 3 -(4-hydroxypheny 1 )propionate, 3 -methyl croton ate, 3,3-diphenylpropionate, 3,4-dihydroxbenzoate,,5-dihydroxybenzoate, 4-acetamido-benzoate, 3,7- dimethyloctanoate, 4-hydroxybenzenesulfonate, 4-hydroxybenzoate, 4-methylhexanoate, 4-methyloctanoate, valerate salts including 4-methylvalerate, 5-norbomene-2-carboxylate, 8-[(2-hydroxybenzoyl)amino]octanoate, abietate, acetylcysteine, aconitate, arachidonate, behenate, caffeate, chenodeoxycholate, citronellate, crotonate, galactonate, deoxy cholate, dihydrocaffeate, 2-phenylpropionate (hydratropate), tropate, eicosanedioate, eicosapentanoate (EP A), elaidate, ellagate, erucate, ethylenediaminetetraacetate (EDTA), geranate, heptanoate, hydrocinnamate (3-phenylpropionate), isovalerate, glutathione reduced, lactate, laurate, levulinate, linoleate, linolenate, lithocholate, mesaconate, nonanoate, oxalate, coumarate, palmitate, perillate, pimelate, 3-phenylpropionate, pivalate, propionate, pyruvate, ricinoleate, salicylate, 2-hydroxybenzoate, sinapinate (3,5-dimethoxy-4-hydroxycinnamate), sorbate, syringate, tiglate, 2-decenoate, 2-hexenoate, 2-octenoate, 3-octenoate, 7-octenoate, ferulate, undecanoate, valerate, vanillate, perchlorate, alginate, bisulfate, borate, butyrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, glycerophosphate, hemisulfate, hydroiodide, lauryl sulfate, 2- naphthalenesulfonate, pectinate, persulfate, phosphate, tartrate, o-(4-hydroxybenzoyl)benzoate, 1,2, -ethanedi sulfonate, chlorobenzenesulfonate, 4-methylbicyclo[2.2,2]oct-2-ene-carboxylate, 4.4’-methylenebis(3-hydroxy-2- ene-1 -carboxylate), trimethylacetate, tertiary butylacetate, lauryl sulfurate, hydroxynaphthoate, muconate, a-ketoglutarate, p-toluenesulfonate, p-coumarate, and p-chlorobenzenesulfonate.

[0217] In some embodiments, the one or more cations of any of the compounds of Table 1 and anionic component are provided in a ratio (cation: anionic component) that is selected from the group consisting of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20 or within a range of any two of these ratios. In some embodiments,WSGR Ref. No.: 56017-743.601the compound is not semaglutide or cagrilintide.

[0218] In some embodiments, the compound (e g., the therapeutic compound) of the invention is a peptide selected from the group consisting of the therapeutic peptides as described in Table 1, provided as a pharmaceutically acceptable anionic salt thereof, having a ratio of anion to peptide of from about 1:1 to about 25:1. In some embodiments, the pharmaceutically acceptable anionic salt thereof has a ratio of anion to peptide of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:l, about 25:1, or a ratio between any two of these values.

[0219] In some embodiments, the compound (e.g., the therapeutic compound) of the invention is a peptide selected from the group consisting of the therapeutic peptides as described in Table 1, provided as a pharmaceutically acceptable cationic salt thereof, having a ratio of cation to peptide of from about 1:1 to about 25:1. In some embodiments, the pharmaceutically acceptable cationic salt thereof has a ratio of cation to peptide of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 21:1, about 22:1, about 23:1, about 24:l, about 25:1, or a ratio between any two of these values.Certain Salt Forms of the Therapeutic Compounds

[0220] In another aspect, provided herein is a compound of the structure of Formula I:O©R1O R2Formula I,wherein:OeR represents one or more anions of any of the compounds of Table 1, wherein in some embodiments, the compound is not semaglutide or cagrilintide. andOone or more carboxyl groups of any of the compounds of Table 1 are in the form of®; and ©R2is one or more choline, betaine, acetylcholine, carnitine or tromethamine cations.© ©

[0221] In some embodiments, R2is one or more choline cations. In some embodiments, R2©is one or more betaine cations. In some embodiments, R2is one or more acetylcholine cations. InWSGR Ref. No.: 56017-743.601® ©some embodiments, R2is one or more carnitine cations. In some embodiments, R2is one or ore tromethamine cations.

[0222] In some embodiments, one or more carboxyl groups of any of the compounds of Table O OA® A®1 are in the form ofu. In some embodiments, the anion, R ®, of any of the compounds of Table 1 and choline are provided in a ratio (aniomcholine) that is selected from the group consisting of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20 or within a range of any two of these ratios.O

[0223] In some embodiments, R0represents the anion of any of the compounds selected from the group consisting of A3, A4, A5, and A6.Biodegradable Polymers & Copolymers

[0224] The microparticles comprise biocompatible, biodegradable polymers. A polymer is biocompatible if the polymer and any degradation products of the polymer are non-toxic to the patient at administered levels and also possess no demonstrated deleterious or untoward effects on the patient’s body, for example a substantial immunological reaction at the injection site. Biodegradable means the polymer will degrade or erode in vivo to form smaller units or chemical species that are ultimately resorbed, metabolized and / or excreted. Degradation can result, for example, by enzymatic, chemical and physical processes.

[0225] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer; wherein the therapeutic compound is selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof; andthe biodegradable polymer is a co-polymer that derives from first monomers of (i) one or both of glycolide and lactide (L, D or DL), and (ii) one or more additional monomers other than glycolide and lactide.

[0226] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound and a biodegradable polymer; wherein: the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof; and the biodegradable polymer is a co-polymer that derives from: (i) first monomers of, glycolide, lactide, or a combination of glycolide and lactide, wherein the lactide is L-lactide, D-lactide or DL-lactide, and (ii) one or more additional monomers other than glycolideWSGR Ref. No.: 56017-743.601and lactide.

[0227] In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers.

[0228] In some embodiments, the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, 8-caprolactone, 1,4-butane diol, 1,4-butanediisocyanate, -CONHCH2CH2CH2CH2NHCO-, 1,6-hexane diol, 1,6-hexanediisocyanate, substituted lactide, substituted glycolide, 5-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, cyclic anhydride, hydroxymethyl -glycolide, succinic acid, butyric acid, valeric acid, 3-hydroxybutyric acid (3-HB), 3 -hydroxy valeric acid (3-HV), glucose, fructose, glucosamine, oxalic acid, diketene acetal, sebacic acid, adipic acid, terephthalic acid, N-vinylpyrrolidone, N-vinyl caprolactam, 2-hydroxyethyl methacrylate, alkyl cyanoacrylate, a diisocyanate, an a-amino acid, a dicarboxylic acid, and a diol.

[0229] In some embodiments, the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, 8-caprolactone, 1,4-butane diol, - CONHCH2CH2CH2CH2NHCO-, 5-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, and cyclic anhydride. In some embodiments, the one or more additional monomer is ethylene glycol. In some embodiments, the one or more additional monomer is p-dioxanone. In some embodiments, the one or more additional monomer is 8-caprolactone. In some embodiments, the one or more additional monomer is 1,4-butane diol. In some embodiments, the one or more additional monomer is 5-valerolactone. In some embodiments, the one or more additional monomer is trimethylene carbonate. In some embodiments, the one or more additional monomer is tetramethylene carbonate. In some embodiments, the one or more additional monomer is 1,4-dioxane-2-one (para-dioxanone). In some embodiments, the one or more additional monomer is 1,5-dioxepane-2-one. In some embodiments, the one or more additional monomer is cyclic anhydride.

[0230] In some embodiments, the one or more additional monomer is selected from the group consisting of ethylene glycol, p-dioxanone, s-caprolactone, 1,4-butane diol, CONHCH2CH2CH2CH2NHCO-, and 1,4-butanediisocyanate.

[0231] In some embodiments, the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PEG-PPG), polytetramethylene ether glycol (PTMG), polycaprolactoneWSGR Ref. No.: 56017-743.601(PCL), polydioxanone (PDO), polyhydroxyalkanoates (PHAs), polyphosphazenes, polylactide-co-glycolide-co-caprolactone, (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polycarbonate, polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylene carbonate (polylactide-co-trimethylenecarbonate, PLTMC), polyhydroxybutyric acid (PHB), poly hydroxybutyrate-co-hydroxy valerate (PHBV), polyorthoester, poly anhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester polysaccharide, poly(butylene succinate lactide) (PBSLA), polyesteramide, polyalkylene oxalates, biodegradable polyurethanes, polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly- (HEMA)), polycyanoacrylate, galactose, polyol, cellulose, starch, chitosan, silk, collagen, polybutylene succinate (PBS), hyaluronic acid, alginate, gelatin and copolymers thereof.

[0232] In some embodiments, the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polycaprolactone (PCL), polydioxanone (PDO), and copolymers thereof.

[0233] In some embodiments, the one or more additional monomers form one or more polyethylene glycol (PEG) polymeric segments. In some embodiments, the one or more additional monomers form one or more polycaprolactone (PCL) polymeric segments. In some embodiments, the one or more additional monomers form one or more polydioxanone (PDO) polymeric segments.

[0234] In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PEA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), poly caprolactone (PCL), polydioxanone (PDO), and copolymers thereof. In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polyethylene glycol (PEG) polymeric segments. In some embodiments, the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments sel ected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polycaprolactone (PCL) polymeric segments. In some embodiments, the first monomers ofWSGR Ref. No.: 56017-743.601glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polydioxanone (PDO) polymeric segments.

[0235] In some embodiments, any of the co-polymers described herein further comprise a difunctional aliphatic chain extender derived from 1,4-butanediisocyanate.

[0236] In some embodiments, any of the co-polymers described herein further comprise an aliphatic segment such as (-CONHCH2CH2CH2CH2NHCO-) derived from 1,4-butanediisocyanate.

[0237] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer.

[0238] Microparticles, pharmaceutical compositions and methods of the invention using the same comprise any biodegradable polymer known to those or ordinary' skill in the art. Representative biodegradable polymers include each of those of any of US8,481,651, US 12,325,776 W02021066650A1, WO2023177300A1, US20220409730A1, US20220332900A1, and WO2013015685A1, the entirety of each of which is incorporated herein by reference.

[0239] In one aspect, provided is a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer; wherein the therapeutic compound is selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof; and the biodegradable polymer is a biodegradable multi¬ block polymer.

[0240] In some embodiments, the biodegradable multi-block copolymer comprises randomly and non-altematingly arranged hydrolysable segments each composed of pre-polymer A or pre¬ polymer B, which segments are randomly and non-altematingly connected to each other by multi¬ functional chain extenders, wherein the multi -block copolymer is amorphous at human body conditions. In some embodiments, the chain extender is an aliphatic diisocyanate such as 1,4-butanediisocyanate, e g., -CONHCH2CH2CH2CH2NHCO-, or 1,6-hexanediisocyanate.

[0241] In some embodiments, the pre-polymer A comprises polyether groups. In some embodiments, the polyether is present as an additional pre-polymer. In some embodiments, the pre-polymer A comprises a reaction product of an ester forming monomer selected from the group consisting of diols, dicarboxylic acids and hydroxycarboxylic acids. In some embodiments, the pre-polymer A comprises reaction products of at least one cyclic monomer with at least one non-cyclic initiator selected from the group consisting of diols, dicarboxylic acids andWSGR Ref. No.: 56017-743.601hydroxycarboxylic acids. In some embodiments, the cyclic monomer is selected from the group consisting of glycolide, lactide (L, D or DL), s-caprolactone, 8-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one and cyclic anhydrides. In some embodiments, the pre-polymer A contains at least two different cyclic monomers. In some embodiments, the pre-polymer A consists of glycolide and 8- caprolactone in a 1: 1 weight ratio. In some embodiments, the pre-polymer A consists of glycolide and lactide in a 1:1 weight ratio. In some embodiments, the non-cyclic initiator is selected from the group of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, ethylene glycol, diethylene glycol, 1,4-butanediol and 1,6-hexanediol. In some embodiments, the polyether groups are selected from the group consisting of PEG (polyethylene glycol), PEG-PPG (polypropylene glycol), PTMG (polytetramethylene ether glycol) and combinations thereof. In some embodiments, PEG is an initiator for ring-opening polymerization with a molecular weight between 150-4000. In some embodiments, the prepolymer A has a number average molecular weight (Mn) between 300 and 30000. In some embodiments, the pre-polymer B comprises 8-caprolactone, 8-valerolactone, trimethylene carbonate, para-dioxanone, DL-lactide and / or glycolide. In some embodiments, the pre-polymer B contains d,l-lactide. In some embodiments, the pre-polymer B has a number average molecular weight (Mn) higher than 300. In some embodiments, the pre-polymer B is present in an amount of 10-90 wt. %. In some embodiments, the copolymer has an intrinsic viscosity of at least 0.1 dl / g, and less than 6 dl / g. In some embodiments, the chain extender is derived from a difunctional aliphatic compound. In some embodiments, the chain-extender is a diisocyanate, such as butane diisocyanate.

[0242] In one aspect, provided is a microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a biodegradable, phase separated, thermoplastic multi-block copolymer comprising at least one amorphous hydrolysable pre-polymer (A) segment and at least one semi -crystalline hydrolysable pre-polymer (B) segment, wherein the multi-block copolymer under physiological conditions has a Tgof 37 °C or less and a Tmof 50-110 °C; the segments are linked by a multifunctional chain extender; the segments are randomly distributed over the polymer chain; and the pre-polymer (B) segment comprises a X — Y — X tri-block copolymer wherein Y is a polymerisation initiator, and X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of 7 or more.

[0243] In one embodiment of the microparticle or pharmaceutical composition comprising theWSGR Ref. No.: 56017-743.601biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of treatment described herein comprise co¬ administration of two or more therapeutic compounds such as co-administration of the SARA pramlintide (compound A6) or a pharmaceutically acceptable salt thereof with the GLP-1 RA semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, or coadministration of the DACRA cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof, with the GLP-1 RA semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, as non-limiting examples.

[0244] In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of 7-35, such as 7-30, a-25, 9-20, 10-15, or 11-14. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a molecular weight distribution Mw / Mnin the range of 1.0-3.0, such as in the range of 1.2-2.0, or in the range of 1.3-1, 6. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, at least part of pre-polymer (A) segment is derived from a water-soluble polymer. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, 30 % or more by total weight of pre-polymer (A) is derived from a water- soluble polymer, such as 40-95 %, 50-90 %, or 60-85 %. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, pre-polymer (A) segment comprisesWSGR Ref. No.: 56017-743.601poly(p-dioxanone). In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the amount of poly(p-dioxanone) in the pre-polymer (A) segment is 80 % or less by total weight of pre-polymer (A), 60 % or less, or 40 % or less, 20 % or less, 10 % or less, or 5 % or less. In one embodiment of the biodegradable, phase separated, thermoplastic multiblock copolymer, 70 % or more by total weight of the pre-polymer (B) segment is poly(p-dioxanone), preferably 80 % or more by total weight of the pre-polymer (B) segment is polyfp-dioxanone), more preferably 90 % or more by total weight of the pre-polymer (B) segment is poly(p-dioxanone). In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a number average molecular weight Mnof 1300-7200 g / mol, preferably 1300-5000 g / mol, more preferably 1500-4500 g / mol, even more preferably 2000-4000 g / mol, most preferably 2200-3200 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a weight average molecular weight Mwof 1800-10080 g / mol, preferably 1800-7000 g / mol, preferably 2100-6300 g / mol, more preferably 2600-5600 g / mol, most preferably 3000-4200 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) has a Tgof less than 0 °C, preferably less than -20 °C, more preferably less than -40 °C. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) has a Tmin the range of 60-100 °C, preferably in the range of 75-95 °C. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the water-soluble polymer comprises one or more selected from the group consisting of polyethers such as polyethylene glycol (PEG), polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacry late) (poly-(HEMA)), polyphosphazenes, or copolymers of these polymers. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the water-soluble polymer is derived from poly(ethylene glycol) (PEG) having a Mnof 150-5000 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the chain-extender is a difunctional aliphatic chain-extender. In one embodiment of the biodegradable, phase separated, thermoplastic multi -block copolymer, the difunctional aliphatic chain -extender is a diisocyanate, such as 1,4-butane diisocyanate or -CONHCH2CH2CH2CH2NHCO-. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, prepolymer (A) comprises reaction products of cyclic monomers and / or non-cyclic monomers, wherein the non-cyclic monomers are preferably selected from the group consisting of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid.WSGR Ref. No.: 56017-743.601ethylene glycol, diethylene glycol, 1,4-butanediol and / or 1,6-hexanediol, and wherein the cyclic monomers are preferably selected from the group consisting of glycolide, lactide, s-caprolactone, 8- valerolactone, trimethylene carbonate, tetramethylenecarbonate, l,5-dioxepane-2-one, 1,4-dioxane-2-one (p-dioxanone) and / or cyclic anhydrides such as oxepane-2, 7-dione. In one embodiment of the biodegradable, phase separated, thermoplastic multi -block copolymer, a water- soluble polymer is present as an additional pre-polymer. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the additional pre-polymer is present in the multi -block copolymer in an amount of 30 % or less by total weight of the multi -block copolymer, such as 20 % or less. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, being a poly(ether ester) multi-block copolymer wherein the pre-polymer (A) segment comprises one or more selected from the group consisting ofand wherein the pre-polymer segment (A) further comprisesoand wherein the pre-polymer segment (B) comprises

[0245] In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (A) segment is represented bywherein n is 4-120, preferably 13-70. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the multi-block copolymer is represented by [(RrR2Jl3)q]r[(R4pR5R6p)]s, wherein R1, and R3are independently selected from the group consisting ofWSGR Ref. No.: 56017-743.601- 0 yR2is, and R3and R4are each, n, being the number of repeating R2nioieties, is 4-120, preferably 13-70, more preferably 20-46; p, being the number of repeating R4and R6moieties is 7 or more, preferably 7-35, more preferably 10-20, even more preferably 11-14; q, being the number average molecular weight of the (R^2nR3) block is 400-10000 g / mol, preferably 1000-6000 g / mol, more preferably 1400-4000 g / mol, even more preferably 1600-3000 g / mol, most preferably 1800-2200 g / mol; and r / s, being the ratio of pre¬ polymer (A) segment over pre-polymer (B) segment is 0.1-2.5, In one embodiment the biodegradable, phase separated, thermoplastic multi-block copolymer, in the form of microparticles. In one aspect, a process for preparing the biodegradable polymer is provided, comprising the steps of: i) performing a chain extension reaction of pre-polymer (A) and prepolymer (B) in the presence of a multifunctional chain-extender, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the chain-extender is di-carboxylic acid, diisocyanate, or diol terminated; or ii) performing a chain extension reaction using a coupling agent, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the coupling agent is preferably di cyclohexyl carbodiimide, wherein the pre-polymer (B) segment comprises a X — Y — X tri¬ block copolymer, wherein Y is a polymerisation initiator, and X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of 7 or more.

[0246] In some embodiments, multi-block copolymer can be composed of at least two different segments each having different physical characteristics, including degradation and swelling characteristics.

[0247] The term “pre-polymer” as used herein is meant to refer to the polymer segments that are randomly linked by a multi-functional chain extender, together making up the multi-block copolymer. Each pre-polymer may be obtained by polymerisation of suitable monomers, which monomers thus are the chemical units of each pre- polymer. The desired properties of the pre¬ polymers and, by consequence, of the multi-block copolymer can be controlled by choosing a prepolymer of a suitable composition, and molecular weight (in particular Mn), such that the required Tmor Tgis obtained.

