Microsphere formulations comprising brexpiprazole and methods for making and using the same

Abstract

Microsphere formulations comprising brexpiprazole are provided. Methods of making and using the microsphere formulations are also provided.

Description

MICROSPHERE FORMULATIONS COMPRISING BREXPIPRAZOLE AND METHODS FOR MAKING AND USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 603,363, filed on November 28, 2023, which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Brexpiprazole (chemical formula C25H27N3O2S; CAS Number 913611-97-9), characterized by the general structure:is a medication used to treat major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease. Brexpiprazole is currently orally administered as a once-daily tablet under the trade name Rexulti®.

[0003] A need exists for an extended-release brexpiprazole-encapsulating microsphere formulation.SUMMARY

[0004] Microsphere formulations comprising brexpiprazole are provided. The microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer comprising either a poly(ortho ester) polymer (a “POE”), a polylactic acid polymer (a “PLA”), or a poly (lactic-co-gly colic) acid polymer (a“PLGA”), wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso). In one aspect, the microsphere formulations are characterized in that the brexpiprazole is released over a period of about 30 days. In other aspects, the microsphere formulations are characterized in that the brexpiprazole is released over a period of about 60 days. In other aspects, the microsphere formulations are characterized in that the brexpiprazole is released over a period of about 90 days.

[0005] In one aspect, the microsphere formulations may be made by a method, the method comprising: (A) mixing: (i) the biodegradable polymer; (ii) a primary solvent; (iii) brexpiprazole; and (iv) a co-solvent, to form a dispersed phase; (B) mixing: (i) water; and (ii) a surfactant, to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.

[0006] In one aspect, a method for treating major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease is provided. The method may comprise administering by intramuscular injection to a patient in need thereof a microsphere formulation made according to the methods described herein, wherein the formulation is administered to the patient with a dosing schedule of about every 30, 60, or 90 days.

[0007] In another aspect, use is disclosed of a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso), in the manufacture of a medicament for thetreatment of major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease.

[0008] In another aspect, a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso), is provided for use as a medicament for the treatment of major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease.

[0009] In another aspect, a kit is provided, the kit comprising polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso).BRIEF DESCRIPTION OF THE FIGURES

[0010] Figure 1 is a schematic depicting a method for making brexpiprazole-encapsulated polymer microspheres.

[0011] Figure 2 is a graph showing in vitro cumulative brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0012] Figure 3 is a graph showing the effect of polymer intrinsic viscosity (IV) on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0013] Figure 4 is a graph showing the effect of drug load on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0014] Figure 5 is a graph showing the effect of co-monomer and IV on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0015] Figure 6 is a graph showing the effect of particle size on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0016] Figure 7 is a graph showing the effect of polymer end cap on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0017] Figure 8 is a graph showing the effect of polymer type (PLA vs. POE) on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.

[0018] Figure 9 is a graph showing example results of a pharmacokinetics study in rats using microsphere formulations as described herein.DETAILED DESCRIPTION

[0019] Microsphere formulations comprising brexpiprazole are provided. The microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso).

[0020] In one aspect, the microsphere formulations may be made by a method, the method comprising: (A) mixing: (i) the biodegradable polymer; (ii) a primary solvent; (iii) brexpiprazole; and (iv) a co-solvent, to form a dispersed phase; (B) mixing: (i) water; and (ii) a surfactant, to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.Brexpiprazole

[0021] In one aspect, the brexpiprazole is a free base. In another aspect, the brexpiprazole is a pharmaceutically acceptable salt.Biodegradable Polymers

[0022] In one aspect, the biodegradable polymer is a PLA. In one aspect, the PLA may have an inherent viscosity of about 0.2 dL / g to about 0.4 dL / g, including about 0.33 dL / g. In one aspect, the PLA may have an inherent viscosity of about 0.1 dL / g to about 0.3 dL / g, including about 0.18 dL / g. In one aspect, the PLA may have an inherent viscosity of about 0.25 dL / g to about 0.35 dL / g, including about 0.32 dL / g. In one aspect, the PLA may have an acid end cap. In one aspect, the PLA may have an ester end cap.

