Microsphere formulations containing lurasidone and methods of making and using same

Abstract

An extended release microsphere formulation comprising lurasidone is provided. In one embodiment, the microsphere formulation is characterized in that lurasidone is released in vivo in humans over a period of about 30 days. Methods of making and using the formulation are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 267,403, filed February 1, 2022, and U.S. Provisional Patent Application No. 63 / 152,943, filed February 24, 2021, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] General structure: [ka] Lurasidone (chemical formula C 28 H 36 N4O2S, CAS number 367514-87-2) is a known antipsychotic drug used to treat depression in people with schizophrenia and bipolar disorder. Lurasidone is currently administered orally in tablets (marketed under the trade name Latuda®). However, long-term maintenance treatment by this route is problematic because it causes withdrawal symptoms due to the rapid rise and fall of drug concentrations in plasma after each administration. Patient compliance and potential for abuse are also drawbacks of this treatment method.

[0003] An existing product for the treatment of schizophrenia, Risperdal® Consta®, is a two-week release microsphere formulation in which risperidone is microencapsulated in poly(D,L-lactide-co-glycolide), 75:25. However, some patients experience side effects from the use of Risperdal® Consta® and may require alternative treatment options.

[0004] Therefore, there is a need for extended release lurasidone-encapsulated microsphere formulations, especially those with high drug loading, small particle size and low initial burst release. Summary of the Invention

[0005] A microsphere formulation comprising lurasidone is provided. The microsphere formulation comprises polymeric microspheres, each polymeric microsphere comprising (i) lurasidone and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of 25 μm (D 50 ) average particle size. In one embodiment, the microsphere formulation is characterized in that at least 50% of the lurasidone is released over a period of about 30 days (i.e., ±10% of 30 days, i.e., 27 to 33 days) of injection into a subject. In another embodiment, the microsphere formulation is characterized in that it has a low initial burst release, i.e., 20% or less of the lurasidone is released within about 24 hours of injection into a subject. In another embodiment, the microsphere formulation is sterilized by irradiation.

[0006] In one embodiment, the microsphere formulation may be produced by a method comprising: (A) mixing (i) a biodegradable polymer, (ii) a primary solvent, (iii) lurasidone, and (iv) a co-solvent to form a dispersed phase; (B) mixing (i) water, (ii) a surfactant, and optionally (iii) a buffer to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer. In another embodiment, the method further comprises sterilizing the microsphere formulation by irradiation.

[0007] In one embodiment, a method for treating depression in a subject suspected of having schizophrenia and / or bipolar disorder is provided.The method can include administering the microsphere formulation produced according to the method described herein to a patient in need thereof by intra-articular, intramuscular or subcutaneous injection, and the formulation is administered to the patient on a dosing schedule of about every 30 days.

[0008] In another embodiment, in the manufacture of a medicament for the treatment of depression in a subject suspected of having schizophrenia and / or bipolar disorder, a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) lurasidone and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymer microsphere, the polymer microspheres having a diameter of 25 μm (D 50 The use of the above microsphere formulations having an average particle size of less than 100 μm is disclosed.

[0009] In another embodiment, a microsphere formulation comprising polymeric microspheres for use as a medicament for the treatment of depression in a subject suspected of having schizophrenia and / or bipolar disorder, wherein each polymeric microsphere comprises (i) lurasidone and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of less than 25 μm (D 50 ) of the microsphere formulation.

[0010] In another aspect, a kit is provided, the kit comprising polymeric microspheres, each polymeric microsphere comprising (i) lurasidone and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of less than 25 μm (D 50 ) average particle size. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram showing a method for producing lurasidone-encapsulated polymeric microspheres.

[0012] [Diagram 2] 1 is a microscopic image of lurasidone-encapsulated polymer microspheres.

[0013] [Diagram 3] 1 is a graph showing in vitro cumulative lurasidone release over time from lurasidone-encapsulated polymeric microspheres.

[0014] [Figure 4] 1 is a graph showing in vitro cumulative lurasidone release over time from non-irradiated and irradiated lurasidone-encapsulated polymeric microspheres.

[0015] [Diagram 5] 1 is a graph showing in vitro cumulative lurasidone release over time from non-irradiated and irradiated lurasidone-encapsulated polymeric microspheres.

[0016] [Figure 6] 1 is a graph showing in vitro cumulative lurasidone release over time from non-irradiated and irradiated lurasidone-encapsulated polymeric microspheres.