[0248] As used herein, the terms "polymer" and "polymers" include "copolymer" andWSGR Ref. No.: 56017-743.601"copolymers.” The terms “block” and “segment” as used herein are meant to refer to distinct regions in a multi-block copolymer. The terms block and segment are used interchangeably.

[0249] The term “multi-block” as used herein is meant to refer to the presence of at least two distinct pre-polymer segments in a polymer chain.

[0250] The term "biodegradable polymer" refers to a polymer that is broken down under aqueous conditions or within the subject following administration. In general, polymers that lose weight over time in the body may also be referred to as absorbable, resorbable, bioabsorbable, or biodegradable polymers. The term applies regardless of their mode of degradation, in other words, biodegradable polymers that are both enzymatically and non-enzymatically hydrolyzed.

[0251] The term “thermoplastic” as used herein is meant to refer to the non-cross-linked nature of the multi-block copolymer. Upon heating, a thermoplastic polymer becomes fluid, whereas it solidifies upon (re-)cooling. Thermoplastic polymers are soluble in proper solvents.

[0252] The term “hydrolysable” as used herein is meant to refer to the ability of reacting with water upon which the molecule is cleaved. Hydrolysable groups include ester, carbonate, phosphazene, amide and urethane groups. Under physiological conditions, ester, carbonate and phosphazene groups react with water in a reasonable time scale.

[0253] The term “multifunctional chain-extender” as used herein is meant to refer to the presence of at least two reactive groups on the chain-extender that allow chemically linking reactive pre-polymers thereby forming a multi-block copolymer.

[0254] The term “water-soluble polymer” as used herein is meant to refer to a polymer that has a good solubility in an aqueous medium, such as water, under physiological conditions. This polymer, when copolymerised with more hydrophobic moieties, renders the resulting copolymer swellable in water. The water-soluble polymer can be a diol, a diamine or a diacid. The diol or diacid is suitably used to initiate the ring-opening polymerisation of cyclic monomers. The term swellable as used herein is meant to refer to the uptake of water by the polymer. The swelling ratio can be calculated by dividing the mass of the water- swollen copolymer by that of the dry copolymer.

[0255] The term “semi-crystalline” as used herein is meant to refer to a morphology of the multi -block copolymer that comprises two distinctive phases, an amorphous phase and a crystalline phase. In one embodiment, the multi-block copolymer is made up of an amorphous phase and a crystalline phase.

[0256] Each of the terms “biologically active compound” and “therapeutic compound” as used herein is intended to be broadly interpreted as any peptide or small molecule that provides a therapeutic or prophylactic effect. Such agents include, but are not limited to, anti-obesity agentsWSGR Ref. No.: 56017-743.601and agents for treatment of weight loss, weight reduction, overweightedness, and other car di om etab ol i c i n di cati on s.

[0257] In some embodiments, multi -block copolymers have a Tmof 50- 110 °C under physiological conditions, such as in the range of 60- 110 °C, in the range of 60-100 °C, in the range of 70-100 °C, or in the range of 70-90 °C. In some embodiments, this is due to the pre¬ polymer (B) segment. The (B) segment comprises 70 % or more by total weight of the pre-polymer (B) segment of poly(p-dioxanone); in another embodiment the (B) segment comprises 80 % or more, 85 % or more, 90 % or more, or 95 % or more by total weight of the pre-polymer (B) segment of poly(p-dioxanone). In one embodiment, the (B) segment is based on a pre-polymer consisting of poly(p-dioxanone). The amorphous phase of the phase separated multi-block copolymers predominantly consists of the soft (A) segments.

[0258] In some embodiments, pre-polymer (B) segment comprises poly(p-dioxanone). In some embodiments, pre-polymer (B) segment can additionally comprise further monomer units such as s-caprolactone and / or 5 -valerolactone.

[0259] In some embodiments, pre-polymer (B) segment comprises an X — Y — X tri-block copolymer, wherein Y is a polymerisation initiator and X is a poly(p-dioxanone) segment. The block length of the poly(p-dioxanone) segment X expressed in terms of p-dioxanone monomer units is 7 or more. In some embodiments, the block length of the poly(p-dioxanone) segment X can be 7-35 p-dioxanone monomer units, such as 7-30 p-dioxanone monomer units, 8-25 p-dioxanone monomer units, 9-20 p-dioxanone monomer units, 10-15 p-dioxanone monomer units, or 11-14 p-dioxanone monomer units.

[0260] In some embodiments, the pre-polymer (B) segment can comprise an X — Y — X tri-block copolymer wherein each poly(p-dioxanone) segment X has a block length expressing in terms of p-dioxanone monomer units of 7 or more.

[0261] In some embodiments, the pre-polymer (B) segment consists of a X Y X tri-block copolymer. In some embodiments, polymerisation initiator Y in the X-Y — X tri-block copolymer can suitably be a diol, such as an aliphatic diol with 2 to 8 carbon atoms. Examples of suitably aliphatic diols to be used as polymerisation initiator Y include ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,3-butanediol, 2, 3 -butanediol, diethylene glycol, dipropylene glycol, tri ethylene glycol, poly(ethylene glycol), 1,5-pentanediol, 1,6-hexanediol, neopentyl glycol, hydrogenated bisphenol A, and glycerol. Preferred polymerisation initiators include ethyleneglycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,3-butanediol, 2,3-butanediol, 1,5-pentanediol, and 1,6-hexanediol. More preferred polymerisation initiators include ethylene glycol, 1,4-butanediol and 1,6-hexanediol. In one embodiment, the polymerisation initiator is 1,4-WSGR Ref. No.: 56017-743.601butanediol.

[0262] In some embodiments, pre-polymer (B) segments can suitably have a molecular weight distribution (Mw / Mn) of 1.0 or more, such as 1.1, or more, 1.2 or more, 1.3 or more, or 1.4 or more. The molecular weight distribution of pre-polymer (B) segments is in one embodiment 3.0 or less. In another embodiment, the molecular weight distribution of pre-polymer (B) segments is 2.0 or less, such as 1.8 or less, 1.6 or less, 1.5 or less, or 1.4 or less.

[0263] In some embodiments, pre-polymer (B) segments can further have a density (as measured according to ASTM DI 505) of 1.1 g / cm3or more, such as 1.15 g / cm3or more, or 1.2 g / cm3or more. The density of pre-polymer (B) can be 1,5 g / cm3or less, such as 1.45 g / cm3or less, or 1.4 g / cm3or less. The melt flow index of pre-polymer (B) segment (as measured at 150 °C with a load of 2.16 kg according to ASTM D1238-86) can be 0.1 g / 10 min or more, such as 0.2 g / 10 min or more, or 0.3 g / 10 min. The melt flow index of pre-polymer (B) (as measured at 150 °C with a load of 2.16 kg according to ASTM D 1238-86) can be 7 g / 10 min or less, such as 6 g / 10 min or less, or 5 g / 10 min or less.

[0264] In some embodiments, hard pre-polymer (B) segment of the multi-block copolymer is typically semi-crystalline, i.e. partly amorphous. The amorphous part of the hard (B) segments will (partly) phase mix with the soft (A) segments and thus both will contribute to the overall Tgof the multi-block copolymer. Therefore, the Tgof the amorphous phase is determined by both the Tgof segment (A) and the Tgof segment (B), in combination with the molar ratio of segment (A) / segment (B). The Tgcan be varied from Tgclose to the Tgof pre-polymer (A) (when a ratio of pre-polymer (A) to pre-polymer (B) of close to one is used) to Tgclose to the Tgof pre-polymer (B) (when a ratio of pre-polymer (A) to pre-polymer (B) of close to zero is used).

[0265] In some embodiments, multi-block copolymers allow the preparation of non-sticky microparticles by various processes including solvent-extraction / evaporation based on emulsification processes such as oil-in-water (O / W), water-in-oil-in-water (W / O / W), solid-in-oil- in-water (S / O / W), water-in-oil-in-oil (W / O / O), or solid-in-oil-in-oil (S / O / O) emulsions.

[0266] In some embodiments, multi-block copolymers comprise segments derived from a water-soluble polymer (such as hydrophilic PEG segments). The presence of such segments promotes swelling of the phase separated multi -block copolymers in an aqueous environment to form a swollen hydrogel providing a natural environment for biologically active compounds such as peptides or small molecules. Swellability of the phase separated multi-block copolymers allows gradual release of any encapsulated compounds by diffusion.

[0267] In some embodiments, the morphology of the multi -block copolymer (or of a construct made thereof) is dependent on the environmental conditions: a DSC (Differential ScanningWSGR Ref. No.: 56017-743.601Calorimetry) measurement may be performed under inert (dry) conditions and the results may be used to determine the dry materials’ thermal properties. However, the morphology and properties under physiological conditions (i.e., in the body) may be different from the morphology and properties under ambient conditions (dry, room temperature). It is to be understood that the transition temperatures, Tgand Traas used herein, refer to the corresponding values of a material when applied in vivo; when at equilibrium with an aqueous environment or an atmosphere that is saturated with water vapour at body temperature. This may be simulated in vitro by performing the DSC measurement after allowing the material to equilibrate with a water-saturated atmosphere. When in dry state, the materials used may have Tgvalues that are somewhat higher than at mammalian body conditions, that is to say, when the dry materials are subjected to DSC, the first inflection point may arise at higher temperatures, for instance at 42 °C, 50 °C, or more. Upon application in vivo, however, the dry' material’s Tgand / or Tmwill drop as a result of the absorption of water, which plasticises the polymer and this final Tgshould be around body temperature or lower. The final Tmshould be present at temperatures between 50 °C and 110 °C under physiological conditions.

[0268] In some embodiments, physicochemical properties (such as degradation, swelling and thermal properties) of the multi-block copolymers can be tuned by changing the type of monomers of the soft and hard segment forming pre-polymers and their chain length and chain ratio and by choosing the type and amount of chain-extender. In some embodiments, the phase transition temperatures are low enough for processing the polymer in the melt. In some embodiments, monomer ratio and distribution of the copolymer can be easily controlled by varying the polymerisation conditions.

[0269] In some embodiments, the phase separated segmented multi-block copolymers have a Tmin the range of 50-110 °C and a Tgof 37 °C or less under physiological conditions. This may be obtained by using a pre-polymer (B) with a Tmin the range of 50- 110 °C under physiological conditions and a pre-polymer (A) with a Tgof 37 °C or less under physiological conditions.

[0270] In some embodiments, at least part of pre-polymer (A) is derived from a water-soluble polymer. The water-soluble polymer may comprise one or more selected from the group consisting of polyethers such as polyethylene glycol (PEG), polytetramethyl eneoxide (PTMO) and polyp ropyleneglycol (PPG); polyvinylalcohol (PVA); polyvinylpyrrolidone (PVP); polyvinylcaprolactam; poly(hydroxyethylmethacrylate) (poly-(HEMA)); polyphosphazenes; poly orthoesters; polyorthoesteramides or copolymers of the previous polymers. In one embodiment, at least part of pre-polymer (A) is derived from PEG.

[0271] Some non-limiting examples of suitable pre-polymer (A) segments include poly(c-WSGR Ref. No.: 56017-743.601caprolactone)-co-PEG-co-poly(e-caprolactone), poly(D, L-lactide)-co-PEG-co-poly(D, L-lactide), poly(glycolide)-co-PEG-co-poly(glycolide), and poly(p- dioxanone) - co- PEG- co-poly(p -dioxanone).

[0272] In any addition, the pre-polymer (A) segment may, at each side of the water-soluble polymer, comprise any copolymer of the above-mentioned monomers. Some non-limiting examples of such pre-polymer (A) segments include [poly(e-caprolactone-co-D, L-lactide)]-co-PEG-co-[poly(e-caprolactone- co-D, L-lactide)], [poly(c-caprolactone-co-glycolide)]-co-PEG-co-[poly(c-caprolactone-co-glycolide)], [poly(e-caprolactone-co-p- dioxanone)] - co-PEG-co-[poly(e-caprolactone-co-p-dioxanone)], [poly(D, L-lactide- co-glycolide)]-co-PEG-co-[poly(D, E-lactide-co-glycolide)], [poly(D, L-lactide-co-p-dioxanone)]-co-PEG-co-tpoly(D, L-lactide-co- p-dioxanone)], and [poly(glycolide-co-p-dioxanone)]-co-PEG- co- [poly(glycolide-co-p-dioxanone)].

[0273] In some embodiments, 30 % or more by total weight of pre-polymer (A) is derived from a water- soluble polymer, such as 40 % or more, 50 % or more, 60 % or more, or 70 % or more. In some embodiments, 95 % or less by total weight of pre-polymer (A) is derived from a water-soluble polymer, such as 90 % or less, 85 % or less.

[0274] In some embodiments, pre-polymer (A) further comprises p-dioxanone. Such introduction of p-dioxanone monomers in the pre-polymer ( ) segment can introduce additional crystallinity in the multi-block copolymers. In some embodiments, the content of such p-dioxanone monomers in pre-polymer (A) may be 80 % or less by weight of the pre-polymer (A), such as 60 % or less, 50 % or less, 40 % or less, 30 % or less, 20 % or less, 10 % or less, or 5 % or less. In some embodiments, the content of p-dioxanone monomers in pre-polymer (A) can be 0.1 % or more, such as 1 % or more, or 2 % or more.

[0275] In some embodiments, pre-polymer (A) can have an Mnof 500 g / mol or more, and in another embodiment 1000 g / mol or more, 1500 g / mol or more, or 2000 g / mol or more. In some embodiments, pre-polymer (A) has an Mnof 10000 g / mol or less. In some embodiments, the content of pre-polymer (A) in the copolymer is in one embodiment 5-95 % based on total weight of the multi-block copolymer; in other embodiments, the content of pre-polymer (A) in the copolymer is 10-90 %, 25-80 % 40-70 %, or 50-60 %.

[0276] In some embodiments, segment R2of formula (1) may be obtained by reaction of pre¬ polymers (B) derived from poly(p-dioxanone). Optional further monomers present in pre-polymer (B) can be selected from L-lactide, D-lactide, hydroxybutyrate, glycolide and combinations thereof.

[0277] In some embodiments, pre-polymer (B) segment comprises poly(p-dioxanone).WSGR Ref. No.: 56017-743.601Poly(p-dioxanone) can be synthesised by reacting p-dioxanone monomers in the presence of a suitably catalyst and a polymerisation initiator, as described herein.

[0278] In some embodiments, polymerisation reaction may be performed at a temperature of 10-120 °C; in another embodiment, the reaction may be performed at 50-100 °C, 60-95 °C, 70-90 °C, or 75-85 °C. The catalyst is a catalyst effective in promoting the polymerisation reaction.

[0279] In some embodiments, pre-polymer (B) segment comprises a X — Y — X tri-block copolymer, wherein the block length of the poly(p-dioxanone) segment X expressed in terms of p-dioxanone monomer units is 7 or more. Pre-polymer (B) may have a number average molecular weight Mnof 1300 g / mol or more, such as 1500 g / mol or more, 2000 g / mol or more, 2200 g / mol or more, or 2500 g / mol or more. The pre-polymer (B) may have a number average molecular weight Mnof 7200 g / mol or less, such as 5000 g / mol or less, 4500 g / mol or less, 4000 g / mol or less, or 3200 g / mol or less. Pre-polymer (B) can have a weight average molecular weight Mwof 1800 g / mol or more, such as 2100 g / mol or more, 2600 g / mol or more, or 3000 g / mol or more. Pre-polymer (B) can have a weight average molecular weight Mw of 10 080 g / mol or less, 7000 g / mol or less, such as 6300 g / mol or less, 5600 g / mol or less, or 4200 g / mol or less.

[0280] Suitably, 70 % or more by total weight of the pre-polymer (B) segment can be poly(p- dioxanone). In one embodiment, 80 % or more by total weight of the pre-polymer (B) segment can be poly(p-dioxanone). In some embodiments, 85 % or more, 90 % or more, or 95 % or more by total weight of the pre-polymer (B) segment can be poly(p-dioxanone).

[0281] In some embodiments, 80 % or more by total weight of the X segment is poly(p-dioxanone). In another embodiment, 85 % or more, 90 % or more, or 95 % or more by total weight of the X segment is poly(p-dioxanone). In one embodiment, the X segment consists of poly(p-dioxanone).

[0282] In some embodiments, content of pre-polymer (B) in the copolymer may be 10-90 % based on total weight of the multi-block copolymer. The content of pre-polymer (B) in the copolymer can, for example, be 25-90 %, 25-70 %, or 30-50 % based on total weight of the multi¬ block copolymer. Such contents generally result in the desired materials with good physical (e.g. swelling) and degradation properties at the temperature of application (viz. about 37 °C for medical applications).

[0283] Particle size distribution of the microparticles can be measured by laser diffraction. Microparticles are suspended in water until transmittance is within 70-90 % and the particle size distribution of the suspension is determined within the range of 10 nm — 5000 gm. The surface morphology of the microparticles is evaluated by scanning electron microscopy.

[0284] In vitro erosion of non-loaded polymer- only microparticles can be measured inWSGR Ref. No.: 56017-743.601buffered aqueous solution (e.g., 100 mM of phosphate buffer pH 7.4; 90-100 nig of microparticles in 10 ml). Samples are incubated at 37 °C. At each sampling point, the microparticles were collected, freeze-dried and weighed.

[0285] In one aspect, provided is a microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, comprising at least one prepolymer (A) segment and at least one hydrolysable amorphous prepolymer (B) segment, wherein the segments are linked by a multifunctional chain extender, wherein the prepolymer (A) segment: a) comprises one or more hydrolysable linkages, and / or b) comprises a water soluble polymer; and wherein the hydrolysable amorphous prepolymer (B) segment comprises the following structure:wherein n is 4-100, such as 5-50; x is 0.25-1 and x + y = 1; p is 0 or 1; Rland R2are independently selected from hydrogen and C1-C4 alkyl; Q1is selected fromwherein r is 1-100; s is 1-12; t is 1-10; R3is selected from hydrogen and Ci-Ce alkyl; R4is selected from hydrogen and C1-C4 alkyl; and R5is selected fromWSGR Ref. No.: 56017-743.601V is I -100, w is 1-12, and R6is selected from hydrogen and Ci-Cs alkyl.

[0286] The term "multiblock" as used herein means that there are at least two different polymer or prepolymer segments in the polymer chain, i.e., the biodegradable polymer,

[0287] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA or DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o- 1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of treatment described herein comprise co-administration of two or more therapeutic compounds such as co-administration of the SARA pramlintide (compound A6) or a pharmaceutically acceptable salt thereof with the GLP-1 RA semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, or co-administration of the DACRA cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof, with the GLP-1 RA semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, as non-limiting examples.