[0023] In one aspect, the biodegradable polymer is a PLGA. In one aspect, the PLGA may have a molar ratio of lactic acid to glycolic acid of about 85: 15. In one aspect, the PLGA may have a molar ratio of lactic acid to glycolic acid of about 75:25. In one aspect, the PLGA may have an inherent viscosity of about 0.4 dL / g to about 0.6 dL / g, including about 0.5 dL / g. In one aspect, the PLGA may have an inherent viscosity of about 0.6 dL / g to about 0.8 dL / g, including about 0.63 dL / g. In one aspect, the PLGA may have an acid end cap. In one aspect, the PLGA may have an ester end cap.

[0024] In one aspect, the biodegradable polymer is a POE. In one aspect, the POE is a cyclohexanedimethanobtriethylene glycol (CHDM:TEG) co-polymer having a CHDM:TEG ratio of about 80:20, with a molecular weight of about 31 kDa.Dispersed Phase

[0025] In one aspect, the dispersed phase comprises a primary solvent. In one aspect, the primary solvent comprises dichloromethane (DCM). The dispersed phase may also include up toabout 50% by weight of a co-solvent capable of optimizing the solubility of brexpiprazole in the dispersed phase. In one aspect, the co-solvent may be benzyl alcohol (BA), dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, acetonitrile, ethanol, N-methyl pyrrolidone, ethyl acetate, or any other solvent that increases the solubility of brexpiprazole in the dispersed phase. In one aspect, the primary solvent comprises DCM, and the co-solvent comprises BA. In one aspect, the ratio of DCM to BA is about 4: 1. The organic solvent is removed from the microspheres during their preparation. A microsphere is considered to be “essentially free” of organic solvent if the microsphere meets the standards set forth in the “ICH Harmonised Guideline, Impurities: Guideline for Residual Solvents Q3C(R8), Current Step 4 version dated 22 April 2021,” which is incorporated herein by reference in its entirety.Continuous Phase

[0026] The dispersed phase may be combined with an aqueous continuous phase that comprises water and, optionally, a surfactant.

[0027] The surfactant component may be present in the continuous phase in an amount of about 0.35% to about 1.0% by weight in water. In one aspect, the surfactant component comprises polyvinyl alcohol (“PVA”) in a concentration of about 1% by weight in water.

[0028] In some aspects, the dispersed phase flow rate to the homogenizer may be from about 25 mL / min where the polymer is a POE, to about 125 mL / min where the polymer is a PLA or a PLGA. In some aspects, the continuous phase flow rate to the homogenizer may be from about 2 L / min (CP:DP = 80:1) where the polymer is a POE, to about 250 mL / min (2:1 emulsion) where the polymer is a PLA or a PLGA. In the case of a 2: 1 emulsion, an additional continuous phase issupplied after the homogenizer at a flow rate of 10 L / min (total CP:DP = 80:1) to further solidify the emulsion.

[0029] The continuous phase may be provided at room temperature or above or below room temperature. In some aspects, the continuous phase may be provided at about 40 °C, about 37 °C, about 35 °C, about 30 °C, about 25 °C, about 20 °C, about 15 °C, about 10 °C, about 5 °C, about 0 °C, and any range or value between any of those temperature values.Homogenizer

[0030] For brevity, and because the methods are equally applicable to either, the phrase “homogenizer” contemplates a system or apparatus that can homogenize the dispersed phase and the continuous phase, emulsify the dispersed phase and the continuous phase, or both, which systems and apparatuses are known in the art. For example, in one aspect, the homogenizer is an in-line Silverson Homogenizer (commercially available from Silverson Machines, Waterside, UK) or a Levitronix® BPS-ilOO integrated pump system used, e.g., as described in U.S. Patent No. 11,167,256, which is incorporated by reference herein in its entirety. In one aspect, the homogenizer is a membrane emulsifier. In one aspect, the homogenizer runs at an impeller speed of about 1,000 to about 4,000 revolutions per minute (“RPM”), including about 1,500 RPM, about 2,000 RPM, about 3,000 RPM, or any value or range between any of those RPM values.Drug Load

[0031] The drug load of each polymer microsphere in a drug to total of solids, including the polymer plus drug, ratio, expressed as a percentage, may be greater than 40 wt / wt%, including about 45 wt / wt%, about 50 wt / wt%, about 55 wt / wt%, about 60 wt / wt%, from 40 wt / wt% to 50 wt / wt%, from 40 wt / wt% to 60 wt / wt%, from 50 wt / wt% to 60 wt / wt%, or any value or range between any of those percentages.Particle Size