[0017] [Figure 7] 1 is a graph showing in vitro cumulative lurasidone release over time from non-irradiated and irradiated lurasidone-encapsulated polymeric microspheres.

[0018] [Figure 8] 1 is a graph showing in vitro cumulative lurasidone release over time from non-irradiated lurasidone-encapsulated polymeric microspheres.

[0019] [Figure 9] 1 is a graph showing the in vitro cumulative lurasidone release over time from irradiated lurasidone-encapsulated polymeric microspheres.

[0020] [Figure 10] 1 is a graph showing the results of a pharmacokinetic study in dogs using non-irradiated and irradiated lurasidone-loaded polymer microspheres.

[0021] [Figure 11]1 is a graph showing in vitro cumulative lurasidone release over time from lurasidone-encapsulated polymeric microspheres. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] A microsphere formulation comprising lurasidone is provided. In one embodiment, the microsphere formulation comprises polymeric microspheres, each polymeric microsphere comprising (i) lurasidone and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of 25 μm (D 50 In one embodiment, the microsphere formulation is characterized in that the lurasidone is released over a period of about 30 days.

[0023] In one aspect, the microsphere formulation may be produced by a process including: (A) mixing (i) a biodegradable polymer, (ii) a primary solvent, (iii) lurasidone, and (iv) a co-solvent to form a dispersed phase; (B) mixing (i) water, (ii) a surfactant, and optionally (iii) a buffer to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.

[0024] Lurasidone In one embodiment, lurasidone has a particular hydrophobicity log P ow = 5.6 (25°C), pKa = 7.6, 8.5, water solubility 0.224 mg / mL, solubility in dichloromethane 24.43 mg / g, and solubility in benzyl alcohol 69.19 mg / g, supplied by Procos SpA.

[0025] Biodegradable Polymers In one embodiment, the dispersed phase may comprise a biodegradable polymer such as poly(D,L-lactide-co-glycolide) ("PLGA"), poly(L-lactide) ("PLA"), or poly(D,L-lactide) ("PLDA"), although it is contemplated that other suitable biodegradable polymers may be used. The biodegradable polymer may be hydrophobic or hydrophilic. In one embodiment, the biodegradable polymer is hydrophobic. In another embodiment, the biodegradable polymer has an intrinsic viscosity of about 0.14 dL / g to about 0.56 dL / g, including about 0.14 dL / g to about 0.29 dL / g, including 0.19 dL / g, 0.20 dL / g, 0.21 dL / g, 0.29 dL / g, and 0.56 dL / g. In one embodiment, the biodegradable polymer comprises Viatel™ DLG7502A, poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25 ("7502A") from Ashland, having an IV=0.19. In one embodiment, the biodegradable polymer comprises Viatel™ DLG7503A, poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25 ("7503A") from Ashland, having an IV=0.29. In one embodiment, the biodegradable polymer comprises Resomer® RG752H, poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25 ("752H") from Evonik Rohm GmbH, having an IV=0.21 dL / g. In one embodiment, the biodegradable polymer comprises Viatel™ DLG7507A, poly(D,L-lactide-co-glycolide), acid terminated, 75:25 lactide:glycolide ("7507A") from Ashland, having an IV=0.56.

[0026] dispersed phase In one embodiment, the dispersed phase comprises a primary solvent. In one embodiment, the primary solvent comprises dichloromethane (DCM). The dispersed phase may also comprise up to about 50% by weight of a co-solvent that can optimize the solubility of lurasidone in the primary solvent. In one embodiment, the co-solvent may be benzyl alcohol (BA), dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, ethanol, N-methylpyrrolidone, ethyl acetate, or any other solvent that increases the solubility of lurasidone in the dispersed phase that contains DCM. In one embodiment, the primary solvent comprises DCM and the co-solvent comprises BA. In one embodiment, the ratio of DCM to BA is about 2:about 1. The organic solvent is removed from the microspheres during their preparation. Microspheres are "essentially free" of organic solvents if they meet the criteria set forth in the ICH Harmonised Guideline, Impurities: Guideline for Residual Solvents Q3C(R8), Current Step 4 version dated April 22, 2021, which is incorporated herein by reference in its entirety.

[0027] Continuous Phase The dispersed phase may be combined with an aqueous continuous phase that comprises water and optionally a buffer, a surfactant, or both.

[0028] In one embodiment, a buffer may be added to the continuous phase to maintain the pH of the solution at about 7.0 to about 8.0. In one embodiment, the buffer may be a phosphate or carbonate buffer. In one embodiment, the buffer may be a 10 mM phosphate or carbonate buffer and may be used to create and maintain a pH level of the system of about 7.6.