[0288] In one embodiment of the microparticle or pharmaceutical composition comprising theWSGR Ref. No.: 56017-743.601biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein R1and R2are independently C1-C4 alkyl, preferably R1and R2are both CH3. In one embodiment of the biodegradable, thermoplastic multiblock copolymer, R1and R2are both CH3, % is 1 and Q1is

[0289] In one embodiment, of the biodegradable, thermoplastic multiblock copolymer, the hydrolysable amorphous prepolymer (B) segment has a glass transition temperature Tgof 40 °C or more, preferably 50 °C or more, such as 60-100 °C. In one embodiment of the biodegradable, thermoplastic multiblock copolymer, the prepolymer (A) segment comprises a water-soluble polymer. In one embodiment the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein the water soluble polymer comprises one or more selected from the group consisting of polyethers such as polyethylene glycol (PEG), polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), poly tetramethylene ether glycol (PTMG), or other water soluble polymers such a, polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly(HEMA)), polyphosphazenes, or copolymers of these polymers, preferably the water-soluble polymer is derived from polyethylene glycol) (PEG) having a Mnof 150-10000 g / mol, more preferably 300-5000 g / mol, most preferably 600-3000 g / mol. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein the multifunctional chain extender is a difunctional aliphatic chain extender, preferably the difunctional aliphatic chain extender is a diisocyanate, such as 1,4-butane diisocyanate. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein prepolymer (A) comprises reaction products of one or more cyclic monomers and / or non-cyclic monomers. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein the cyclic monomers are selected from the group consisting of glycolide, lactide, s-caprolactone, 5-valerolactone, trimethylene carbonate, tetramethylenecarbonate, l,5-dioxepane-2-one, l,4-dioxane-2-one (p-dioxanone), cyclic anhydrides (such as oxepane-2, 7-dione), N-carboxyanhydrides of natural amino acids and their derivatives (such as N-carboxyalanine anhydride) and morpholine-2, 5-diones based cyclic depsipeptides (such as 6-methyl-morpholine-2, 5-dione). In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein the non-cyclic monomers are selected from the group consisting of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, natural amino acids and theirWSGR Ref. No.: 56017-743.601derivates (such as alanine), ethylene glycol, diethylene glycol, 1,4-butanediol, 1,6-hexanediol, 1,4-butanediamine, and 1,6-hexanediamine. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic niultiblock copolymer, wherein prepolymer (A) has a number average molecular weight (Mn) of between 300 and 30000 g / mol, preferably between 500 g / mol and 10000 g / mol, more preferably between 1000 and 8000 g / mol, such as between 1500 and 8000 g / mol, or between 2000 and 7000 g / mol. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein prepolymer (B) has a number average molecular weight (Mn) of 1000 g / mol or more, preferably between 2000 and 10000 g / mol, or between 3000 and 8000 g / mol. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein prepolymer (A) is present in an amount of 1-99 % based on total weight of the multiblock copolymer, such as 5-95 %, 10-90 %, 20-80 %, 30-70 %, or 40-60 %. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein prepolymer (B) is present in an amount of 1-99 % based on total weight of the multiblock copolymer, such as 5-95 %, 10-90 %, 20-80 %, 30-70 %, or 40-60 %. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, having an intrinsic viscosity of 0.1 dl / g or more, preferably 0.1-3 dl / g, more preferably 0.2-2 dl / g, such as 0.3-1 dl / g. In one embodiment, the biodegradable polymer is a biodegradable, thermoplastic multiblock copolymer, wherein the prepolymer segments are randomly distributed in the multiblock copolymer. In one aspect, a process for preparing the biodegradable polymer is provided, comprising the steps of. conducting a chain-extension reaction of prepolymer (A) and prepolymer (B) in the presence of a multifunctional chain extender. In one embodiment, the pharmaceutical composition comprising the biodegradable polymer is in the form of one or more selected from the group consisting of microspheres, microparticles, nanoparticles, nanospheres, rods, solid implants, or gels. In one embodiment, the pharmaceutical composition comprising the biodegradable polymer is in the form of microspheres and / or microparticles, wherein the average diameter of the microspheres and / or microparticles is preferably in the range of 0.1-1000 gm, more preferably in the range of 1-100 gm, even more preferably in the range of 10-70 gm. In one embodiment, the pharmaceutical composition comprising the biodegradable polymer is in the form of an in situ forming implant, wherein the biologically active compound is dissolved or suspended in a solution of the biodegradable, thermoplastic multiblock copolymer in an acceptable organic solvent such as n-methyl pyrrolidone, dimethyl sulphoxide, benzyl benzoate, benzyl alcohol, triacetin, glycofurol, polyethylene glycol and which solution, following administration into the body, forms in situ a depot by replacement of the organic solvent by aqueous body fluids thereby entrapping theWSGR Ref. No.: 56017-743.601biologically active compound in the biodegradable, thermoplastic multiblock copolymer depot, from which the biologically active compound is subsequently gradually released. In one embodiment, the pharmaceutical composition comprising the biodegradable polymer is in the form of a solid implant prepared by hot-melt extrusion or injection moulding, and wherein the biologically active compound is incorporated in the biodegradable, thermoplastic multiblock copolymer as a molecular blend or as a dispersion of solid particles.

[0290] In one aspect, provided is a microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, comprising (a) any of the compounds or pharmaceutically acceptable salts thereof, as described herein; (b) a biodegradable multi -block copolymer matrix, wherein the compound or pharmaceutically acceptable salts thereof, is present in the multi-block copolymer matrix, wherein the biodegradable multi-block copolymer comprises one or more biodegradable, phase separated, thermoplastic multi -block copolymers comprising at least one amorphous hydrolysable pre polymer (A) segment and at least one semi-crystalline hydrolysable pre-polymer (B) segment, wherein the multi-block copolymer under physiological conditions has a Tgof about 37° C. or less and a Tmof about 50° C. to about 110° C.; the segments are linked by a multifunctional chain extender; the segments are randomly distributed over the polymer chain; and the pre-polymer (B) segment comprises a X Y - X triblock copolymer wherein Y is a polymerisation initiator, and X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of about 7 or more.

[0291] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA or DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-WSGR Ref. No.: 56017-743.6011061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of treatment described herein comprise co-administration of two or more therapeutic compounds such as co-administration of the SARA pramlintide (compound A6) or a pharmaceutically acceptable salt thereof with the GLP-1 RA semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, or co-administration of the DACRA cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof, with the GLP-1 RA semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, as non-limiting examples.

[0292] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the biodegradable polymer is a multi-block copolymer matrix that releases less than about 3% to about 40% of the compound or pharmaceutically acceptable salts thereof based on total weight of compound or pharmaceutically acceptable salts thereof present in the multi¬ block copolymer matrix within about 24 hours. In one embodiment of the biodegradable polymer, the pre-polymer (B) segment comprises about 70% or more of poly(p-dioxanone) by total weight of the pre-polymer (B) segment. In one embodiment of the biodegradable polymer, the block length of the poly(p-dioxanone) segment X expressed in terms of p-dioxanone monomer units is about 7 to about 35. In one embodiment of the biodegradable polymer, the polymerisation initiator Y is a polymerisation initiator selected from the group consisting of ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,3 -butanediol, 2,3-butanediol, diethylene glycol, dipropylene glycol, triethylene glycol, poly(ethylene glycol), 1,5 -pentanediol, 1,6-hexanediol, neopentyl glycol, hydrogenated bisphenol A, and glycerol. In one embodiment of the biodegradable polymer, the pre-polymer (B) segment has a number average molecular weight Mnof about 1300 g / mol or more to about 7200 g / mol. In one embodiment of the biodegradable polymer, the pre-polymer (B) segment has weight average molecular weight Mwof about 1800. In one embodiment of the biodegradable polymer, the content of the pre-polymer (B) segment in the copolymer is about 5% to about 95% by total weight of the multi-block copolymer. In one embodiment of the biodegradable polymer, the pre-polymer (A) segment comprises reaction products of one or more selected from the group consisting of glycolide, lactide (d and / or 1), s-caprolactone, 6- valerolactone, trimethylene carbonate, tetramethylene carbonate, 1,5-dioxepane-2-one, l,4-dioxane-2-one (p-dioxanone), and cyclic anhydrides. In one embodiment of the biodegradable polymer, the pre-polymer (A) comprises reaction products of glycolide, lactide (d and / or 1), and / or a-caprolactone. In one embodiment of the biodegradable polymer, about 30% orWSGR Ref. No.: 56017-743.601more by total weight of pre-polymer (A) is derived from a water-soluble polymer. In one embodiment of the biodegradable polymer, the water-soluble polymer comprises one or more selected from the group consisting of poly(ethylene glycol) (PEG), poly(tetramethylene oxide) (PTMO), polypropylene glycol) (PPG), poly(vinylalcohol) (PVA), poly(vinylpyrrolidone) (PVP), poly(vinylcaprolactam), poly(hydroxyethylmethacrylate) (poly-(HEMA)), poly(phosphazenes), poly(orthoesters), poly(orthoesteramides), and copolymers of any of these polymers. In one embodiment of the biodegradable polymer, the water-soluble polymer comprises, or is, poly(ethylene glycol). In one embodiment of the biodegradable polymer, the pre¬ polymer (A) segment comprises poly(s-caprolactone)-co-PEG-co-poly(s-caprolactone). In one embodiment of the biodegradable polymer, the pre-polymer (A) segment has a number average molecular weight Mnof about 500 g / mol to about 10000 g / mol. In one embodiment of the biodegradable polymer, the content of pre-polymer (A) in the multi-block copolymer is from about 5% to about 95% based on total weight of the multi-block copolymer. In one embodiment of the biodegradable polymer, the multifunctional chain extender is a diisocyanate. In one embodiment of the biodegradable polymer, the dosage form is in the form of one or more selected from the group consisting of microspheres, microparticles, nanospheres, nanoparticles, a rod, an implant, a film, a sheet, a tube, a membrane, a mesh, fibres, a plug, a coating, and a gel. In one embodiment of the biodegradable polymer, the dosage form is in the form of microparticles having an average diameter of from about 1 pm to about 200 pm. In one embodiment of the biodegradable polymer, the multi-block copolymer matrix releases less than about 20% of protein or antibody or antigen binding fragment thereof based on total weight of protein or antibody or antigen binding fragment thereof present in the multi-block copolymer matrix within about 24 hours. In one embodiment of the biodegradable polymer, the administration is via intradermal, transdermal, intramuscular, subcutaneous, or injectable administration.

[0293] In one aspect, provided is a microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a biodegradable, phase separated, thermoplastic multi-block copolymer comprising at least one amorphous hydrolysable pre-polymer (A) segment and at least one semi-crystalline hydrolysable pre-polymer (B) segment, wherein the multi-block copolymer under physiological conditions has a Tgof 37° C. or less and a Tmof 50-110° C.; the segments are linked by a multifunctional chain extender; the segments are randomly distributed over the polymer chain; and the pre-polymer (B) segment comprises a X-Y-X tri-block copolymer wherein Y is a polymerisation initiator, and X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units ofWSGR Ref. No.: 56017-743.6017 or more.

[0294] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of treatment described herein comprise co-administration of two or more therapeutic compounds such as co-administration of the SARA pramlintide (compound A6) or a pharmaceutically acceptable salt thereof with the GLP-1 RA semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, or co-administration of the DACRA cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof, with the GLP-1 RA semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, as non-limiting examples.

[0295] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the biodegradable, phase separated, thermoplastic multi-block copolymer, X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of 7-35. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a molecular weight distribution Mw / Mnin the range of 1.0-3.0. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, at least part of pre-polymer (A) segment is derived from a water-soluble polymer. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, 30% or more by total weight of pre-polymer (A) is derived from a water-soluble polymer. In oneWSGR Ref. No.: 56017-743.601embodiment of the phase separated, thermoplastic multi-block copolymer, pre-polymer (A) segment comprises poly(p-dioxanone). In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the amount of poly(p-dioxanone) in the pre-polymer (A) segment is 80% or less by total weight of pre-polymer (A), In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, 70% or more by total weight of the pre-polymer (B) segment is poly(p-dioxanone). In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a number average molecular weight Mnof 1300-7200 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a weight average molecular weight Mwof 1800-10,080 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) has a Tgof less than 0° C. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) has a Tmin the range of 60-100° C, In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the water-soluble polymer comprises one or more selected from the group consisting of polyethers such as polyethylene glycol (PEG), polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), polyvinylalcohol (PVA), polyvinylpyrrolidone (PVT), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly-(HEM A)), polyphosphazenes, or copolymers of these polymers. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the water-soluble polymer is derived from poly(ethylene glycol) (PEG) having a Mnof 150-5000 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the chain-extender is a difunctional aliphatic chain-extender. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, wherein the difunctional aliphatic chain-extender is a diisocyanate. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, pre-polymer (A) comprises reaction products of cyclic monomers and / or non-cyclic monomers, wherein the non-cyclic monomers are selected from the group consisting of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, ethylene glycol, diethylene glycol, 1,4-butanediol and / or 1,6-hexanediol, and wherein the cyclic monomers are selected from the group consisting of glycolide, lactide, s-caprolactone, 6-valerolactone, trimethylene carbonate, tetramethylenecarbonate, I,5-dioxepane-2-one, 1,4-dioxane-2-one (p-dioxanone) and / or cyclic anhydrides such as oxepane-2, 7-dione. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, a water-soluble polymer is present as an additional pre¬ polymer. In one embodiment of the biodegradable, phase separated, thermoplastic multi-blockWSGR Ref. No.: 56017-743.601copolymer, the additional pre-polymer is present in the multi-block copolymer in an amount of 30% or less by total weight of the multi-block copolymer. In one embodiment, the biodegradable, phase separated, thermoplastic multi-block copolymer is a poly(ether ester) multi-block copolymer, wherein the pre-polymer (A) segment comprises one or more selected from the group consisting ofand wherein the pre-polymer (A) segment further comprisesand wherein the pre-polymer (B) segment comprises

[0296] In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (A) segment is represented bywherein n is 4-120.

[0297] In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the multi-block copolymer is represented by [(RrR2nR3)q]r[(R4PR3R6P)]s, wherein R1, and R3are independently selected from the group consisting ofWSGR Ref. No.: 56017-743.601and any combination thereof,R2isandR4and R6are eachn, being the number of repeating R2moi eties, is 4-120; p, being the number of repeating R4and R6moi eties is 7 or more; q, being the number average molecular weight of the (RlR2nR3) block is 400-10,000 g / mol; and r / s, being the ratio of pre-polymer (A) segment over pre-polymer (B) segment, is 0.1 -2.5.

[0298] In one embodiment, the pharmaceutical composition comprising the biodegradable, phase separated, thermoplastic multi-block copolymer is in the form of microparticles. In one aspect, a process is provided for preparing the biodegradable, phase separated, thermoplastic multi-block copolymer as described herein, comprising: performing a chain extension reaction of pre-polymer (A) and pre-polymer (B) in the presence of a multifunctional chain-extender, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the chain-extender is di-carboxylic acid, diisocyanate, or diol terminated; or ii) performing a chain extension reaction using a coupling agent, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the coupling agent is preferably dicyclohexyl carbodiimide, wherein the pre-polymer (B) segment comprises a X-Y-X tri-block copolymer, wherein Y is a polymerisation initiator, and X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of 7 or more. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, X is a poly(p-dioxanone) segment with a block length expressed in p-dioxanone monomer units of 11-14. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a number average molecular weight Mnof 2200-WSGR Ref. No.: 56017-743.6013200 g / mol. In one embodiment of the biodegradable, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment has a weight average molecular weight Mwof 3000-4200 g / mol.

[0299] In one aspect, provided is a microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, the copolymer being characterised in that: a) it comprises at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment, b) the multi-block copolymer having a Tgof 37 °C or less and a Tmof 110-250 °C under physiological conditions; c) the segments are linked by a multifunctional chain-extender; d) the segments are randomly distributed over the polymer chain; e) at least part of the pre-polymer (A) segment is derived from a water- soluble polymer.

[0300] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions and methods of treatment described herein comprise co-administration of two or more therapeutic compounds such as co-administration of the SARA pramlintide (compound A6) or a pharmaceutically acceptable salt thereof with the GLP-1 RA semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, or co-administration of the DACRA cagrilintideWSGR Ref. No.: 56017-743.601(compound A3) or a pharmaceutically acceptable salt thereof, with the GLP-1 RA semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, as non-limiting examples.

[0301] In one embodiment, the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, the chain-extender is a difunctional aliphatic chainextender, preferably a diisocyanate, such as 1,4-butane diisocyanate. In one embodiment, the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, wherein pre-polymer (A) comprises reaction products of cyclic monomers and / or non cyclic monomers, wherein the non cyclic monomers are preferably selected from the group consisting of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, ethylene glycol, diethylene glycol, 1,4-butanediol and / or 1,6-hexanediol, and wherein the cyclic monomers are preferably selected from the group consisting of glycolide, lactide, s-caprolactone, 6-valerolactone, trimethylene carbonate, tetramethylenecarbonate, l,5-dioxepane-2-one, 1,4-dioxane-2-one (para-dioxanone) and / or cyclic anhydrides such as oxepane-2, 7-dione. In one embodiment, the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, wherein the water-soluble polymer is selected from the group consisting of polyethers such as polyethylene glycol (PEG), polytetramethyleneoxide (PTMO) and polyp ropyleneglycol (PPG); polyvinylalcohol (PVA) polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly-(HEMA)), polyphosphazenes, polyorthoesters, polyorthoesteraniides or copolymers of the previous polymers, preferably the water-soluble polymer is derived from poly(ethylene glycol) (PEG) having a Mnof 150-5000 g / mol. In one embodiment, the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, wherein a water-soluble polymer is present as an additional pre-polymer. In one embodiment of the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, the pre-polymer (B) segment comprises a crystallisable polymer derived from hydroxyalkanoate, glycolide, L-lactide or D-lactide, preferably the pre-polymer (B) segment comprises L-lactide pre-polymers and D-lactide pre-polymers in such amounts and ratio that stereocomplexation between L-lactide and D-lactide is achieved, preferably the pre-polymer (B) is poly(L-lactic acid) with an Mnof 1000 g / mol or more, preferably 2000 g / mol or more, more preferably 3000 g / mol or more. In one embodiment, the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer has a swelling ratio under physiological conditions varies from 1 to 4, more preferably 1 to 2, most preferably 1 to 1.5. In one embodiment, of the biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, the copolymer has an intrinsic viscosity of at least 0.1 dl / g, and preferably between 0.2 and 2 dl / g. In one embodiment, the biodegradable, semi-crystalline, phase separated, thermoplastic multi-blockWSGR Ref. No.: 56017-743.601copolymer comprises i) performing a chain extension reaction of pre-polymer (A) and pre¬ polymer (B) in the presence of a multifunctional chain-extender, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the chain-extender is di-carboxylic acid or diol terminated; or ii) performing a chain extension reaction using a coupling agent, wherein prepolymer (A) and (B) are both diol or diacid terminated and the coupling agent is preferably di cyclohexyl carbodiimide. In one embodiment, the biologically active compound is a biologically active polypeptide having a molecular weight which is 10000 Da or less, preferably the multi¬ block copolymer contains poly(ethylene glycol), as a segment of pre-polymer (A) and / or as an additional pre-polymer, and wherein the poly(ethylene glycol) i) has a molecular weight of from 400 to 3000 g / mol, preferably from 600 to 1500 g / mol; and / or ii) is present in an amount of from 5 wt.% to 60 wt.%, preferably of from 5 wt.% to 40 wt.%. In one embodiment, the biologically active compound is a biologically active polypeptide having a molecular weight of 10000 Da or more, preferably the multi-block copolymer contains poly(ethylene glycol), as a segment of prepolymer (A) and / or as an additional pre-polymer, and wherein the poly(ethylene glycol) i) has a molecular weight of from 600 to 5000 g / mol, preferably of from 1000 to 3000 g / mol; and / or ii) is present in an amount of from 5 wt.% to 70 wt.%, more preferably of from 10 wt.% to 50 wt.%. In one embodiment, the pharmaceutical composition is in the form of microparticles, microparticles, nanoparticles, nanospheres, rods, implants, gels, coatings, films, sheets, sprays, tubes, membranes, meshes, fibres, or plugs. In one embodiment, the pharmaceutical composition in the form of microparticles and / or microparticles, wherein the average diameter of the microparticles and / or microparticles is preferably in the range of 0.1-1000 μm, more preferably in the range of 1-100 μm, even more preferably in the range of 10-50 μm In one embodiment, the biologically active compound is dissolved or dispersed throughout the polymer matrix.