[0032] The polymer microspheres may be any size that is safely and efficaciously injectable. In one aspect, the polymer microspheres may have a particle size between about 15 pm (Dso) and about 75 pm (Dso), between about 15 pm (Dso) and about 60 pm (Dso), between about 15 pm (D50) and about 50 pm (Dso), between about 20 pm (Dso) and about 50 pm (D50), between about 20 pm (D50) and about 45 pm (D50), between about 25 pm (D50) and about 50 pm (D50), between about 30 pm (D50) and about 45 pm (D50), between about 45 pm (D50) and about 60 pm (D50), less than about 55 pm (D50), and less than 60 pm (D50), or any value or range between any of those particle sizes.Extended Release

[0033] The microsphere formulations may be characterized in that they have a duration of release of at least about 30 days, at least about 60 days, or about 90 days.Therapeutic Benefits

[0034] In one aspect, a method for treating major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease is provided. The method may comprise administering by intramuscular injection to a patient in need thereof a microsphere formulation made according to the methods described herein, wherein the formulation is administered to the patient with a dosing schedule of about every 30, 60, or 90 days.

[0035] In another aspect, use is disclosed of a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (D50), in the manufacture of a medicament for thetreatment of major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease.

[0036] In another aspect, a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso), is provided for use as a medicament for the treatment of major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease.

[0037] In another aspect, a kit is provided, the kit comprising polymer microspheres, each polymer microsphere comprising: (i) brexpiprazole; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of about 15 pm to about 50 pm (Dso).EXAMPLESExample 1 - General preparation of polymer microspheres comprising brexpiprazole

[0038] Microsphere Formation Phase. With reference to Figure 1, a dispersed phase (“DP”) 10 is formed by dissolving a polymer matrix (such as a PLA, a PLGA, or a POE polymer) in an organic solvent system (such as DCM and BA), followed by the addition of brexpiprazole with mixing until completely dissolved. The DP 10 is filtered using a 0.2 pm sterilizing PTFE or PVDF membrane filter (such as EMFLON, commercially available from Pall or SartoriousAG) and pumped into a homogenizer 30 at a defined flow rate. A continuous phase (“CP”) 20 comprising water and surfactant (1% PVA) is also pumped into the homogenizer 30 at a defined flow rate.The speed of the homogenizer 30 is generally fixed to achieve a desired polymer microsphere size distribution. A representative continuous “upstream” microsphere formation phase is described in U.S. Pat. No. 5,945,126, which is incorporated by reference herein in its entirety.

[0039] Microsphere Processing Phase. The formed or forming microspheres exit the homogenizer 30 and enter a solvent removal vessel (“SRV”) 40. Water may be added to the SRV 40 during microsphere formation to minimize the solvent level in the aqueous medium. See, e.g., U.S. Patent No. 9,017,715, which is incorporated by reference herein in its entirety. After the DP 10 has been exhausted, the CP and water flow rates are stopped, and the washing steps are initiated. Solvent removal is achieved using water washing and a hollow fiber filter (commercially available as HFF from Cytiva) 50. A representative “downstream” microsphere processing phase is described in U.S. Pat. No. 6,270,802, which is incorporated by reference herein in its entirety.

[0040] The washed microspheres are collected and freeze-dried overnight in a lyophilizer (Virtis) to remove any moisture. The resulting microspheres are a free-flowing off-white bulk powder.Example 2 - Preparation of Brexpiprazole-Encapsulated PLA Polymer Microspheres - Batch 26

[0041] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 1, reference Batch 26 was prepared:Table 1

[0042] Figure l is a graph showing in vitro cumulative brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres.Example 3 - Effect of Polymer IV on Release Profile of Brexpiprazole-Encapsulated PLA PolymerMicrospheres - Batch 26 vs. Batch 15

[0043] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 2, Batch 15 having a lower polymer intrinsic viscosity (IV) was prepared.Table 2

[0044] Figure 3 is a graph showing the effect of polymer IV on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres. As shown in Figure 3, underin vitro conditions, Batch 26 has a 20-day lag, followed by a 40-day release. By lowering the polymer IV, Batch 15 has no lag, and the release is reduced to 25 days.Example 4 - Effect of Drug Load on Release Profile of Brexpiprazole-Encapsulated PLA Polymer Microspheres - Batches 26 and 15 vs. Batch 17