[0029] 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 embodiment, the surfactant component comprises polyvinyl alcohol ("PVA") at a concentration of 0.35% by weight in water.

[0030] In some embodiments, the dispersed phase flow rate to the homogenizer may be about 10 mL / min to about 30 mL / min, including about 20 mL / min and about 25 mL / min. In some embodiments, the continuous phase flow rate to the homogenizer may be about 2 L / min. Thus, in one embodiment, the continuous phase:dispersed phase ratio may be about 66:1 to about 200:1, including about 100:1 and about 80:1.

[0031] The continuous phase may be provided at room temperature or above or below room temperature, hi some embodiments, 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 these values.

[0032] Homogenizer For the sake of brevity, and because the present method is equally applicable to either, the term "homogenizer" contemplates a system or device capable of homogenizing the dispersed and continuous phases, emulsifying the dispersed and continuous phases, or both, which systems and devices are known in the art. For example, in one embodiment, the homogenizer is an in-line Silverson homogenizer (commercially available from Silverson Machines, Waterside, UK) or a Levitronix® BPS-i100 integrated pump system, used as described, for example, in U.S. Pat. No. 11,167,256, the entirety of which is incorporated herein by reference. In one embodiment, the homogenizer is a membrane emulsifier. In one embodiment, the homogenizer operates at an impeller speed of about 1,000 to about 4,000 revolutions per minute (RPM), including about 1,600 RPM, about 2,500 RPM, and about 3,500 RPM.

[0033] Drug burden The drug loading of each polymeric microsphere in terms of drug to polymer ratio, expressed as a percentage, may range from greater than 55 wt / wt% to about 70 wt / wt%, from about 60 wt / wt% to about 70 wt / wt%, from about 60 wt / wt% to about 65 wt / wt%, from about 65 wt / wt% to about 70 wt / wt%, greater than 55 wt / wt%, and greater than 60 wt / wt%.

[0034] particle size In one embodiment, the polymer microspheres are 10 μm (D 50 )~30μm(D 50 ), approximately 20 μm (D 50 ) or less than 25μm(D 50 ) and 14μm (D 50 )~25μm(D 50 ) average particle size.

[0035] extended release The microsphere formulation is characterized by having an in vivo release duration of about 30 days in humans. In one embodiment, the microsphere formulation is characterized by releasing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100%, and any range between any of these values, of the lurasidone over a period of about 30 days of injection into a subject. For example, in one embodiment, the microsphere formulation is characterized by releasing about 75%-100% of the lurasidone over a period of about 30 days of injection into a subject. In another embodiment, the microsphere formulation is characterized by having a low initial burst release, i.e., about 20% or less of the lurasidone is released within about 24 hours of injection into a subject.

[0036] Therapeutic Benefits Potential conditions that may be treated using lurasidone microsphere formulations containing lurasidone include schizophrenia and depression in people with bipolar disorder. In one embodiment, schizophrenia and depression may be treated using lurasidone microsphere formulations, the microsphere formulations being administered every 30 days.

[0037] In one embodiment, a method for treating depression in a subject suspected of having schizophrenia and / or bipolar disorder is provided.The method can include administering the microsphere formulation produced according to the method described herein to a patient in need thereof by intra-articular, intramuscular or subcutaneous injection, and the formulation is administered to the patient on a dosing schedule of about every 30 days.

[0038] In another embodiment, in the manufacture of a medicament for the treatment of depression in a subject suspected of having schizophrenia and / or bipolar disorder, a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising (i) lurasidone and (ii) a biodegradable polymer, each polymer microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymer microsphere, the polymer microspheres having a diameter of 25 μm (D 50 The use of the above microsphere formulations having an average particle size of less than 100 μm is disclosed.

[0039] In another embodiment, a microsphere formulation comprising polymeric microspheres for use as a medicament for the treatment of depression in a subject suspected of having schizophrenia and / or bipolar disorder, wherein each polymeric microsphere comprises (i) lurasidone and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of less than 25 μm (D 50 ) of the microsphere formulation.

[0040] In another aspect, a kit is provided, the kit comprising polymeric microspheres, each polymeric microsphere comprising (i) lurasidone and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of lurasidone of greater than 55% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of less than 25 μm (D 50 ) average particle size.