[0302] In one aspect, a method is provided of manufacturing the pharmaceutical composition, comprising the successive steps of a) emulsifying an aqueous solution of a water-soluble biologically active compound in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer in an organic solvent, such as dichloromethane or ethyl acetate; b) subsequently emulsifying the resultant emulsion of a) in an aqueous solution comprising a surfactant such as polyvinyl alcohol, thereby yielding a water-in-oil-in-water (W / O / W) emulsion; and c) extracting the organic solvent to solidify microparticles. In one embodiment, the method of manufacturing comprises the successive steps of a) dispersing the biologically active compound as a solid powder in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer (as described herein) in an organic solvent, such as dichloromethane or ethyl acetate; b) emulsifying the resultant dispersion of a) in anWSGR Ref. No.: 56017-743.601aqueous solution comprising a surfactant such as polyvinyl alcohol, thereby yielding a solid-in-oil-in-water (S / OAV) emulsion; and c) extracting the organic solvent to solidify the microparticles. In one embodiment, the method of manufacturing comprises the successive steps of the successive steps of a) emulsifying an aqueous solution of a water-soluble biologically active compound in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multiblock copolymer in an organic solvent, such as dichloromethane or ethyl acetate; b) adding a polymer precipitant, such as silicon oil, to the resultant emulsion of a) to form embryonic microparticles; and c) extracting the polymer precipitant and the organic solvent to solidify the microparticles. In one embodiment, the method of manufacturing comprises the successive steps of a) dispersing the biologically active compound as a solid powder in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer in an organic solvent, such as dichloromethane or ethyl acetate; b) adding a polymer precipitant, such as silicon oil, to the resultant dispersion of a) to form embryonic microparticles; and c) extracting the polymer precipitant and the organic solvent to solidify the microparticles.

[0303] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer.

[0304] Pharmaceutical compositions and methods using the same comprise any biodegradable polymer known to those or ordinary skill in the art. Representative biodegradable polymers include each of those of any of US20230096928A1, WO2024248572A1, WO2024248574A1 and W02024010379A1 the entirety of each of which is incorporated herein by reference.

[0305] In one aspect, provided is pharmaceutical composition comprising sustained-release microparticles comprising any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, and a biodegradable polymer. In some embodiment, the microparticles have a content of compound that is 8 wt% or more based on the total weight of the microparticles. In some embodiments, the microparticles comprise a “first excipient” as defined herein, and optionally an “acidic excipient” as defined herein. In one embodiment, the first excipient is provided in a quantity of from about 5 ppm to about 2000 ppm. In one embodiment, the present invention provides a pharmaceutical composition comprising sustained-release microparticles comprising any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, and a biodegradable polymer, wherein the content of the compound is 8 wt% or more based on the total weight of the microparticles and the initial release of the drug is 10% or less.

[0306] In one embodiment of the microparticle or pharmaceutical composition comprisingWSGR Ref. No.: 56017-743.601sustained-release microparticles comprising any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, and a biodegradable polymer, the compound is any of the small molecules or peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the compound is a pharmaceutically acceptable salt such as the sodium salt, acetate salt, benzoate salt, hydroxynaphthoate salt, napadicylate salt, choline salt, or pamoate salt. In one embodiment, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is semaglutide or pharmaceutically acceptable salts thereof, such as an acetate, benzoate, chloride, hydroxynaphthoate, nafadisylate or pamoate salt of semaglutide. In one embodiment, the peptide is a SARA / D ACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a GIP receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof, such as an acetate, benzoate, chloride, hydroxynaphthoate, nafadisylate or pamoate salt of cagrilintide. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof, such as an acetate, benzoate, chloride, hydroxynaphthoate, nafadisylate or pamoate salt of pramlintide. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof, such as an acetate, benzoate, chloride, hydroxy naphthoate, nafadisylate or pamoate salt of i2o-1061. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof, such as an acetate, benzoate, chloride, hydroxynaphthoate, nafadisylate or pamoate salt of i2o-2248. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0307] In one embodiment, the biodegradable polymer is selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polylactide-co-glycolide (PLGA), polydioxanone, poly caprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), polylactide-co-hydroxymethyl glycolide (PLGMGA), polyalkylcarbonate, polytrimethylenecarbonate (PTMC), polylactide-co-trimethylenecarbonate (PLTMC), a polymer selected from the group consisting of block copolymers of polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerateWSGR Ref. No.: 56017-743.601(PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosph azene, polyphosphoester, polysaccharide and polyfbutylene succinate lactide) (PBSLA); simple mixtures of two or more thereof; copolymers of the above polymers and polyethylenglycol (PEG). In one embodiment, the biodegradable polymer is a polymer-sugar complex in which the polymer or copolymer is combined with a sugar. In one embodiment, the biodegradable polymer is one or more selected from the group consisting of a polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polylactide-co-glycolide (PLGA) which is a copolymer of lactide and glycolide, polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and polyalkylcarbonate; a copolymer or simple mixture of 2 or more thereof; a copolymer of the polymer and polyethyleneglycol (PEG); and a polymer-sugar complex which the polymer or copolymer is linked with sugar.

[0308] In one embodiment, the composition may further comprise at least one first excipient. As used herein the term “first excipient” is selected from the group consisting of a phosphate salt, a hydroxide salt, a phosphide salt, a phosphite salt, a carbonate salt, a bicarbonate salt, a chromate salt, a dichromate salt, an oxide salt, an oxalate salt, a silicate salt, a sulfate salt, a sulfide salt, a sulfite salt, a tartrate salt, a tetraborate salt, a thiosulfate salt, an arsenate salt, an arsenite salt, a citrate salt, a ferricyanide salt, and a nitride salt of an alkali metal, an alkaline earth metal, or an ammonium. In another aspect, the first excipient may be at least one selected from the group consisting of disodium phosphate, dipotassium phosphate, and diammonium phosphate. In one embodiment, the pharmaceutical composition further comprises one or more acidic excipients selected from the group consisting of butyric acid, valeric acid, caproic acid, enantic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, hydroxynaphthoic acid, napadisylic acid and pamoic acid. In one embodiment, the first excipient may be a salt that is dissolved in the continuous phase during the production of microparticles containing a compound and maintains the pH of the continuous phase at 7.0 or higher.

[0309] In one embodiment, the composition may further comprise at least one second excipient. As used herein the term “second excipient” is selected from the group consisting of poloxamer, benzathine, procaine, lidocaine, bupivacaine, ropivacaine, oxytetracycline, sunitinib, lizolutin, and benzofuran.

[0310] In one embodiment, the composition may further comprise at least one acidic excipient. As used herein the term “acidic excipient” is selected from butyric acid, valeric acid.WSGR Ref. No.: 56017-743.601caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecylic acid, behenic acid, arachidic acid, isocrotonic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, arachidonic acid, benzoic acid, hydroxy naphthoic acid, napadicylic acid, naphthalene sulfonic acid, and pamoic acid.

[0311] In one embodiment, the biodegradable polymer has an inherent viscosity of about 0.16 to 1.7 dL / g. In one embodiment, the biodegradable polymer comprises poly(lactide-co-glycolide) or polylactide and has an inherent viscosity of about 0.16 to 1.7 dL / g. In one embodiment, the average particle size of the microparticle is 5 pm to 100 pm. In one embodiment, the sustained-release microparticles have a span value of 1.5 or less, 1.2 or less, 0.1 to 1.5, 0.3 to 1.5, 0.5 to 1.5, 0.1 to 1.0, 0.4 to 1.0, 0.6 to 1.0, 0.2 to 0.8, or 0.4 to 0.8. The term used in the present invention, “size distribution” or “span value” is an index indicating uniformity of the particle size of the microparticle, and means a value obtained by the formula of span value = (Dv0.9-Dv0.1) / Dv0.5. Herein, DvO.l is a particle size corresponding to 10% of volume % in a particle size distribution curve of the microparticle, and Dv0.5 is a particle size corresponding to 50% of volume % in a particle size distribution curve of the microparticle, and Dv0.9 means a particle size corresponding to 90% of volume % in a particle size distribution curve of the microparticle. In one embodiment, the weight of the microparticle containing the compound or pharmaceutically acceptable salts thereof is 20 to 1000 mg.

[0312] In one aspect, a method is provided for preparation of a pharmaceutical composition comprising sustained-release microparticles comprising any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, and a biodegradable polymer, comprising (a) dissolving the compound or pharmaceutically acceptable salts thereof and one or more biodegradable polymer in an organic solvent to prepare solution (dispersed phase) containing the compound or pharmaceutically acceptable salts thereof and the polymer; (b) adding the solution containing the compound or pharmaceutically acceptable salts thereof and the polymer prepared in the step (a) to an aqueous phase (continuous phase) containing a surfactant to prepare emulsion; (c) extracting and evaporating the organic solvent from the dispersed phase in an emulsion state prepared in the step (b) to the continuous phase to form a microparticle; and (d) collecting the microparticle from the continuous phase of the step (c) to prepare a microparticle comprising compound or pharmaceutically acceptable salts thereof.

[0313] In one embodiment of the method, the compound is any of the small molecules or peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the compound is a pharmaceutically acceptable salt such as the sodium salt, acetate salt, benzoate salt,WSGR Ref. No.: 56017-743.601hydroxynaphthoate salt, napadicylate salt, choline salt, or pamoate salt. In one embodiment, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non¬ limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0314] In one embodiment of the method, the biodegradable polymer is a mixture of 2 or more biodegradable polymers different each other. In one embodiment of the method, the organic solvent of the step (a) is one or more organic solvents selected from the group consisting of dichloromethane, chloroform, ethyl acetate, methylethylketone, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methyl pyrrolidone, acetate, methyl alcohol, ethyl alcohol, propyl alcohol and benzyl alcohol. In one embodiment, the method further comprises a sieving process between the step (c) and the step (d). In one embodiment of the method, the surfactant of the step (b) is polyvinylalcohol. In one embodiment of the method, the continuous phase of the step (b) is water, or a mixed solvent of water and one or more selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol and ethyl acetate. In one embodiment of the method, the pH of the continuous phase in the step (b) is 5 or less. In one embodiment, the method further comprises: (a') dissolving compound or pharmaceutically acceptable salts thereof and 2 or more biodegradable polymers different each other in an organic solvent to prepare a solution (dispersed phase) containing the compound or pharmaceutically acceptable salts thereof and the polymer; (b') adding the solution containing the compound or pharmaceutically acceptable salts thereof and the polymer prepared in the step (a') to an aqueous phase (continuous phase) containing a surfactant to prepare emulsion; (c') extracting and evaporating the organic solventWSGR Ref. No.: 56017-743.601from the dispersed phase in an emulsion state prepared in the step (b') to the continuous phase to form a microparticle; and (d') repeating a process for preparing a microparticle comprising collecting a microparticle from the continuous phase in the step (c') to prepare a microparticle 2 times or more to prepare 2 or more microparticles different each other, (e') mixing the 2 or more microparticles consisting of different kinds of polymers each other.

[0315] In one embodiment, the method further comprises: (a") dissolving compound or pharmaceutically acceptable salts thereof and 2 or more biodegradable polymers different each other in an organic solvent, respectively, to prepare 2 or more solutions (dispersed phase) containing the compound or pharmaceutically acceptable salts thereof and the polymer; (b") adding the 2 or more solutions (dispersed phase) containing the compound or pharmaceutically acceptable salts thereof and polymer prepared in the step (a") to an aqueous phase (continuous phase) containing a surfactant, respectively, to prepare 2 or more emulsions; (c") extracting and evaporating the organic solvent from the 2 or more dispersed phase in an emulsion state prepared in the step (b") to the continuous phase, by putting the 2 or more dispersed phase in emulsion state prepared in the step (b') into the same reactor, to form microparticles; and (d") collecting microparticles from the continuous phase in the step (c").

[0316] Pharmaceutical compositions and methods using the same comprise any biodegradable polymer known to those or ordinary skill in the art. Representative biodegradable polymers include each of those of any of WO2024128882A1 and US20240307500A1, the entirety of each of which is incorporated herein by reference.

[0317] In one aspect, provided is pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a sustained-release microparticle comprising poly(lactide-co-glycolide (PLGA)), wherein the PLGA is a mixture of one type of low-molecular weight PLGA with an intrinsic viscosity of 0.14 to 0.24 dL / g and two or more types of high-molecular weight PLGA with an intrinsic viscosity of 0.32 to 0.60 dL / g.

[0318] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceuticallyWSGR Ref. No.: 56017-743.601acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g,, wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0319] In one embodiment, the compound or pharmaceutically acceptable salts thereof is included in an amount of 3 to 12% by weight of the total weight%. In one embodiment, the weight ratio of the one type of low-molecular weight PLGA and the two or more types of high-molecular weight PLGA in the mixture is 1:0.2 to 5. In one embodiment, the two or more types of high viscosity PLGA are one or more types of PLGA having a molar ratio of lactide to glycolide of 45-55:45-55 and one or more types of PLGA having a molar ratio of lactide to glycolide of 60-80:20-40. In one embodiment, the poly(lactide-co-glycolide) is 88 to 97% by weight of the total weight% of the sustained-release microparticles.

[0320] In one aspect a process is provided for the preparation of sustained-release microparticles, comprising mixing the compound or pharmaceutically acceptable salts thereof and the poly(lactide-co-glycolide) in glacial acetic acid to yield a mixed solution; and spraying the mixed solution with an ultrasonic spray nozzle, and volatilizing the glacial acetic acid with dry air. In one embodiment of the process, 3 to 12% by weight of the compound or pharmaceutically acceptable salts thereof is mixed with 88 to 97% by weight of poly(lactide-co-glycolide) and a solvent, followed by spraying the mixed solution with an ultrasonic spray nozzle and then volatilizing the solvent with dry air to produce microparticles. In one embodiment, the frequency of the ultrasonic spray nozzle is 40 to 80 kHZ.

[0321] In one embodiment, following administration of the pharmaceutical composition or sustained-release microparticles to rats or minipigs, less than 5% of the compound or pharmaceutically acceptable salts thereof, is released from the sustained-release microparticles within 24 hours, not more than 10% within 1 week, not more than 20% within 9 days, and / or not more than 50% released within 2 weeks. In one embodiment, following administration of theWSGR Ref. No.: 56017-743.601pharmaceutical composition or sustained-release microparticles to rats or minipigs, at least 10% of the compound or pharmaceutically acceptable salts thereof, is released from the sustained-release microparticles within 1 week, at least 20% is released within 9 days, and / or at least 50% is released within 2 weeks. In one embodiment, the pharmaceutical composition or sustained-release microparticles are configured for monthly or quarterly per year dosing. In one embodiment, the sustained-release microparticles have an average particle size of 15 to 25 um.

[0322] In one aspect, provided is pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a sustained-release microparticle comprising poly(lactide-co-glycolide); wherein the compound or pharmaceutically acceptable salts thereof is included in an amount of 3% by weight or more and less than 9% by weight of the sustained-release microparticles, and wherein the poly(lactide-co-glycolide) is a mixture of low-molecular weight PLGA having an intrinsic viscosity of 0.14 to 0.24 dL / g and high-molecular weight PLGA having an intrinsic viscosity of 0.32 to 0.44 dL / g.

[0323] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.WSGR Ref. No.: 56017-743.601

[0324] In one embodiment, the sustained-release microparticle has a weight ratio of the low- molecular weight PLGA and the high-molecular weight PLGA in the mixture is 1:0.2 to 5, In one embodiment, the sustained-release microparticle has a molar ratio of lactide to glycolide in the high-molecular weight PLGA is 50:45 to 55,

[0325] In one aspect a process is provided for the preparation of sustained-release microparticles, comprising mixing the compound or pharmaceutically acceptable salts thereof and the poly(lactide-co-glycolide) in glacial acetic acid and spraying the same using an ultrasonic spray nozzle, followed by volatilizing the solvent using dry air. In one embodiment, the ultrasonic spray nozzle has a frequency of 60 KHz. In one embodiment, the process comprises mixing the compound or pharmaceutically acceptable salts thereof and the poly(lactide-co-glycolide) in an organic solvent to yield a mixed solution; and drying the mixed solution to obtain microparticles, wherein the poly(lactide-co-glycolide) is a mixture of low-molecular weight PLGA having an intrinsic viscosity of 0.14 to 0.24 dL / g and high-molecular weight PLGA having an intrinsic viscosity of 0.32 to 0.44 dL / g. In one embodiment, the drying of the mixed solution is performed by a spray drying process. In one embodiment, the sustained-release microparticles have a weight ratio of the low-molecular weight PLGA and the high-molecular weight PLGA in the mixture is 1:0.2 to 5.

[0326] In one embodiment, following administration of the pharmaceutical composition or sustained-release microparticles to rats or minipigs, less than 5% of the compound or pharmaceutically acceptable salts thereof, is released from the sustained-release microparticles within 24 hours, not more than 10% within 1 week, not more than 20% within 9 days, not more than 30% within two weeks, and / or not more than 60% is released within 4 weeks. In one embodiment, following administration of the pharmaceutical composition or sustained-release microparticles to rats or minipigs, at least 10% of the compound or pharmaceutically acceptable salts thereof, is released from the sustained-release microparticles within 1 week, at least 20% is released within 9 days, at least 30% is released within 2 weeks, and / or at least 60% is released within 4 weeks. In one embodiment, less than 5% of the compound is released within 24 hours after administration to rats, and 30% or more is released within 2 weeks, or 60% or more is released within 4 weeks. In one embodiment, the pharmaceutical composition or sustained-release microparticles are configured for monthly or quarterly per year dosing.

[0327] In one embodiment, the poly(lactide-co-glycolide) is 91 to 97% by weight of the sustained-release microparticles. In one embodiment, the sustained-release microparticles have an average particle size of 15 to 25 pm. In one embodiment, the sustained-release microparticles have a molar ratio of lactide to glycolide in the high-molecular weight PLGA is 50:45 to 55. InWSGR Ref. No.: 56017-743.601one embodiment, the pharmaceutical composition is used for treatment of diabetes, obesity, non¬ alcoholic steatohepatitis or degenerative brain disease. In one embodiment, the degenerative brain disease is any of those selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, Creutzfeldt-Jakob disease, stroke, and multiple sclerosis.

[0328] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer.

[0329] Pharmaceutical compositions and methods using the same comprise any biodegradable polymer known to those or ordinary skill in the art. Representative biodegradable polymers include each of those of US11865213B2, the entirety of which is incorporated herein by reference,

[0330] In one aspect, provided is pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, wherein the biodegradable polymer is a sustained-release microparticle comprising poly(lactide-co-glycolide (PLGA)), wherein the compounds or pharmaceutically acceptable salts thereof and the PLGA are combined in a ratio from 1: 1 to 1: 100, wherein the composition releases less than 20% of the compound or pharmaceutically acceptable salts thereof over 24 hours in a phosphate buffer at pH 7.4, the composition releases less than 80% of the compound or pharmaceutically acceptable salts thereof over 14 days in a phosphate buffer at pH 7.4, the composition releases more than 80% of the compound or pharmaceutically acceptable salts thereof over 28 days in a phosphate buffer at pH 7.4, the compound is released from the composition in a continuous manner over 14 days upon dissolution in a phosphate buffer at pH 7.4, and / or the composition releases the compound over a period of about four weeks to about six months.