[0045] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 3, Batch 17 having a higher drug load was prepared.Table 3

[0046] Figure 4 is a graph showing the effect of drug load on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres. As shown in Figure 4, by increasing the target drug load to 60% in Batch 17, the burst is slightly increased, and the rate of release is slightly slower. Drug loading ostensibly has a lesser impact on in vitro release than polymer IV.Example 5 - Effect of Co-Monomer and Polymer IV on Release Profile of Brexpiprazole- Encapsulated Polymer Microspheres - Batch No. 26 vs. Batches 18 and 21

[0047] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 4, Batches 18 and 21 comprising a PLGA polymer and higher IVs were prepared.Table 4

[0048] Figure 5 is a graph showing the effect of co-monomer and IV on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres. As shown in Figure 5, a decrease in co-monomer ratio (and a corresponding increase in polymer IV) primarily affects the lag period, not the actual period of release. The lag period of Batch 18 and Batch 21 follow the trend that a decrease in co-monomer ratio increases the rate of release.Example 6 - Effect of Particle Size on Release Profile of Brexpiprazole-Encapsulated PLA Polymer Microspheres - Batch 26 vs. Batch 24

[0049] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 5, Batch 24 having a smaller particle size was prepared.Table 5

[0050] Figure 6 is a graph showing the effect of particle size on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres. As shown in Figure 6, by decreasing the particle size to 14 pm in Batch 24, there is an early linear release from 0-20 days.However, after this initial period, Batches 24 and 26 have an identical burst around day 25, which is unexpected.Example 7 - Effect of Polymer End Cap on Release Profile of Brexpiprazole-Encapsulated PLAPolymer Microspheres - Batch 26 vs. Batch 29

[0051] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 6, Batch 29 having an ester end cap was prepared.Table 6

[0052] Figure 7 is a graph showing the effect of polymer end cap on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres. As shown in Figure 7, using an ester end cap led to an increase in burst on day 1. Ester batches have demonstrated a sustained release of API rather than the “lag and burst” demonstrated by acid end cap batches.Example 8 - Effect of Polymer Type (PLA vs. POE) on Release Profde of Brexpiprazole- Encapsulated Polymer Microspheres - Batch 26 vs. Batch 31

[0053] Following the general procedure described in Example 1, illustrated in Figure 1, and detailed in Table 7, Batch 31 comprising a POE was prepared.Table 7

[0054] Figure 8 is a graph showing the effect of polymer type (PLA vs. POE) on in vitro brexpiprazole release over time from brexpiprazole-encapsulating polymer microspheres. As shown in Figure 8, Batch 31, using a POE polymer, demonstrates a different release profile, the burst of which is likely caused by acidic release media conditions.Example 9 - Pharmacokinetics Study in Rats of Batch Nos. 17 and 21

[0055] The pharmacokinetic profile of brexpiprazole following a subcutaneously injected dose of time-released brexpiprazole formulation in male Sprague-Dawly rats was studied. The rats received a 100 mg / kg dose of the indicated Batch No., having a brexpiprazole concentration of 66.66 mg / mL and a volume of 1.5 mL / kg. Microsphere suspension concentrations (mg / mL) were as follows: (a) Batch No. 17: 113; and (b) Batch No. 21 : 141. Blood was collected at 0.5, 1, 2, and 4 hours, and at 1, 2, 7, 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, and 120 days. Figure 9 is a graph showing the measured mean blood concentration(ng / mL) of brexpiprazole as a function of time for Batches Nos. 17 (Example 4) and 21 (Example 5).

[0056] In use, the microspheres may be suspended in a diluent for administration (injection). The diluent may generally contain a thickening agent, a tonicity agent, and a surfactant. The thickening agent may include carboxymethyl cellulose-sodium (CMC -Na) or other suitable compounds. An appropriate viscosity grade and suitable concentration of CMC-Na may be selected so that the viscosity of the diluent is 3 cps or higher. Generally, a viscosity of about 10 cps is suitable; however, a higher viscosity diluent may be preferred for larger microspheres in order to minimize the settling of microspheres in the suspension.

[0057] Uniform microsphere suspension without particle settling will result in a consistent delivered dose during drug administration by injection. To have a tonicity of the diluent closer to the biological system, about 290 milliosmole (mOsm), solutes such as mannitol, sodium chloride, or any other acceptable salt may be used.