[0041] example Example 1 - General preparation of polymeric microspheres containing lurasidone Microsphere-forming phase. Referring to FIG. 1, a dispersed phase ("DP") 10 is formed by dissolving a polymer matrix (such as a PLGA polymer) in an organic solvent system (such as DCM and BA), followed by adding lurasidone and mixing until completely dissolved. The DP 10 is filtered using a 0.2 μm sterile PTFE or PVDF membrane filter (e.g., EMFLON, available from Pall or Sartorious AG) and pumped at a prescribed flow rate into a homogenizer 30, such as an in-line Silverson homogenizer (available from Silverson Machines, Waterside, UK) or a Levitronix i100 (as described in U.S. Pat. No. 11,167,256). A continuous phase ("CP") 20, including water, surfactant, and buffer, is also pumped at a prescribed flow rate into the homogenizer 30. The speed of the homogenizer 30 is generally fixed to achieve the desired polymer microsphere size distribution. An exemplary continuous "upstream" microsphere-forming phase is described in US Pat. No. 5,945,126, which is incorporated herein by reference in its entirety.

[0042] Microsphere Processing Phase. The formed or forming microspheres exit the homogenizer 30 and enter the 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. After the DP 10 is discharged, the CP 20 and water flow rate are stopped and a washing step is initiated. Solvent removal is accomplished using a water wash and hollow fiber filter (commercially available as HFF from Cytiva) 50. An exemplary "downstream" microsphere processing phase is described in U.S. Patent No. 6,270,802, which is incorporated herein by reference in its entirety.

[0043] The washed microspheres are collected and lyophilized in a freeze dryer (Virtis) to remove any moisture. The resulting microspheres are a free-flowing off-white bulk powder.

[0044] Example 2 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 1 According to the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 400g of 752H polymer (IV = 0.21 dL / g) in 4,000g of DCM and 2,000g of BA (DCM / BA (2:1)), then adding lurasidone (600g) and mixing until completely dissolved. The DP was filtered and pumped into a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM. The CP, containing 0.35% PVA and phosphate buffer (pH = 7.6), was also pumped into the homogenizer at a specified flow rate.

[0045] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder. The resulting microspheres were lyophilized using a 9.2 (D 50 ) mean particle size and drug loading of 66.7%.

[0046] Example 3 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 2 According to the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 400g of 752H polymer (IV = 0.21 dL / g) in 4,000g of DCM and 2,000g of BA (DCM / BA (2:1)), then adding lurasidone (600g) and mixing until completely dissolved. The DP was filtered and pumped into a Levitronix® BPS-i100 integrated pump system operating at 4,000 RPM. The CP, containing 0.35% PVA and phosphate buffer (pH = 7.6), was also pumped into the homogenizer at a specified flow rate.

[0047] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder. The resulting microspheres were lyophilized at 14.8 (D 50 ) mean particle size and 65.5% drug loading.

[0048] FIG. 2 is a micrograph of lurasidone-encapsulated polymeric microspheres from batch no. 2.

[0049] FIG. 3 is a graph comparing the cumulative lurasidone release over time from Batch No. 1 with Batch No. 2.

[0050] Example 4 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 3 and 3I According to the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 120 g of 7502A polymer (IV = 0.20 dL / g) in 800 g of DCM and 400 g of BA (DCM / BA (2:1)), then adding lurasidone (180 g) and mixing until completely dissolved. The DP was filtered and pumped at a flow rate of 25 mL / min into a Levitronix® BPS-i100 integrated pump system operating at 2,500 RPM. The CP, containing 0.35% PVA and 10 mM phosphate buffer (pH = 7.6), was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0051] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0052] A portion of the powder was subjected to gamma irradiation at ambient temperature to 25 kGy. The non-irradiated portion (batch no. 3) had a diameter of 22 μm (D 50), a drug loading of 60.4 wt%, and a molecular weight of 16.9 kDa. The irradiated section (batch no. 3I) had an average particle size of 21 μm (D 50 ), a drug loading of 60.2 wt%, and a molecular weight of 15.8 kDa. The microspheres contained 5.9 mg of residual DCM and 0.6 mg of residual BA.

[0053] Figure 4 is a graph comparing the in vitro cumulative lurasidone release over time from batches no. 3 and 3I. Figure 4 demonstrates that batches no. 3 and 3I have a low initial burst release and that the release profile of the microsphere formulations is not adversely affected by sterilization of the polymeric microspheres by irradiation.