[0331] In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein, the compound is any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment of the microparticle or pharmaceutical composition comprising the biodegradable polymer and any of the compounds described herein, the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide orWSGR Ref. No.: 56017-743.601pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0332] In one embodiment, the pharmaceutical composition is suitable for injectable administration to a subject at a frequency of once every four weeks to once every six months.

[0333] In one embodiment, the sustained-release microparticles are formed by drying water- in-oil -in-water (w / o / w) double emulsion droplets comprising: a) an internal aqueous phase comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salts thereof; b) a water immiscible polymeric phase comprising a biodegradable polymer selected from the group consisting of polylactides, polyglycolides, polycaprolactones, and combinations thereof, and a first surfactant comprising a fatty acid or a derivative thereof; and c) an external aqueous phase. In one embodiment, the external aqueous phase comprises a tonicity modifier. In one embodiment, the tonicity modifier comprises sodium chloride. In one embodiment, wherein the sustained-release microparticles comprise a coating layer. In one embodiment, wherein the sustained-release microparticles are devoid of any coating layer.

[0334] In one embodiment, the compound is released from the pharmaceutical composition at a first-order controlled release. In one embodiment, at least one of the internal and external aqueous phases further comprises a second surfactant. In one embodiment, the second surfactant is selected from the group consisting of polyvinyl alcohol (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymers, polyethylene glycol, and cellulose esters. In one embodiment, the biodegradable polymer is a polymer selected from the group consisting of poly(D, L-lactide-co-glycolide) (PLGA), poly(D, L-lactide) (PLA), polyglycolide (PGA), polycaproactone (PCL), and combinations thereof. In one embodiment, the biodegradable polymer is poly(D, L-lactide-co-glycolide) (PLGA). In one embodiment, the first surfactant comprising a fatty acid or a derivative thereof is lecithin, hydrogenated lecithin, stearic acid, or a mixture of combination thereof. In one embodiment, the water-in-oil-in-water (w / o / w) double emulsion droplets are formed by a process comprising the steps of (i) dispersing an aqueous suspension or solution of the compound or pharmaceutically acceptable salts thereof in a solutionWSGR Ref. No.: 56017-743.601of a biodegradable polymer and the first surfactant in a water-immiscible volatile organic solvent, thereby obtaining a water-in-oil emulsion; and (ii) dispersing the water-in-oil emulsion in a continuous external water phase comprising the second surfactant and the tonicity modifier, to form microparticles comprising water-in-oil -in-water (w / o / w) double emulsion droplets. In one embodiment, the process further comprises the step of (iii) collecting the thus formed microparticles by filtration or centrifugation. In one embodiment, the process further comprises the step of (iv) washing the collected microparticles. In one embodiment, the process further comprises the step of drying the collected or washed microparticles. In one embodiment, the pharmaceutical composition comprises a physiologically acceptable solvent.

[0335] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer.

[0336] Pharmaceutical compositions and methods using the same comprise any biodegradable polymer known to those of ordinary skill in the art. Representative biodegradable polymers include each of those prepared by the processes of WO2024023501A2, the entirety' of which is incorporated herein by reference.

[0337] In one aspect, provided is a continuous process for the preparation of microscopic particles, e.g. nanoparticles or microparticles, wherein the microscopic particles comprise any of the pharmaceutical compositions comprising a biodegradable polymer and any of the compounds (peptides or small molecules) described herein, the process comprising the steps of (i) controlling provision of a first liquid phase to a first membrane, the first membrane defining a first plurality of apertures; (ii) controlling provision of a second liquid phase to the first membrane via the first plurality of apertures to form a mixture; optionally (iii) controlling provision of the mixture to a second membrane, the second membrane defining a second plurality of apertures; (iv) controlling provision of a pH buffer liquid phase to the second membrane via the second plurality of apertures to form a stabilised suspension of particles; (v) concentrating the suspension of particles and controlling provision of the pH buffered mixture to a third membrane, the third membrane defining a third plurality of apertures; (vi) controlling provision of a diafiltration buffering liquid phase to the third membrane via the third plurality of apertures to remove solvent and exchange the particles into an excipient buffer; and (vii) controlling provision of the stabilised mixture to a fourth membrane for microfiltration, to isolate the microscopic particles.

[0338] In one embodiment, the continuous process is for the preparation of microscopic particles comprising a biodegradable polymer and any of the compounds or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the continuous process is for theWSGR Ref. No.: 56017-743.601preparation of microscopic particles comprising a biodegradable polymer and any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the continuous process is for the preparation of microscopic particles comprising a biodegradable polymer and any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof, non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0339] In one embodiment of the continuous process, the microscopic particles are nanoparticles. In one embodiment of the continuous process, the microscopic particles are microparticles. In one embodiment of the continuous process, steps (i) to (vii) are carried out sequentially with or without an intervening isolation or purification step. In one embodiment of the continuous process, each of the membranes may be the same or different. In one embodiment of the continuous process, each of the membranes, which may be the same or different, comprises a laboratory dispersion cell (LDC) or a crossflow apparatus (AXF®). In one embodiment of the continuous process, the number of membranes used in the continuous process is from about 1 to about 4. In one embodiment of the continuous process, at least one of the membranes comprises a crossflow apparatus (AXF®). In one embodiment of the continuous process, the membranes comprise a mixture conventional tubular membranes and crossflow membranes. In one embodiment of the continuous process, all of the membranes comprise crossflow apparatus (AXF®). In one embodiment of the continuous process, in step (v) the concentration of the suspension of particles is achieved using single pass tangential flow filtration cassette equipped with an ultrafiltration or microfiltration membrane suitably sized to retain the particles. In one embodiment of the continuous process, an AXF® cross-flow apparatus (available from Micropore Technologies Limited) equipped with membranes comprising slotted apertures is used. In one embodiment of the continuous process, step (iv) comprises formation of a pH buffered mixture byWSGR Ref. No.: 56017-743.601controlling provision of the mixture to a second membrane and controlling provision of a pH adjustment buffer to form a stabilised mixture. In one embodiment of the continuous process, the microscopic particles are microparticles or nanoparticles including a chemically or biologically active substance. In one embodiment of the continuous process, the microscopic particles are solidified particles, e.g. crystalline particles. In one embodiment, the continuous process comprises one or more analytical characterisation points are included. In one embodiment, the continuous process comprises an analytical characterisation point is included at or towards the end of each step of the continuous process or each pair of steps of the continuous process. In one embodiment, the continuous process comprises an analytical characterisation point is included at or towards the end of one or more of steps (ii), (iv) and (vi). In one embodiment, the continuous process comprises at least one crossflow membrane apparatus (AXF®) wherein the crossflow emulsification apparatus comprises: an outer tubular sleeve provided with a first inlet at a first end; a lipid vesicle outlet; and a second inlet, distal from and inclined relative to the first inlet; a tubular membrane provided with a plurality of pores and adapted to be positioned inside the tubular sleeve; and optionally an insert adapted to be located inside the tubular membrane, the insert comprising an inlet end and an outlet end, each of the inlet end and an outlet end being provided with a chamfered region; the chamfered region is provided with a plurality of orifices and a furcation plate; and controlling provision of the first liquid phase to the tubular membrane; and controlling provision of a second liquid phase to the tubular membrane via the plurality of pores to form a lipid vesicle suspension. In one embodiment of the continuous process, the crossflow apparatus includes an insert and the first inlet is a continuous phase first inlet and the second inlet is a disperse phase inlet; such that the disperse phase travels from outside the tubular membrane to inside. In one embodiment of the continuous process, the crossflow apparatus does not include an insert and the first inlet is a disperse phase first inlet and the second inlet is a continuous phase inlet; such that the disperse phase travels from inside the tubular membrane to outside. In one embodiment of the continuous process, the disperse phase is the lipid phase and the continuous phase is a solvent phase. In one embodiment of the continuous process, the disperse phase is the solvent phase and the continuous phase is a lipid phase. In one embodiment of the continuous process, the solvent phase includes one or more active agents (i.e., therapeutic compounds described herein, whether peptides or small molecules). In one embodiment of the continuous process, the crossflow apparatus includes an insert, and wherein said insert is tapered, such that the spacing between the insert and the tubular membrane may be divergent along the length of the membrane. In one embodiment of the continuous process, the crossflow apparatus comprises more than one tubular membrane located inside the outer tubular sleeve. In oneWSGR Ref. No.: 56017-743.601embodiment of the continuous process, the membranes, which may be the same or different, comprise a material, such as glass; ceramic; metal, e.g. stainless steel or nickel; polymer / plastic, such as a fluoropolymer; or silicon. In one embodiment of the continuous process, any one of the membranes includes an insert includes a furcation plate adapted to split the flow of continuous phase or the disperse phase into a number of branches. In one embodiment of the continuous process, the furcation plate is a bifurcation plate or a tri-furcation plate to provide a uniform continuous phase flow within the annular region between the insert and the membrane. In one embodiment, the continuous process comprises the use laminar flow for at least one membrane in the process, i.e, whilst generally avoiding or minimising any turbulent flow. In one embodiment of the continuous process, the shape of the pores is substantially tubular or linear, e.g. slotted pores.

[0340] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer.

[0341] Pharmaceutical compositions and methods using the same comprise any biodegradable polymer known to those of ordinary skill in the art. Representative biodegradable polymers include each of those prepared by the processes of U. S. Patent Nos.: 7,976,759, 8,518,316, and 9,545,737, the entirety of each of which is incorporated herein by reference.

[0342] In one aspect, provided is pharmaceutical composition comprising the biodegradable polymer and any of the compounds (peptides or small molecules) or pharmaceutically acceptable salts thereof, as described herein, formulated into sustained-release microparticles.

[0343] In one embodiment, provided is a method of forming such microparticles, comprising methods known to one of ordinary skill in the art for the manufacture of microparticles, such as milling, freeze-drying, spray-drying, spray-freeze-drying, supercritical fluid-drying, or more recently developed manufacturing technologies such as particle replication in non-wetting templates (PRINT), inkjet-printing (UP), thin-film freezing (TFF), and hot-melt extrusion (HME).

[0344] PRINT is soft lithography techniques that use perfluoropolyether elastomers as a molding template on a silicone master plate to create different shaped micro to nano size particulate matters. PRINT has been used to improve the size and flow property of microparticles. Likewise, UP is another technology that can precisely control the morphology of microparticles with a digital imaging system. In this technology, the processing liquid materials can be impelled dropwise on suitable substrates with defined particle size and morphology. TFF is a freezing technology, where the freezing of liquid is controlled under the influence of a fluid dynamic system. In this process, liquid formulations are rapidly spread in the form of thin film on aWSGR Ref. No.: 56017-743.601cryogenically cooled surface, where the transfer of heat from the spread liquid droplets takes place within a fraction of second to convert it into solid mass, which is further lyophilized to get dry powder. Microparticles prepared by this TFF technology have low bulk density and smaller size. FEME is used in the pharmaceutical industry to enhance the solubility of low soluble drugs and formulate prolonged drug delivery formulations. In this technology, a solid mixture of drug / polymers is heated together into a mold beyond its glass transition temperature (Tg) to melt into a viscous mass, which is further collected as a slug to micronize as a fine powder.

[0345] In one embodiment, provided is a method of forming such microparticles, comprising (a) applying a substantially liquid composition to a mold, wherein the mold comprises a polymer and defines a plurality of cavities each having a broadest cross-sectional dimension of less than about 100 micrometers; (b) passing the mold through a nip point such that the substantially liquid composition enters the cavities of the mold, wherein passing the mold through the nip point comprises nipping the substantially liquid composition between a cover sheet and the mold; (c) removing the cover sheet from the mold such that the substantially liquid composition not in the cavities of the mold remains adhered to the cover sheet, the land area of the mold between the cavities is substantially free from the substantially liquid composition, and the cavities of the mold remain filled with the substantially liquid composition; and (d) hardening the substantially liquid composition in the cavities of the mold to form a particle within each cavity, wherein the particle has a size and shape that substantially mimics the size and shape of the cavity of the mold. In one embodiment, provided is a method of harvesting such microparticles, comprising: (a) passing a base substrate and an array of micro- or nano-particles coupled therewith through a nip point, wherein the base substrate is coupled with a single surface of each particle in the array of microparticles; (b) applying a solvent to the nip point, wherein the solvent disengages the microparticles from the base substrate and releases the microparticles into a solution substantially contained near the nip point; and (c) collecting the solution containing the released microparticles. In one embodiment, provided is a method of harvesting such microparticles, comprising: (a) coupling a single surface of each of a plurality of micro- or nano-particles with a soluble substance on a base substrate; (b) introducing a solvent to the base substrate having the micro- or nano¬ particles coupled therewith; (c) allowing the solvent to release the micro- or nano-particles from the base substrate by disengaging the soluble substance from the base substrate; and(d) collecting the released micro- or nano-particles.

[0346] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and a biodegradable polymer.WSGR Ref. No.: 56017-743.601Pharmaceutical compositions and methods using the same comprise any biodegradable polymer known to those or ordinaiy skill in the art. Representative biodegradable polymers include each of the biodegradable polymer-drug conjugates, biodegradable polymer-drug prodrugs and covalently and reversibly (i.e., biodegradable) conjugated drug moieties of any of WO2024184354A1, WO2024184352A1, and WO202418435I Al, the entirety of each of which is incorporated herein by reference.

[0347] In one aspect, provided is a microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound (e.g., derived from a peptide or small molecule described herein) or pharmaceutically acceptable salts thereof, wherein the conjugated-compound comprises at least two covalently and reversibly conjugated drug moieties, each of the at least two drug moieties comprises an albumin-binding moiety, and wherein the conjugated-compound releases the drug moieties as their corresponding free drug molecules.

[0348] In one embodiment, the conjugated-compound is a conjugated version of any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the conjugated-compound is a conjugated version of any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non¬ limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0349] In one embodiment, the half-life of the drug released from the conjugated-compound is it at least 1.5-fold higher than the corresponding free drug’s half-life. In one embodiment, the half-life of the drug released from the conjugated-compound is it at least 2.5-fold higher than the corresponding free drug’s half-life. In one embodiment, the half-life of the drug released from theWSGR Ref. No.: 56017-743.601conjugated-compound is it at least 5-fold higher than the corresponding free drug’s half-life. In one embodiment, half-life of the drug released from the conjugated-compound is it at least 7.5-fold higher than the corresponding free drag’s half-life. In one embodiment, half-life of the drug released from the conjugated-compound is it at least 10-fold higher than the corresponding free drug’s half-life. In one embodiment, the release half-life of the conjugated-compound is at least the circulation half-life of the corresponding free drug. In one embodiment, the release half-life of the conjugated-compound is at least 2-fold higher than the circulation half-life of the corresponding free drag. In one embodiment, the release half-life of the conjugated-compound is at least 3 -fold higher than the circulation half-life of the corresponding free drug. In one embodiment, the distance between any two moieties -AB of a conjugated-compound is such that they are capable of binding to two different albumin molecules or to two different binding sites on the same albumin moiety. In one embodiment, the distance between any two moieties -AB of a conjugated-compound is such that they are capable of binding to two different albumin molecules. In one embodiment, the distance between any two moieties -AB of a conjugated- compound is such that they are capable of binding to two different binding sites on the same albumin moiety. In one embodiment, the pharmaceutical composition comprises at least one excipient.

[0350] In one aspect, provided is a microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound (e.g., derived from a peptide or small molecule described herein) or pharmaceutically acceptable salts thereof of formula (la) or (lb)AB14L2-L1-D-AB2|X (IA)AB1“L2" L11D“AB2(lb),(lb), wherein each -D- is independently a drug moiety; each -AB1and -AB2is independently an albumin-binding moiety; each -L1- is independently a linker moiety covalently and reversibly connected to -D-; each -L2- is independently a spacer or is absent; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25; and y is an integer selected from the group consisting of 2, 3, 4 and 5.

[0351] In one embodiment, the conjugated-compound is a conjugated version of any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the conjugated-compound is a conjugated version of any of the peptides orWSGR Ref. No.: 56017-743.601pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramiintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramiintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein nonlimiting examples of combinations of compounds include semaglutide and pramiintide, or semaglutide and cagrilintide.

[0352] In one embodiment, the conjugated-compound is of formula (la) with x = 1. 3. In one embodiment, -AB1and / or -AB2is / are independently a fatty acid-based albumin binding moiety. In one embodiment, -AB1and / or -AB2is / are independently of formula (A):> s A i B ’' (A),the dashed line indicates attachment to -L2- or -D-, respectively; -F° is of formula (a-l )0(a-1),the dashed line indicates attachment to -LA-; -R° is selected from the group consisting of - CR1RlaRlb, -COOR1,t H, / / W-J-S-OH* A1NO atid Hfrom the group consisting of -H, methyl, ethyl, propyl and isopropyl; n is an integer ranging from and including 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22; -LA- is absent or is of formula (a-2)p(a-2).WSGR Ref. No.: 56017-743.601wherein the unmarked dashed line indicates attachment to -LB-; the dashed line marked with the asterisk indicates attachment to -F°; -Ra- is selected from the group consisting ofandwherein the dashed line marked with the asterisk indicates attachment to -F°; the unmarked dashed line indicates attachment to the remainder of -LA-; -Rb- isorm is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; -LB- is absent or is of formula (a-3)R' (a-3),wherein the unmarked dashed line indicates attachment to -L2- or -D-; the dashed line marked with the asterisk indicates attachment to -LA; -Rc- isH ON.t> ' or-Rd- is selected from the group consisting of Cj-so alkyl, C2- 0 alkenyl or C2-50 alkynyl, wherein Cn 50 alkyl, C2-50 alkenyl, and C2-50 alkynyl may be substituted with one or more -R1, which may be the same or different, and which C1-50 alkyl, C2-50 alkenyl or C2-50 alkynyl may be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R2)-, -S(O)2N(R2)-, -S(O)N(R2)-, -S(O)2-, -S(O)-, -N(R2)S(O)2N(R2a)-, -S-, -N(R2)-, -OC(OR2)(R2a)-, -N(R2)C(O)N(R2a)-, and -OC(O)N(R2)-; each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11 -membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each -T- may independently be substituted with one or more -R1, which may be the same or different; each -R1is independently selected from the group consisting of halogen, -CN, oxo (=0), -COOR3, -OR3, -C(O)R3, -C(O)N(R3R3a), -S(O)2N(R3R3a), -S(O)N(R3R3a), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3R3a), -SR3, -N(R3R3a), -NO2, -OC(O)R3, - N(R3)C(O)R3a, -N(R3)S(O)2R3a, -N(R3)S(O)R3a, -N(R3)C(O)OR3a, -N(R3)C(O)N(R3aR3b), - OC(O)N(R3R3a), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -R2, -R2a, -R3, -R3aand -R3bis independentlyWSGR Ref. No.: 56017-743.601selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl may be substituted with one or more halogen, which may be the same or different; ando9< JU-Re- is selected from the group consisting of -CH2-,

[0353] In one embodiment, -AB1and / or -AB2is independently a peptidic albumin binding moiety. In one embodiment, -L1- is of formula (II):

[0354] wherein the dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D-; - X- is selected from the group consisting of -C(R4R4a)-; -N(R4)-; -O-; -C(R4R4a)- C(R5R5a)-; - C(R5R5a)-C(R4R4a)-; -C(R4R4a)-N(R6)-; -N(R6)-C(R4R4a)-; C(R4R4a)-O-; -O-C(R4R4a)-; and - C(R7R7a)-; X1is selected from the group consisting of C and S(O); -X2- is selected from the group consisting of -C(R8R8a)-; and -C(R8R8a)-C(R9R9a)-;:::X3is selected from the group consisting of =0; =S; and =N-CN; -R1, -Rla, -R2, -R2a, -R4, -R4a, -R5, -R5a, -R6, -R8, -R8a, -R9, and -R9aare independently selected from the group consisting of -H; and C1-6 alkyl; -R3, and -R3aare independently selected from the group consisting of -H; and C1-6 alkyl, provided that in case one of -R3, -R3aor both are other than -H they are connected to N to which they are attached through an SP3-hybridized carbon atom; -R7is selected from the group consisting of -N(R10R10a); and - NR10-(C=O)-Rn; -R7a, -R10, -R10a, and -R11are independently of each other selected from the group consisting of -H; and C1-6 alkyl; optionally, one or more of the pairs -Rla / -R4a, -Rla / -R5a, -R!a / -R7a, -R4a / -R5a, and -R8a / -R9aform a chemical bond; optionally, one or more of the pairs -R1 / - Rla, -R2 / -R2a, -R4 / -R4a, -R5 / -R5a, -R8 / -R8a, and -R9 / -R9aare joined together with the atom to which they are attached to form a C3-10 cycloalkyl; or 3- to 10-membered heterocyclyl; optionally, one or more of the pairs -RV-R4, -RV-R5, -R' / -Rfi, -RJ / -R7a, -R4 / -R5, -R4 / -R6, -R8 / -R9, and -R2 / -R3 are joined together with the atoms to which they are attached to form a ring A; optionally, R3 / R3aare joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle; A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobi cyclyl; and wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2- or a substituent. In one embodiment, -L1- is of formula (Ila)WSGR Ref. No.: 56017-743.601othe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-. In one embodiment, -L2- is of formula (XII-ii)the dashed line marked with the asterisk indicates attachment to -L1-; the unmarked dashed line indicates attachment to -AB1; a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; x ranges from 2 to 1000; -R1and -R2are independent of each other selected from the group consisting of -H and C1-6 alkyl. In one embodiment, a is 5, b is 2, c is 2, and both -R1and -R2are -H. In one embodiment, x is approx 108. In one embodiment, x is approx 23.