[0058] The aspects disclosed herein are not intended to be exhaustive or to be limiting. A skilled artisan would acknowledge that other aspects or modifications to instant aspects can be made without departing from the spirit or scope of the invention. The aspects of the present disclosure, as generally described herein and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are contemplated herein.

[0059] Unless otherwise specified, “a,” “an,” “the,” “one or more of,” and “at least one” are used interchangeably. The singular forms “a”, “an,” and “the” are inclusive of their plural forms. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). The terms “comprising” and “including”are intended to be equivalent and open-ended. The phrase “consisting essentially of’ means that the composition or method may include additional ingredients and / or steps, but only if the additional ingredients and / or steps do not materially alter the basic and novel characteristics of the claimed composition or method. The phrase “selected from the group consisting of’ is meant to include mixtures of the listed group.

[0060] When reference is made to the term “each,” it is not meant to mean “each and every, without exception.” For example, if reference is made to microsphere formulation comprising polymer microspheres, and “each polymer microsphere” is said to have a particular API content, if there are 10 polymer microspheres, and two or more of the polymer microspheres have the particular API content, then that subset of two or more polymer microspheres is intended to meet the limitation.

[0061] The term “about” in conjunction with a number is simply shorthand and is intended to include ±10% of the number. This is true whether “about” is modifying a stand-alone number or modifying a number at either or both ends of a range of numbers. In other words, “about 10” means from 9 to 11. Likewise, “about 10 to about 20” contemplates 9 to 22 and 11 to 18. In the absence of the term “about,” the exact number is intended. In other words, “10” means 10.

[0062] The term “therapeutic level” means the concentration of brexpiprazole, or a pharmaceutically acceptable form thereof, required to be present in a use environment (for example, in the blood) to provide effective treatment of a disease.

Claims

CLAIMSWhat is claimed is:

1. A microsphere formulation, comprising: polymer microspheres, each polymer microsphere comprising: brexpiprazole; and a biodegradable polymer, wherein each polymer microsphere comprises a drug load of brexpiprazole of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have a particle size of between about 15 pm to about 50 pm (Dso).

2. The microsphere formulation of claim 1, wherein the brexpiprazole comprises brexpiprazole as a base.

3. The microsphere formulation of claim 1, wherein the biodegradable polymer comprises a poly(lactic acid) polymer.

4. The microsphere formulation of claim 1, wherein the biodegradable polymer comprises a poly (lactic acid-co-glycolic acid) (PLGA) polymer.

5. The microsphere formulation of claim 4, wherein the PLGA polymer is a 75:25 PLGA.

6. The microsphere formulation of claim 4, wherein the PLGA polymer is an 85: 15 PLGA.

7. The microsphere formulation of claim 1, wherein the biodegradable polymer comprises a poly(ortho)ester (POE).

8. The microsphere formulation of claim 7, wherein the POE polymer comprises a cyclohexanedimethanol :triethylene glycol (CHDM:TEG) co-polymer.

9. The microsphere formulation of claim 8, wherein the CHDM:TEG co-polymer has a CHDM:TEG ratio of about 80: about 20.

10. The microsphere formulation of claim 3, wherein the poly(lactic acid) polymer has a polymer inherent viscosity of about 0. 18 dL / g.

11. The microsphere formulation of claim 3, wherein the drug load drug load of brexpiprazole is about 50% to about 60% by weight of the polymer microsphere.

12. The microsphere formulation of claim 3, wherein the polymer microspheres have a particle size of about 20 pm to about 40 pm (Dso).

13. The microsphere formulation of claim 5, wherein the PLGA polymer has a polymer inherent viscosity of about 0.63 dL / g.

14. The microsphere formulation of claim 5, wherein the drug load drug load of brexpiprazole is about 40% to about 50% by weight of the polymer microsphere.

15. The microsphere formulation of claim 5, wherein the polymer microspheres have a particle size of about 35 pm to about 55 pm (Dso).

16. A pharmaceutical composition comprising any one of the microsphere formulations according to claims 1-15.

17. A method for treating major depressive disorder, schizophrenia, or agitation associated with dementia due to Alzheimer’s disease, the method comprising administering by intramuscular injection to a patient in need thereof the pharmaceutical composition of claim 16 no more frequently than about every 30, 60, or 90 days.

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