[0355] In one embodiment, -D- or -D-AB2is any of the peptides, or pharmaceutically acceptable salts thereof, as described herein. In one embodiment, -D- or -D-AB2is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB2is semaglutide. In one embodiment, -D- or -D-AB2is any of the GIP receptor agonist moieties or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is any of the SARA / DACRA moieties or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, -D- or -D-AB2is cagrilintide or pharmaceutically acceptable salts thereof.

[0356] In one embodiment, -D- is conjugated to -L1- through the N-terminal amine functional group.

[0357] In one embodiment, -AB1is of formula (XIX)WSGR Ref. No.: 56017-743.601o or,. O"HO,„ A. xw zxAz\.'Ox><_;¥ ’ - o '- - pO O ' = (XIX);the dashed line indicates attachment to -L2-; and a is 14, 15, 16, 17, 18, 19, 20, 21 or 22. In one embodiment, a is 18, In one embodiment, the pharmaceutical composition further comprises at least one conjugated-compound and at least one excipient.

[0358] In one embodiment, any of the pharmaceutical compositions comprising the conjugated-compound is for use as a medicament. In one embodiment, any of the pharmaceutical compositions comprising the conj ugated-compound is for use in the treatment of a disease selected from the group consisting of (i) all forms of diabetes, (ii) obesity, (iii) non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), (iv) cardiovascular disease, (v) neurodegenerative disorders, (vi) chronic kidney disease (CKD), (vii) diabetic kidney disease (DKD), (viii) peripheral arterial disease (PAD), and / or (ix) heart failure (HF). In one embodiment, any of the pharmaceutical compositions comprising the conjugated-compound is for use in the treatment of a disease selected from the group consisting of dyslipidemia and / or diseases where one or more of the following clinical outcomes are the treatment goal: lowering total serum lipids; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in a human; inhibiting generation of apolipoprotein A (apo(A)). In one embodiment, any of the pharmaceutical compositions comprising the conjugated-compound is for use in the treatment of a disease selected from the group consisting of Alzheimer's disease and Parkinson's disease.

[0359] In one aspect, provided is a microparticle or pharm ceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound (e g., derived from a peptide or small molecule described herein) or pharmaceutically acceptable salts thereof, wherein the conjugated-compound comprises at least one polymeric moiety, to which at least two moieties of formula (I) are conjugated and / or to which at least one moiety of formula (F ) is conjugated, wherein formula (I) and (F) are’ (I)I a (F ),wherein each -L2- is independently a spacer moiety or is absent; each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -L1- is independently a linkerWSGR Ref. No.: 56017-743.601moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; each -AB is independently an albumin-binding moiety; and each a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.

[0360] In one embodiment, the conjugated-compound is a conjugated version of any of the small molecules or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the conjugated-compound is a conjugated version of any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o- 1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non¬ limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0361] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, the at least one polymeric moiety of the conjugated-compound is a linear polymeric moiety -P-. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound, the conjugated-compound is of formula (I- A) or (I-A’)AB__D-L^L2^p___L2„L1_D-AB— L2~-L1rD~AB1AL Ja(W),wherein each -L2- is independently a spacer moiety or is absent; each -I,1- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drugWSGR Ref. No.: 56017-743.601moiety; each -AB is independently an albumin-binding moiety; -P- is a polymeric moiety; and each a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.

[0362] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, the at least one polymeric moiety of the conjugated-compound of the present invention is a multi-arm polymeric moiety. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, the conjugated-compound comprises at least one branching point B, to which at least two moieties of formula (lb) and / or at least one moiety of formula (lb’) are conjugated, wherein formula (lb) and (lb ’) are■'!”A“L2”L1~D”AB / tu.(ID)-;-A-L2-L’'jD-AB]a {lb,xwherein the dashed line indicates attachment to a branching point B; -A- is a polymeric moiety each -L2- is independently a spacer moiety or is absent; each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; each -AB is independently an albumin-binding moiety; and each a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, the conjugated-compound is of formula ( I-b4)X4-A— L2-L1-D-ABAB— D—L1-L2-A" X7“|-“XS“A“L2“L5“D~ABX6~A— L2-L1“D-AB (i-b4), wherein -X4-, -X5-, -X6- are independently of each other selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, - N(Ryl)S(O)2N(Ryla)-, -S-, -N(Ry1)-, -OC(ORyl)(Ryla)-, -N(Ryi)C(O)N(Ry!a)-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, Cj.so alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selectedWSGR Ref. No.: 56017-743.601from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, - S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a)-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a)-, - N(Ry3)C(O)N(Ry3a)-, and -OC(O)N(Ry3)-; -Ryland -Rylaare independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, Ci-soalkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-> -S(O)-, -N(Ry4)S(O)2N(Ry4a)-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a)-, -N(Ry4)C(O)N(Ry4a)-, and -OC(O)N(Ry4)-; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3-to I O-membered heterocyclyl, 8- to 11-membered heterobi cyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30- membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different; each -Ry2is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00Ry5, -ORy5, - C(0)Ry5, -C(O)N(Ry5Ry5a), -S(O)2N(Ry5Ry5a), -S(O)N(Ry5Ry5a), -S(O)2Ry5, -S(O)Ry5, - N(Ry5)S(O)2N(Ry5aRy5b), -SR''. -N(Ry5Ry5a), -NO2, -0C(0)Ry5, -N(Ry5)C(O)Ry5a, - N(Ry5)S(O)2Ry5a, -N(Ry5)S(O)Ry5a, -N(Ry5)C(O)ORy5a, -N(Ry5)C(O)N(Ry5aRy5b), OC(O)N(Ry5Ry5a), and Cl-6 alkyl; wherein Cl-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5aand -Ry5bis independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -A- is a polymeric moiety; each -L2- is independently a spacer moiety or is absent; each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; and each -AB is independently an albumin-binding moiety. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conj ugated-compound or pharmaceutically acceptable salts thereof, -L1- is of formula (II):wherein the dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D-; -X- is selected from the group consisting of -C(R4R4a)-; -N(R4)-; -O-; -C(R4R4a)- C(R5R5a)-; -C(R5R5a)-C(R4R4a)-; -C(R4R4a)-N(R6)-; -N(R6)-C(R4R4a)-; C(R4R4a)-O-; -O-C(R4R4a)-; and -C(R7R7a)-; X1is selectedWSGR Ref. No.: 56017-743.601from the group consisting of C; and S(O); -X2- is selected from the group consisting of -C(R8R8a)-; and -C(R8R8a)-C(R9R9a)-;:::X3is selected from the group consisting of:::0;:::S; and::::N-CN; -R1, -Rla, -R2, -R2a, -R4, -R4a, -R5, -R'a, -R6, -R8, -R8a, -R9, and -R9aare independently selected from the group consisting of -H; and Ci-6 alkyl; -R3, and -R3aare independently selected from the group consisting of -H; and Ci-6 alkyl, provided that in case one of -R3, -R3aor both are other than -H they are connected to N to which they are attached through an SP3-hybridized carbon atom; -R7is selected from the group consisting of -N(R10R10a); and -NRl0-(C=O)-R11; -R7a, -R10, -RlOa, and - R11are independently of each other selected from the group consisting of -H; and Ci-6 alkyl; optionally, one or more of the pairs -Rla / -R4a, -Rla / -R3a, -Rla / -R7a, -R4a / -R5a, and -R8a / -R9aform a chemical bond; optionally, one or more of the pairs -R7-Rla, -R2 / -R2a, -R4 / -R4a, -R5 / -R5a, -R8 / -R8a, and -R9 / -R9aare joined together with the atom to which they are attached to form a C3-I0 cycloalkyl; or 3- to 10-membered heterocyclyl; optionally, one or more of the pairs -R -R4, -R1 / -R5, -RV-R6, -R7-R7a, -R4 / -R5, -R4 / -R6, -R8 / -R9, and -R2 / -R3are joined together with the atoms to which they are attached to form a ring A; optionally, R3 / R3aare joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle; A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C3-10 cycloalkyl; 3- to 10- membered heterocyclyl; and 8- to 11 -membered heterobicyclyl; and wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2- or a substituent. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, -L1- is of formula (Ila)wherein the dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, -L1- is of formula (Ilab)(Ilab),WSGR Ref. No.: 56017-743.601wherein the dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof -L2- is a spacer moiety selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, - S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl)S(O)2N(Ryla)-, -S-, -N(Ry1)-, - OC(ORyi)(Ry1a)-, -N(Ryi)C(O)N(Ryfa)-, -OC(O)N(Ry1)-, Cj.5o alkyl, C2.5o alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of - T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, - N(Ry3)S(O)2N(Ry3a)-, -S-. -N(Ry3)-, -OC(ORy3)(Ry3a)-, -N(Ry3)C( O)N(Ry3a)-, and -OC(O)N(Ry3)-; -Ryland -Rylaare independently of each other selected from the group consisting of -H, -T, Ci-50 alkyl, C2 -50 alkenyl, and C2-50 alkynyl; wherein -T, Ci-soalkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, - S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a)-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a)-, - N(Ry4)C(O)N(Ry4a)-, and -OC(O)N(Ry4)-; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11 -membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30- membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different; each -Ry2is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a), -S(O)2N(Ry5Ry5a), -S(O)N(Ry5Ry5a), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5aRy5b), -SRy5, - N(Ry5Ry5a), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a, -N(Ry5)S(O)2Ry5a, -N(Ry5)S(O)Ry5a, - N(Ry5)C(O)ORy5a,-N(Ry5)C(O)N(Ry5aRy5b), -OC(O)N(Ry5Ry5a), and Ci-6alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5aand -Ry5bis independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated- compound or pharmaceutically acceptable salts thereof, L2- is of formula (XI)WSGR Ref. No.: 56017-743.601"t: S i *:h (XI),wherein the unmarked dashed line indicates attachment to -L1-; the dashed line marked with the asterisk indicates attachment to the at least one polymeric moiety; h is an integer selected from the group consisting of I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15 and 16. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, -D-AB is a GLP-1 receptor agonist moiety.

[0363] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof wherein the compound is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a GLP-1 receptor agonist moiety is semaglutide, or a pharmaceutically acceptable salt. In one embodiment, the peptide is semaglutide or a pharmaceutically acceptable salt. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0364] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, wherein -D-AB is any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, -D-AB is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB isWSGR Ref. No.: 56017-743.601pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is a GIP receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, -D-AB is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, -D-AB is a is a combination of two or more compounds, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and cagrilintide,

[0365] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, comprising the conjugated-compound of formula (2c”):wherein the dashed line indicates attachment to the N-terminal amine functional group of any of the peptides or pharmaceutically acceptable salts thereof as described herein; and nl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In oneWSGR Ref. No.: 56017-743.601embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0366] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound or pharmaceutically acceptable salts thereof, comprising the conjugated-compound of formula (2c’):WSGR Ref. No.: 56017-743.601wherein the dashed line indicates attachment to the N-terminal amine functional group of any of the peptides or pharmaceutically acceptable salts thereof as described herein; and nl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compound s, e.g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0367] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound, nl, n2, n3 and n4 are independently an integer of about 28. In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound, nl, n2, n3 and n4 are independently an integer of about 56.

[0368] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound, the conjugated-compound is of formula (2g’)WSGR Ref. No.: 56017-743.601(2g’);wherein n is independently an integer ranging from about 22 to about 230; dashed lines indicate attachment to a moietyHN-T*szwherein the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2g’); and the dashed line marked with the asterisk indicates attachment to the N-terminal amine functional group of any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GL. P-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e g., wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0369] In one embodiment of the microparticle or pharmaceutical composition comprising a biodegradable polymer, wherein the biodegradable polymer comprises a conjugated-compound, wherein the conjugated-compound is of formula (2g)WSGR Ref. No.: 56017-743.601wherein n is independently an integer ranging from about 22 to about 230; dashed lines indicate attachment to a moietyHN-r*s Szwherein the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2g); and the dashed line marked with the asterisk indicates attachment to the N-terminal amine functional group of any of the peptides or pharmaceutically acceptable salts thereof as described herein. In one embodiment, the peptide is a GLP-1 receptor agonist moiety or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is semaglutide choline or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide or pharmaceutically acceptable salts thereof. In one embodiment, the compound is pramlintide acetate or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-1061 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 or pharmaceutically acceptable salts thereof. In one embodiment, the compound is i2o-2248 choline or pharmaceutically acceptable salts thereof. In one embodiment, the peptide is a SARA / DACRA moiety or pharmaceutically acceptable salts thereof. In one embodiment, the compound is cagrilintide or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a combination of two or more compounds, e.g,, wherein non-limiting examples of combinations of compounds include semaglutide and pramlintide, or semaglutide and cagrilintide.

[0370] In one embodiment, the biocompatible, biodegradable polymer is a poly(lactide-co-glycolide) copolymer (“PLGA”) having a lactide:glycolide ratio from 70:30 to 30:70, or from 60:40 to 40:60 or about 50:50. In some embodiments, the PGLA has a ratio of lactide to glycolide of from 75:25 to 25:75.WSGR Ref. No.: 56017-743.601

[0371] Acceptable molecular weights for the biocompatible, biodegradable polymers can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical properties such as mechanical strength, end group chemistry and rate of dissolution of polymer. Typically, an acceptable range of mol ecular weight is of about 2,000 Daltons to about 5,000,000 Daltons. Tin some embodiments, the PGLA has an average molecular weight of from about 2 kDa to about 5,000 kDa. The biocompatible, biodegradable polymer can also be selected based upon the polymer’s inherent viscosity. Suitable inherent viscosities of poly(lactide-co-glycolide), poly glycolide, or polylactide are about 0.16 to 1.7 dL / g, 0.04 to 1.1 dL / g; about 0.1 to 0.7 dL / g; or about 0.3 to 0.5 dL / g.Hydrogels

[0372] In an aspect, provided herein is, inter alia, a microparticle comprising a therapeutic compound, or a pharmaceutically acceptable salt thereof, and any of the biodegradabl e polymers described herein, wherein the biodegradable polymer forms a hydrogel upon contact with an aqueous solution or environment such as plasma.

[0373] In some hydrogel -related embodiments, the pharmaceutical composition is formulated from microparticles (prior to administration) that form a hydrogel upon contact with an aqueous solution or environment such as plasma. In some hydrogel-related embodiments, the pharmaceutical composition forms a hydrogel in situ in the subject upon (i.e., after) administration. In some hydrogel-related embodiments, the diluent is aqueous. In some hydrogel-related embodiments, the diluent is non-aqueous. In some hydrogel-related embodiments, the diluent is Miglyol®. In some hydrogel-related embodiments, the diluent is Miglyol 812. Additional embodiments of the hydrogel-related methods and pharmaceutical composition are described herein. Development and applications of sustained release hydrogels for drag delivery are known to those or ordinary skill in the art and have been recently described in W02025011664A1 and Gels 2024, 70(8), 497, the entirety of which is incorporated herein by reference. Hydro-gel microparticles are prepared by methods known to those or ordinary skill in the art including via emulsion solvent evaporation; solvent casting / particulate leaching; electrospinning; thermal gelation; and photopolymerization methods.'

[0374] The term “Miglyol 812,” as used herein, refers to, a pharmaceutical -grade medium¬ chain triglyceride (MCT) oil, a clear, odorless liquid derived from coconut / palm kernel oils. In some embodiments, Miglyol 812 is composed mainly of caprylic (C8) and capric (CIO) fatty acids. In some embodiments, Miglyol 812 contains ester of glycerol with saturated caprylic (C8) and capric (CIO) fatty acids, usually in a 60:40 ratio.WSGR Ref. No.: 56017-743.601Autoinjector Comprising an Injection Needle

[0375] In another aspect, provided herein is an injection device comprising a chamber and an injection needle, wherein the chamber contains any of the microparticles described herein or any of the pharmaceutical compositions described herein. In some embodiments of the injection device, the injector is an autoinjector. In some embodiments of the injection device, the injector is an autoinjector for subcutaneous self-administration by a patient. In some embodiments of the injection device, the injection needle has a needle gauge of 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.

[0376] In one embodiment, provided is a microparticle or pharmaceutical composition comprising a compound or pharmaceutically acceptable salts thereof and a biodegradable polymer, for injectable seif-administration (including periodic injectable subcutaneous administration) via an injector comprising an injection needle. In one aspect, provided is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salts thereof and a biodegradable polymer, for injectable seif-administration (including periodic injectable intradermal, transdermal, intramuscular, or subcutaneous administration) via an injector comprising an injection needle. In some embodiments, the injector is an autoinjector comprising an injection needle. In some embodiments, the injection needle has a width corresponding to 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, 33 gauge, 34 gauge or 35 gauge.

[0377] In some embodiments, the pharmaceutical composition comprising a compound or pharmaceutically acceptable salts thereof and a biodegradable polymer, is for injectable selfadministration as a single injection per dose. In such embodiments, each (maintenance) dose is self-administered as a single injection of a single injection volume. For example, as one single injection per each periodic monthly administration. In alternative embodiments, the pharmaceutical composition comprising a compound or pharmaceutically acceptable salts thereof and a biodegradable polymer, is for injectable self-admini stration as multiple injections per each (maintenance) dose. In such embodiments, each (maintenance) dose is self-administered as two or more sequential injections, each of a single injection volume. For example, under this embodiment, two, three of four sequential injections, each of a single injection volume, would be self-admini stered each month.

[0378] In some embodiments, the pharmaceutical composition comprising a compound or pharmaceutically acceptable salts thereof and a biodegradable polymer, is for injectable self¬ administration at an injection volume that is 0.25 mL, 0.33mL, 0.5 mL, 0.75 mL, 1.0 mL, 1.25WSGR Ref. No.: 56017-743.601mL, 1.5 mL, 1.75 niL, 2.0 mL, 2.25 mL, 2.5 mL, 2.75 mL, 3.0 mL or a volume between any two of those values.Pharmaceutical Compositions

[0379] In another aspect, provided herein is a pharmaceutical composition comprising any of the microparticles described herein, suspended in a diluent, as explained in greater detail below. In some embodiments, provided herein is a pharmaceutical composition comprising any of the microparticles and / or any of the biodegradable co-polymers described herein, further comprises a diluent for intradermal, transdermal, intramuscular, or subcutaneous injection via an injection device. In some embodiments, provided herein is a pharmaceutical composition comprising any of the microparticles and / or any of the biodegradable co-polymers described herein, further comprises a diluent for subcutaneous injection via an injection device.

[0380] In some embodiments, the pharmaceutical composition is for subcutaneous injection via an injection device comprising an injection needle. In some embodiments, the pharmaceutical composition is for injection through an injection needle having a needle gauge of from 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.

[0381] In some embodiments of the pharmaceutical composition, the therapeutic compound is one or more compounds selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments of the pharmaceutical composition, the therapeutic compound is one or more compounds selected from the group consisting of the compounds as described in Table 1, or a pharmaceutically acceptable salt thereof In some embodiments, the compound (e.g., the therapeutic compound) of the invention is any one compound selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, and A8, or a pharmaceutically acceptable salt thereof.

[0383] In some embodiments of the pharmaceutical composition, the therapeutic compound is semaglutide (compound Al) or a pharmaceutically acceptable salt thereof. In some embodiments of the pharmaceutical composition, the therapeutic compound is semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments of the pharmaceutical composition, the therapeutic compound is cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof.

[0385] In some embodiments of the pharmaceutical composition, the therapeutic compound is i2o-1061 (compound A4) or a pharmaceutically acceptable salt thereof.

[0386] In some embodiments of the pharmaceutical composition, the therapeutic compound is i2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof. In some embodimentsWSGR Ref. No.: 56017-743.601of the pharmaceutical composition, the therapeutic compound is i2o-2248 choline (compound A8) or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments of the pharmaceutical composition, the therapeutic compound is pramlintide (compound A6) or a pharmaceutically acceptable salt thereof.

[0388] In some embodiments of the pharmaceutical composition, the therapeutic compound is pramlintide acetate (compound A7) or a pharmaceutically acceptable salt thereof.

[0389] In another aspect, provided herein is an injection device comprising a chamber and an injection needle, wherein the chamber contains the microparticle as described herein or the pharmaceutical composition as described herein.

[0390] In some embodiments, the injector is an autoinjector.

[0391] In some embodiments, the injector is an autoinjector for subcutaneous selfadministration by a patient.

[0392] In some embodiments, the injection needle has a needle gauge of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.

[0393] In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject the microparticle as described herein or the pharmaceutical composition as described herein via injectable administration, wherein the microparticle or the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein administration of the maintenance dose is in the absence of a prior dose titration comprising one or more prior doses less than the maintenance dose, and further in the absence of a subsequent dose titration compri sing one or more subsequent doses greater than the maintenance dose.Diluent

[0394] In some embodiments, the microparticles comprise any of the therapeutic compounds (e g., peptides or small molecules described herein), or pharmaceutically acceptable salts thereof, and biodegradable polymer are suspended in a diluent, such as an aqueous or non-aqueous diluent.

[0395] In some embodiments of the pharmaceutical composition, the diluent is an aqueous diluent. In some embodiments of the pharmaceutical composition, the diluent is an aqueous diluent buffered to pH 4.0 to 9.0. In some embodiments of the pharmaceutical composition, the diluent is an aqueous diluent buffered to pH 7.0 to 8.0. In some embodiments of the pharmaceutical composition, the diluent is a non-aqueous diluent. In some embodiments of theWSGR Ref. No.: 56017-743.601pharmaceutical composition, the non-aqueous diluent is a Miglyol®. In some embodiments of the pharmaceutical composition, the non-aqueous diluent is Miglyol 812.

[0396] In some embodiments, the diluent is substantially inert so that it does not interact with the microparticles, biodegradable polymers or therapeutic compounds described herein and is non¬ toxic so that it does not negatively impact the subject. In some embodiments, the diluent is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in human subjects.

[0397] In some embodiments, the diluent is “non-solubilizing” with respect to the microparticles, biodegradable polymers or therapeutic compounds described herein. In some embodiments, the diluent is “non-aqueous,” which does not exclude trace amounts of residual water such as less than about 0.1% (w / v) water or less than about 0.25% (w / v) water. In some embodiments, the diluent is “non-swelling” meaning it does not cause substantial swelling of the microparticles, for example, less than about 1-5% swelling of the microparticles.

[0398] In some embodiments, the diluent is one or more pharmaceutically acceptable oils, such as coconut oil, palm oil, palm kernel oil, sesame oil, soybean oil, almond oil, rapeseed oil, corn oil, sunflower oil, peanut oil, olive oil, castor oil, soybean oil, safflower oil, cottonseed oil, ethyl oleate, and the like. The diluent may include one oil or a combination of two or more oils.

[0399] In some embodiments, the diluent is a long chain triglyceride, a medium chain triglyceride, a diglyceride, a monoglyceride, a propylene glycol fatty acid diester, or a combination of two or more thereof.

[0400] In some embodiments, the diluent is a medium chain triglyceride. The medium chain triglyceride may be synthetic or natural (e.g., produced from fractionated oils, such as coconut oil and / or palm kernel oil), “Medium chain triglyceride” refers to esters of glycerol having three Co to C12 fatty acid chains, where the three fatty acid chains may be the same or different. In some embodiments, the diluent is a medium chain triglyceride comprising esters of (i) three Cs fatty acids; (ii) three Cio fatty acids; (iii) two Cs fatty acids and one Cio fatty acid; (iv) two Cio fatty acids and one Cs fatty acid; (v) two Cs fatty acids and one Co fatty acid; (vi) two Cio fatty acids and one Co fatty acid; (vii) one Cs fatty acid, one Cio fatty acid, and one Co fatty acid; or (viii ) any other combination of Co, Cs, Cio, and C12 fatty acids. In one embodiment, the medium chain triglyceride comprises two Cs fatty acids and one Cio fatty acid. In one embodiment, the medium chain triglyceride comprises two Cio fatty acids and one Cs fatty acid. In some embodiments, the diluent comprises medium chain triglycerides comprising esters of (i) 0 to 2 wt % Co fatty acid, 65 to 80 wt % Cs fatty acid, 20 to 35 d % Cio fatty acid, and 0 to 2 wt % C12 fatty acid; (ii) 0 to 2 wt % Co fatty acid, 50 to 65 wt % Cs fatty acid, 30 to 45 wt % Cio fatty acid, and 0 to 2 wt % C12WSGR Ref. No.: 56017-743.601fatty acid; (iii) 0 to 2 wt % Ce fatty acid, 45 to 65 wt % Cs fatty acid, 30 to 45 wt % Cio fatty acid, 0 to 3 wt % C12 fatty acid; and 0 to 5 wt % linoleic acid; or (iv) 0 to 2 wt % Ce fatty acid, 45 to 55 wt % Cs fatty acid, 30 to 40 wt % Cio fatty acid, 0 to 3 wt % C12 fatty acid, and 10 to 20 succinic. In one embodiment, the medium chain triglyceride comprises 0 to 2 wt % Ce fatty acid, 50 to 65 wt % Cs fatty acid, 30 to 45 wt % Cio fatty acid, and 0 to 2 wt % C12 fatty acid, and which is commercially available as MIGLYOL® 812 (Sasol Germany GmbH, Witten, Germany). The weight % is based of the total fatty acid content of the triglycerides. In one embodiment, the medium chain triglycerides may comprise up to 2% C14 fatty acids. In some embodiments, the diluent may comprise one, two, three, four or more different medium chain triglycerides. In one embodiment, the diluent comprises a medium chain triglyceride comprising esters of two Cg fatty acids and one Cio fatty acid. In one embodiment, the diluent comprises a medium chain triglyceride comprising esters of one Cs fatty acid and two Cio fatty acids. In one embodiment, the diluent comprises two different medium chain triglycerides, where a first medium chain triglyceride comprises esters of two Cs fatty acids and one Cio fatty acid and a second medium chain triglyceride comprises esters of one Csfatty acid and two Ciofatty acids. In one embodiment, the diluent comprises a medium chain triglyceride which comprises 0 to 2 wt % Ce fatty acid, 50 to 65 wt % Cs fatty acid, 30 to 45 wt % Cio fatty acid, 0 to 2 wt % C12 fatty acid, based on the total fatty acid content of the medium chain triglyceride. The triglycerides are commercially available as MIGLYOL® 810, 812, 818, 829 (Sasol Germany GmbH, Witten, Germany) or NEOBEE® 1053, 895, M-5 (Stepan Company, Northfield, Ill.).

[0401] In some embodiments, the diluent is a propylene glycol diester of saturated vegetable fatty acids with chain lengths of Cs and Cio (caprylic and capric acid). An example of one such commercially available diluent is MIGLYOL® 840 (Sasol Germany GmbH, Witten, Germany). The pharmaceutically acceptable, non-aqueous diluent may optionally comprise other pharmaceutically acceptable excipients. Exemplary excipients include sugars (e.g., sucrose, glucose, dextrose, galactose, maltose, trehalose, fructose, maltodextrin); sugar alcohols (e.g., glycol, glycerol, erythritol, threitol, arabitol, ribitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, mannitol, xylitol); preservatives (e.g., benzoic acid, sorbic acid, meta cresol, sodium benzoate, potassium sorbate, methylparaben, propylparaben, butylparaben, benzalkonium chloride, and the like, generally oil-soluble, with some solubility in the selected diluent); and antioxidants (e.g., sodium metabisulfite, butylated hydroxy anisole, butylated hydroxy toluene, sodium sulfite, tocopherol, thymol, ascorbate, propyl gallate, and the like). In one embodiment, the diluent optionally comprises mannitol, maltodextrin, sorbitol, or a combination of two or more thereof. In some embodiments, the diluent has a viscosity of from 5 cP to 200 cP or from 10 cP toWSGR Ref. No.: 56017-743.60190 cP. In other embodiments the viscosity of the diluent is from 20 cP to 80 cP or from 30 cP to 70 cP.

[0402] In some embodiments, the ratio of microparticles relative to diluent, meaning the weight percentage of compound-loaded microparticles, relative to the weight percentage of the diluent is a (wt. %) selected from the group consisting of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, 50.0, 50.1, 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9, 51.0, 51.1, 51.2, 51.3, 51.4, 51.5, 51.6, 51.7, 51.8, 51.9, 52.0, 52.1, 52.2, 52.3, 52.4, 52.5, 52.6, 52.7, 52.8, 52.9, 53.0, 53.1 53.2, 53.3, 53.4 53.5, 53.6. 53.7, 53.8, 53.9, 54.0, 54.1, 54.2, 54.3, 54.4. 54.5,WSGR Ref. No.: 56017-743.60154.6, 54.7, 54.8, 54.9, 55.0, 55.1, 55.2, 55.3, 55.4, 55.5, 55.6, 55.7, 55.8, 55.9, 56.0, 56.1, 56.2, 56.3, 56.4, 56.5, 56.6, 56.7, 56.8, 56.9, 57.0, 57.1, 57.2, 57.3, 57.4, 57.5, 57.6, 57.7, 57.8, 57.9, 58.0, 58.1, 58.2, 58.3, 58.4, 58.5, 58.6, 58.7, 58.8, 58.9, 59.0, 59.1, 59.2, 59.3, 59.4, 59.5, 59.6, 59.7, 59.8, 59.9, 60.0, 60.1, 60.2, 60.3, 60.4, 60.5, 60.6, 60.7, 60.8, 60.9, 61.0, 61.1, 61.2, 61.3, 61.4, 61.5, 61.6, 61.7, 61.8, 61.9, 62.0, 62.1, 62.2, 62.3, 62.4, 62.5, 62.6, 62.7, 62.8, 62.9, 63.0, 63.1, 63.2, 63.3, 63.4, 63.5, 63.6, 63.7, 63.8, 63.9, 64.0, 64.1, 64.2, 64.3, 64.4, 64.5, 64.6, 64.7, 64.8, 64.9, 65.0, 65.1, 65.2, 65.3, 65.4, 65.5, 65.6, 65.7, 65.8, 65.9, 66.0, 66.1, 66.2, 66.3, 66.4, 66.5, 66.6, 66.7, 66.8, 66.9, 67.0, 67.1, 67.2, 67.3, 67.4, 67.5, 67.6, 67.7, 67.8, 67.9, 68.0, 68.1, 68.2, 68.3, 68.4, 68.5, 68.6, 68.7, 68.8, 68.9, 69.0, 69.1, 69.2, 69.3, 69.4, 69.5, 69.6, 69.7, 69.8, 69.9, 70.0, 70.1, 70.2, 70.3, 70.4, 70.5, 70.6, 70.7, 70.8, 70.9, 71.0, 71.1, 71.2, 71.3, 71.4, 71.5, 71.6, 71.7, 71.8, 71.9, 72.0, 72.1, 72.2, 72.3, 72.4, 72.5, 72.6, 72.7, 72.8, 72.9, 73.0, 73.1, 73.2, 73.3, 73.4, 73.5, 73.6, 73.7, 73.8, 73.9, 74.0, 74.1, 74.2, 74.3, 74.4, 74.5, 74.6, 74.7, 74.8, 74.9, 75.0, 75.1, 75.2, 75.3, 75.4, 75.5, 75.6, 75.7, 75.8, 75.9, 76.0, 76.1, 76.2, 76.3, 76.4, 76.5, 76.6, 76.7, 76.8, 76.9, 77.0, 77.1, 77.2, 77.3, 77.4, 77.5, 77.6, 77.7, 77.8, 77.9, 78.0, 78.1, 78.2, 78.3, 78.4, 78.5, 78.6, 78.7, 78.8, 78.9, 79.0, 79.1, 79.2, 79.3, 79.4, 79.5, 79.6, 79.7, 79.8, 79.9, 80.0, 80.1, 80.2, 80.3, 80.4, 80.5, 80.6, 80.7, 80.8, 80.9, 81.0, 81.1, 81.2, 81.3, 81.4, 81.5, 81.6, 81.7, 81.8, 81.9, 82.0, 82.1, 82.2, 82.3, 82.4, 82.5, 82.6, 82.7, 82.8, 82.9, 83.0, 83.1, 83.2, 83.3, 83.4, 83.5, 83.6, 83.7, 83.8, 83.9, 84.0, 84.1, 84.2, 84.3, 84.4, 84.5, 84.6, 84.7, 84.8, 84.9, 85.0, 85.1, 85.2, 85.3, 85.4, 85.5, 85.6, 85.7, 85.8, 85.9, 86.0, 86.1, 86.2, 86.3, 86.4, 86.5, 86.6, 86.7, 86.8, 86.9, 87.0, 87.1, 87.2, 87.3, 87.4, 87.5, 87.6, 87.7, 87.8, 87.9, 88.0, 88.1, 88.2, 88.3, 88.4, 88.5, 88.6, 88.7, 88.8, 88.9, 89.0, 89.1, 89.2, 89.3, 89.4, 89.5, 89.6, 89.7, 89.8, 89.9, and 90.0, or within a range of any two of the above values.

[0403] In another aspect, provided is a non-aqueous pharmaceutical composition comprising microparticles comprising a therapeutic compound or pharmaceutically acceptable salts thereof; and a non-aqueous liquid; wherein the non-aqueous pharmaceutical composition is formulated for subcutaneous injection at a maintenance dose in the absence of a dose titration of one or more doses less than the maintenance dose; and the therapeutic compound selected from the group of compounds of Table 1, or pharmaceutically acceptable salts thereof. In some embodiments, the microparticles comprise from about 0.1% to about 80% (w / v or w / w) of the one or more therapeutic compounds and from about 0.1% ...

Claims

1. WSGR Ref. No.: 56017-743.601CLAIMSWhat is claimed is:

1. A microparticle comprising a therapeutic compound and a biodegradable polymer;wherein:the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof; and the biodegradable polymer is a co-polymer that derives from:(i) first monomers of glycolide, lactide, or a combination of glycolide and lactide, wherein the lactide is L-lactide, D-lactide or DL-lactide, and(ii) one or more additional monomers other than glycolide and lactide.

2. The microparticle of claim 1, wherein the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), and co-polymers thereof.

3. The microparticle of claim 1 or 2, wherein the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, s-caprolactone, 1,4-butane diol, 1,4-butanediisocyanate, -CONHCH2CH2CH2CH2NHCO-, 1,6-hexane diol, 1,6- hexanediisocyanate, substituted lactide, substituted glycolide, 8-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), 1,5-di ox epane-2 - one, cyclic anhydride, hydroxymethyl-glycolide, succinic acid, butyric acid, valeric acid, 3- hydroxybutyric acid (3-HB), 3-hydroxyvaleric acid (3-HV), glucose, fructose, glucosamine, oxalic acid, diketene acetal, sebacic acid, adipic acid, terephthalic acid, N-vinylpyrrolidone, N-vinylcaprolactam, 2-hydroxyethyl methacrylate, alkyl cyanoacrylate, a diisocyanate, an a- amino acid, a dicarboxylic acid, and a diol.

4. The microparticle of any one of claims 1-3, wherein the one or more additional monomers are selected from the group consisting of ethylene glycol, p-dioxanone, 8-caprolactone, 1,4-butane diol, 8-valerolactone, trimethylene carbonate, tetramethylene carbonate, l,4-dioxane-2-one (para-dioxanone), l,5-dioxepane-2-one, and cyclic anhydride.

5. The microparticle of any one of claims 1-4, wherein the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PEG-PPG), polytetramethylene ether glycol (PTMG), polycaprolactone (PCL), polydioxanone (PDO), polyhydroxyalkanoates (PHAs), polyphosphazenes, polylactide-co-glycolide-co-caprolactone, (PLGC), polylactide-co- hydroxymethyl glycolide (PLGMGA), polycarbonate, polyalkylcarbonate,WSGR Ref. No.: 56017-743.601polytrimethylenecarbonate (PTMC), polylactide-co-trimethylene carbonate (polylactide-co- trimethylenecarbonate, PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co- hydroxyvalerate (PHBV), polyortlroester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudo polyaminoacid, polyalkyl cyanoacrylate, polyphosphazene, polyphosphoester polysaccharide, poly(butylene succinate lactide) (PBSLA), polyesteramide, polyalkylene oxalates, biodegradable polyurethanes, polytetramethyleneoxide (PTMO), polypropyleneglycol (PPG), polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly-(HEMA)), polycyanoacrylate, galactose, polyol, cellulose, starch, chitosan, silk, collagen, polybutylene succinate (PBS), hyaluronic acid, alginate, gelatin, and copolymers thereof.

6. The microparticle of any one of claims 1-5, wherein the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), poly caprolactone (PCL), -CONHCH2CH2CH2CH2NHCO-, polydi oxanone (PDO), and copolymers thereof.

7. The microparticle of claim 1, wherein the first monomers of glycolide, lactide, or a combination of glycolide and lactide form one or more polymeric segments selected from the group consisting of polylactide (PLA), polyglycolide (PGA) and poly(lactide-co-glycolide) (PLGA) co-polymers, and the one or more additional monomers form one or more polymeric segments selected from the group consisting of polyethylene glycol (PEG), polycaprolactone (PCL), polydioxanone (PDO), and copolymers thereof.

8. The microparticle of any one of claims 1-7, wherein the microparticle further comprises an excipient.

9. The microparticle of claim 8, wherein the excipient is selected from the group consisting of a buffer, a pharmaceutically acceptable salt, a solvent, an amino acid, a poly(amino acid), a cyclodextrin, a viscosity modifier, a polysaccharide, a surfactant, a hydrogel, or any combination thereof.

10. The microparticle of claim 9, wherein:(i) the buffer comprises TRIS (Tris(hydroxymethyl)aminomethane), sodium phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, choline bicarbonate, EDTA, or any combination thereof;(ii) the pharmaceutically acceptable salt comprises sodium chloride, choline chloride, betaine HC1, carnitine HC1, or any combination thereof;WSGR Ref. No.: 56017-743.601(iii) the solvent comprises methylene chloride, methanol, ethanol, acetic acid, formic acid, tri fluoroacetic acid, polyvinyl alcohol, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), benzyl alcohol, or any combination thereof;(iv) the amino acid comprises arginine, histidine, lysine, aspartic acid, glutamic acid, or any combination thereof;(v) the polyfamino acid comprises poly(glutamic acid), poly(aspartic acid), or any combination thereof;(vi) the cyclodextrin comprises hydroxypropyl-beta-cyclodextrin (HPBCD), sulfobutyl ether beta-cyclodextrin (SBE-P-CD), carboxy methyl cyclodextrin (CMCD), sulfated cyclodextrin, or any combination thereof;(vii) the viscosity modifier comprises carboxymethyl cellulose (CMC), hyaluronic acid, or any combination thereof;(viii) the polysaccharide comprises carrageenan, alginate, dextran sulfate, trehalose, or any combination thereof;(ix) the surfactant comprises a pluronic;(x) the hydrogel comprises a thermogelling aliphatically modified block copolymer; or (xi) any combination thereof.

11. The microparticle of claim 10, wherein:(a) the sulfobutyl ether beta-cyclodextrin is Captisol®);(b) the pluronic comprises pluronic Fl 27; or(c) a combination thereof.

12. The microparticle of any one of claims 1-11, wherein the microparticle comprises a loading % of the therapeutic compound of from about 5% (wt / wt %) to about 50% (wt / wt %).

13. The microparticle of any one of claims 1-11, wherein the microparticle comprises a loading % of the therapeutic compound of from about 5% (wt / wt %) to about 25% (wt / wt %).

14. The microparticle of any one of claims 1-11, wherein the microparticle comprises a loading % of the therapeutic compound of from about 10% (wt / wt %) to about 20% (wt / wt %).

15. The microparticle of any one of claims 1-14, wherein the microparticle comprises a weight % of the biodegradable polymer of from about 50% (wt / wt %) to about 95% (wf / wf %).

16. The microparticle of any one of claims 1-14, wherein the microparticle comprises a weight % of the biodegradable polymer of from about 50% (wt / wt %) to about 95% (wt / wt %) and further comprises a loading % of the therapeutic compound of from about 10% (wt / wt %) to about 25% (wt / wt %).WSGR Ref. No.: 56017-743.60117. The microparticle of any one of claims 1-16, wherein the microparticle has a mean diameter of from about 20 pm to about 80 pm.

18. The microparticle of any one of claims 1-17, wherein the therapeutic compound is selected from the group consisting of a GLP-1 (glucagon -like peptide-1) Receptor Agonist (RA), GIP (glucose-dependent insulinotropic polypeptide) R / X, Amylin RA, Selective Amylin Receptor Agonist (SARA), Dual Amylin & Calcitonin Receptor Agonist (DACRA), Glucagon RA, PYY RA, GIP Receptor Antagonist, an oxyntomodulin analogue, and any combination thereof.

19. The microparticle of any one of claims 1-18, wherein the therapeutic compound is a peptide of from about 20 to about 50 amino acids.

20. The microparticle of any one of claims 1-19, wherein the therapeutic compound is a peptide of from about 20 to about 50 amino acids, and the peptide further comprises a fatty diacid moiety covalently attached to the peptide via a linker moiety.

21. The microparticle of any one of claims 1-18, wherein the therapeutic compound comprises an antibody or antibody conj gate.

22. The microparticle of any one of claims 1-18, wherein the therapeutic compound is a small molecule.

23. The microparticle of any one of claims 1-17, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

24. The microparticle of any one of claims 1-17 and 23, wherein the therapeutic compound is any one compound selected from the group consisting of Al, A2, A3, A4, A5, A6, A7, and A8, or a pharmaceutically acceptable salt thereof.

25. The microparticle of any one of claims 1-17, 23, and 24, wherein the therapeutic compound is semaglutide (compound Al) or a pharmaceutically acceptable salt thereof.

26. The microparticle of any one of claims 1-17, 23, and 24, wherein the therapeutic compound is semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof.

27. The microparticle of any one of claims 1-17, 23, and 24, wherein the therapeutic compound is i 2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof.

28. The microparticle of any one of claims 1-17, 23, and 24, wherein the therapeutic compound is i2o-2248 choline (compound A8) or a pharmaceutically acceptable salt thereof.

29. The microparticle of any one of claims 1-17, 23, and 24, wherein the therapeutic compound is pramlintide (compound A6) or a pharmaceutically acceptable salt thereof.WSGR Ref. No.: 56017-743.60130. The microparticle of any one of claims 1-17, 23, and 24, wherein the therapeutic compound is pramlintide acetate (compound A7) or a pharmaceutically acceptable salt thereof.

31. The microparticle of any one of claims 1-30, wherein the pharmaceutically acceptable salt is selected from the group consisting of an acetate salt, a choline salt, a sodium salt, and a chloride salt.

32. The microparticle of any one of claims 1-31, wherein the pharmaceutically acceptable salt is a choline salt.

33. A pharmaceutical composition comprising the microparticle of any one of claims 1-32 suspended in a diluent.

34. The pharmaceutical composition of claim 33, wherein the diluent is an aqueous diluent.

35. The pharmaceutical composition of claim 33, wherein the diluent is a non-aqueous diluent.

36. The pharmaceutical composition of claim 35, wherein the non-aqueous diluent is a Miglyol®.

37. The pharmaceutical composition of claim 35, wherein the non-aqueous diluent is Miglyol 812.

38. The pharmaceutical composition of any one of claim 33-37, wherein the pharmaceutical composition is formulated for injection through an injection needle having a needle gauge of 24, 25, 26, 27, 28, 29. 30, 31, 32. 33, 34, 35 or 36 gauge.

39. An injection device comprising a chamber and an injection needle, wherein the chamber contains the microparticle of any one of claims 1-32 or the pharmaceutical composition of any one of claims 33-38.

40. The injection device of claim 39, wherein the injector is an autoinjector.

41. The injection device of claim 39 or 40, wherein the injector is an autoinjector for subcutaneous self-administration by a patient.

42. The injection device of any one of claims 39-41, wherein the injection needle has a needle gauge of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 gauge.

43. A method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject the microparticle of any one of claims 1 -32 or the pharmaceutical composition of any one of claims 33-38 via injectable administration, wherein the microparticle or the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; and wherein administration of the maintenance dose is in the absence of a prior dose titration comprising one or more prior doses less than the maintenance dose, and further in the absence of a subsequent dose titration comprising one or more subsequent doses greater than the maintenance dose.

44. A method of treating a disease or disorder in a subject in need thereof, comprising:WSGR Ref. No.: 56017-743.601administrating to the subject a pharmaceutical composition via injectable administration, wherein the pharmaceutical composition comprises a suspension of microparticles in a diluent, wherein the microparticles comprise a therapeutic compound, and a biodegradable polymer,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof;wherein the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein administration of the maintenance dose is in the absence of a prior dose titration comprising one or more prior doses less than the maintenance dose, and further in the absence of a subsequent dose titration comprising one or more subsequent doses greater than the maintenance dose.

45. A method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject a pharmaceutical composition via injectable administration, wherein the pharmaceutical composition comprises a suspension of microparticles in a diluent, wherein the microparticles comprise a therapeutic compound, and a biodegradable polymer;the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein a Tmax of the therapeutic compound in the subject is reached from about 10 days to about 60 days following a first administration of the pharmaceutical composition.

46. The method of claim 45, wherein the Tmax of the therapeutic compound is attained in the subject as a substantially single bell-shaped peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound, following the first administration.

47. The method of claim 45 or 46, wherein the Tmax of the therapeutic compound is attained in the subject as a substantially unimodal peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound following the first administration.

48. The method of any one of claims 45-47, wherein the Tmax of the therapeutic compound is attained in the subject as a substantially single bell-shaped peak, in the absence of prior burst release in plasma absorption of the therapeutic compound of up to 20% of the Tmax following the first administration.WSGR Ref. No.: 56017-743.60149. The method of any one of claims 45-48, wherein the Tmax of the therapeutic compound is attained in the subject as a substantially unimodal peak, in the absence of prior burst release in plasma absorption of the therapeutic compound of up to 20% of the Tmax following the first administration.

50. The method of any one of claims 45-48, wherein a plasma concentration of the therapeutic compound in the subject is not more than 10% of the Tmax within about 2 days following the first administration.

51. The method of any one of claims 45-48, wherein a plasma concentration of the therapeutic compound in the subject is not more than 25% of the Tmax within about 7 days following the first administration.

52. The method of any one of claims 45-48, wherein a plasma concentration of the therapeutic compound in the subject is not more than 50% of the Tmax within about 10 days following the first administration.

53. The method of any one of claims 45-52, wherein a plasma concentration of therapeutic compound in the subject is not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%. 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the Tmax within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 days following the first administration.

54. A method of treating a disease or disorder in a subject in need thereof, comprising:administrating to the subject a pharmaceutical composition via injectable administration, wherein the pharmaceutical composition comprises a suspension of microparticles in a diluent;wherein the microparticles comprise a therapeutic compound, and a biodegradable polymer;wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof;WSGR Ref. No.: 56017-743.601wherein the pharmaceutical composition is administered to the subject at a maintenance dose of from about 4 mg to about 100 mg of the therapeutic compound; andwherein the pharmaceutical composition is administered such that the ratio between the plasma half-life of the therapeutic compound in days in the subject and the dosing interval of the pharmaceutical composition in days is from about 1: 100 to about 1:2.

55. The method of claim 54, wherein the ratio between the plasma half-life of the therapeutic compound in days in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:50 to about 1:2.

56. The method of claim 54, wherein the ratio between the plasma half-life of the therapeutic compound in days in in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:25 to about 1:2.

57. The method of claim 54, wherein the ratio between the plasma half-life of the therapeutic compound in days in in the subject and the dosing interval of the pharmaceutical composition in days is from about 1:10 to about 1:2.

58. The method of claim 54, wherein the therapeutic compound is semaglutide (compound Al), having a plasma half-life of about 7 days in the subject and a dosing interval of about 30 days, wherein the ratio between the plasma half-life of the therapeutic compound in days in the subject and the dosing interval of the pharmaceutical composition in days is about 1:4.

3.

59. The method of any one of claims 54-58, wherein the maintenance dose is from about 5 mg to about 50 mg of the therapeutic compound per administration.

60. The method of any one of claims 54-58, wherein the maintenance dose is from about 10 mg to about 25 mg of the therapeutic compound per administration.

61. The method of any one of claims 54-58, wherein the therapeutic compound is semaglutide (compound Al) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg semaglutide for administration once per month.

62. The method of any one of claims 54-58, wherein the therapeutic compound is semaglutide choline (compound A2) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg semaglutide choline for administration once per month.

63. The method of any one of claims 54-58, wherein the therapeutic compound is cagrilintide (compound A3) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg cagrilintide for administration once per month.WSGR Ref. No.: 56017-743.60164. The method of any one of claims 54-58, wherein the therapeutic compound is i2o-1061 (compound A4) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg i2o-1061 for administration once per month.

65. The method of any one of claims 54-58, wherein the therapeutic compound is i2o-2248 (compound A5) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg i2o-2248 for administration once per month.

66. The method of any one of claims 54-58, wherein the therapeutic compound is i2o-2248 choline (compound A8) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg i2o-2248 choline for administration once per month.

67. The method of any one of claims 54-58, wherein the therapeutic compound is pramlintide (compound A6) or pramlintide acetate (compound A7) or a pharmaceutically acceptable salt thereof, and the monthly maintenance dose is from about 10 mg to about 15 mg pramlintide or pramlintide acetate, for administration once per month,68. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 10% to about 30% weight reduction in the population of subjects.

69. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 15% to about 35% weight reduction in the population of subjects.

70. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 20% gastrointestinal adverse events (GI AEs) in the population of subjects.

71. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 10% GI AEs in the population of subjects.

72. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 15% incidence of nausea in the population of subjects.WSGR Ref. No.: 56017-743.60173. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 10% incidence of nausea in the population of subjects.

74. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 15% incidence of vomiting in the population of subjects.

75. The method of any one of claims 54-67, wherein the maintenance dose of the therapeutic compound, upon administration of the pharmaceutical composition to a population of subjects, induces, or is shown to induce, from about 1% to about 10% incidence of vomiting in the population of subjects.

76. The method of any one of claims 54-75, wherein the microparticle or the pharmaceutical composition is administered to the subject or a population of subjects at the maintenance dose of the therapeutic compound for a period of time from about four (4) weeks to about one hundred (100) weeks.

77. The method of claim 76, wherein the population of subjects comprises from about twenty (20) to about twenty thousand (20,000) subjects.

78. The method of any one of claims 54-77, wherein the microparticle or the pharmaceutical composition is administered via subcutaneous injection.

79. The method of any one of claims 54-78, wherein the microparticle or the pharmaceutical composition is administered via self-administered subcutaneous injection.

80. The method of any one of claims 54-79, wherein the microparticle or the pharmaceutical composition is administered once per week, once per two weeks, once per month, once per two months, once per three months, once per a quarter year, once per four months, once per five months, once per six months, or once per year.

81. The method of any one of claims 54-79, wherein the microparticle or the pharmaceutical composition is administered once per week, once per two weeks, once per three weeks, once per four weeks, once per month, once per two months, once per three months, once per four months, once per five months, once per six months, once per seven months, once per eight months, once per nine months, once per ten months, once per eleven months, once per twelve month, once per a quarter year, or once per year.

82. The method of any one of claims 54-79, wherein the microparticle or the pharmaceutical composition is administered once per month.WSGR Ref. No.: 56017-743.60183. The method of any one of claims 54-79, wherein the microparticle or the pharmaceutical composition is administered once per a quarter year.

84. The method of any one of claims 54-83, wherein the disease or disorder is selected from the group consisting of a metabolic disease or disorder, a cardiometabolic disease or disorder, a cardiovascular disease or disorder, kidney related disease, and a neurological disease or disorder.

85. The method of any one of claims 54-83, wherein the disease or disorder is selected from the group consisting of type 1 diabetes, type 2 diabetes, a pre-diabetic condition, obesity, overweight, need for weight loss, metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH, i.e., nonalcoholic steatohepatitis NASH), arrhythmia, coronary artery disease, heart failure, valve disease, aortic disease, congenital heart disease, heart attack, angina, cardiomyopathy, peripheral arterial disease, atherosclerosis, cardiac dysrhythmias, pericarditis, pulmonary hypertension, stroke, cerebrovascular disease, rheumatic heart disease, atrial fibrillation, Brugada syndrome, aortic stenosis, bradycardia, endocarditis, high cholesterol, long QT syndrome, chronic kidney disease, epilepsy, / Mzheimer disease, dementias, stroke, multiple sclerosis, Parkinson’s disease, neuroinfections, brain tumors, amyotrophic lateral sclerosis (ALS), tauopathies, age- related macular degeneration, sleep apnea, arthritis, infertility, alcohol addiction and drug addiction.

86. The method of any one of claims 54-83, wherein the disease or disorder is a cardiometabolic indication.

87. The method of any one of claims 54-83, wherein the disease or disorder is overweightedness or obesity.

88. The method of any one of claims 43-87, wherein the subject is a human.

89. A microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining the ratio between the plasma half-life of the therapeutic compound in days in a subject and the dosing interval of the microparticle in days that is from about 1: 100 to about 1:2, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

90. A microparticle comprising a therapeutic compound and a biodegradable polymer for administering a therapeutic compound to a subject in the absence of a prior dose titration comprising one or more prior doses less than a maintenance dose of from about 4 mg to aboutWSGR Ref. No.: 56017-743.601100 mg, and further in the absence of a subsequent dose titration comprising one or more subsequent doses greater than the maintenance dose of from about 4 mg to about 100 mg, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

91. A microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound in a subject that is reached from about 10 days to about 60 days following a first administration of the therapeutic compound, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

92. A microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound that is attained in a subject as a substantially single bell-shaped peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

93. A microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound that is attained in a subject as a substantially unimodal peak in the absence of prior smaller peaks in plasma absorption of the therapeutic compound following the first administration, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

94. A microparticle comprising a therapeutic compound and a biodegradable polymer for obtaining a Tmax of the therapeutic compound that is attained in a subject as a substantially unimodal peak, in the absence of prior burst release in plasma absorption of the therapeutic compound not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,WSGR Ref. No.: 56017-743.60194%, 95%, 96%, 97%, 98%, 99% of the Tmax within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 days following the first administration, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the subject,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

95. A microparticle comprising a therapeutic compound and a biodegradable polymer for inducing from about 10% to about 30% weight reduction in a population of subjects, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the population of subjects,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

96. A microparticle comprising a therapeutic compound and a biodegradable polymer for inducing from about 1% to about 20% gastrointestinal adverse events (GI AEs) in a population of subjects, upon administration of the therapeutic compound at a maintenance dose of from about 4 mg to about 100 mg to the population of subjects,wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

97. A microparticle comprising a therapeutic compound and a biodegradable polymer for administering the therapeutic compound to a subject once per week, once per two weeks, once per three weeks, once per four weeks, once per month, once per two months, once per three months, once per four months, once per five months, once per six months, once per seven months, once per eight months, once per nine months, once per ten months, once per eleven months, once per twelve month, once per a quarter year, or once per year, wherein the therapeutic compound is any one compound selected from the group consisting of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

98. The microparticle of any one of claims 89-97, wherein the biodegradable polymer is a co¬ polymer that derives from:(i) first monomers of, glycolide, lactide, or a combination of glycolide and lactide, wherein the lactide is L-lactide, D-lactide or DL-lactide, and(ii) one or more additional monomers other than glycolide and lactide.

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