[0054] Example 5 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 4 and 4I According to the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 120 g of 7502A polymer (IV = 0.20 dL / g) in 800 g of DCM and 400 g of BA (DCM / BA (2:1)), then adding lurasidone (180 g) and mixing until completely dissolved. The DP was filtered and pumped at a flow rate of 25 mL / min into a Levitronix® BPS-i100 integrated pump system operating at 3,500 RPM. The CP, containing 0.35% PVA and 10 mM phosphate buffer (pH = 7.6), was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0055] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0056] A portion of the powder was subjected to gamma irradiation at ambient temperature to 25 kGy. The non-irradiated portion (batch no. 4) had a diameter of 15 μm (D 50), a drug loading of 60.5 wt%, and a molecular weight of 16.9 kDa. The irradiated section (batch no. 4I) had an average particle size of 15 μm (D 50 ), a drug loading of 60.0 wt%, and a molecular weight of 15.9 kDa. The microspheres contained 4.7 mg of residual DCM and 0.3 mg of residual BA.

[0057] Figure 5 is a graph comparing the in vitro cumulative lurasidone release over time from batches No. 4 and 4I. Figure 5 demonstrates that batches No. 4 and 4I have a low initial burst release and that the release profile of the microsphere formulations is not adversely affected by sterilization of the polymeric microspheres by irradiation.

[0058] Example 6 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 5 and 5I Following the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 120 g of 7503A polymer (IV = 0.29 dL / g) in 800 g of DCM and 400 g of BA (DCM / BA (2:1)), then adding lurasidone (180 g) and mixing until completely dissolved. The DP was filtered and pumped at a flow rate of 25 mL / min into a Levitronix® BPS-i100 integrated pump system operating at 3,500 RPM. The CP, containing 0.35% PVA and 10 mM phosphate buffer (pH = 7.6), was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0059] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0060] A portion of the powder was subjected to gamma irradiation at ambient temperature to 25 kGy. The non-irradiated portion (batch no. 5) had a diameter of 18 μm (D 50), a drug loading of 58.7 wt%, and a molecular weight of 29.9 kDa. The irradiated section (batch no. 5I) had an average particle size of 18 μm (D 50 ), a drug loading of 58.8 wt%, and a molecular weight of 27.2 kDa. The microspheres contained 5.0 mg of residual DCM and 0.4 mg of residual BA.

[0061] Figure 6 is a graph comparing the in vitro cumulative lurasidone release over time from batches No. 5 and 5I. Figure 6 demonstrates that batches No. 5 and 5I have a low initial burst release and that the release profile of the microsphere formulations is not adversely affected by sterilization of the polymeric microspheres by irradiation.

[0062] Example 7 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 6 and 6I According to the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 120 g of 752H polymer (IV = 0.21 dL / g) in 800 g of DCM and 400 g of BA (DCM / BA (2:1)), then adding lurasidone (180 g) and mixing until completely dissolved. The DP was filtered and pumped at a flow rate of 25 mL / min into a Levitronix® BPS-i100 integrated pump system operating at 3,500 RPM. The CP, containing 0.35% PVA and 10 mM phosphate buffer (pH = 7.6), was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0063] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0064] A portion of the powder was subjected to gamma irradiation at ambient temperature to 25 kGy. The non-irradiated portion (batch no. 6) had a diameter of 16 μm (D 50), a drug loading of 59.4 wt%, and a molecular weight of 15.6 kDa. The irradiated section (batch no. 6I) had an average particle size of 16 μm (D 50 ), a drug loading of 60.1 wt%, and a molecular weight of 14.9 kDa. The microspheres contained 5.2 mg of residual DCM and 0.3 mg of residual BA.

[0065] Figure 7 is a graph comparing the in vitro cumulative lurasidone release over time from batches no. 6 and 6I. Figure 7 demonstrates that batches no. 6 and 6I have a low initial burst release and that the release profile of the microsphere formulations is not adversely affected by sterilization of the polymeric microspheres by irradiation.

[0066] Figure 8 is a graph comparing the in vitro cumulative lurasidone release over time from batch numbers 3, 4, 5, and 6. Figure 9 is a graph comparing the in vitro cumulative lurasidone release over time from batch numbers 3I, 4I, 5I, and 6I.

[0067] Example 8 - Pharmacokinetic study in dogs of batches no. 3, 3I, 4, 4I, 5, 5I, 6, and 6I The pharmacokinetic profile of lurasidone after subcutaneous injection dose of sustained release lurasidone formulation in dogs was studied. Dogs received a 10 mg / kg dose of the indicated batch number with a lurasidone concentration of 100 mg / mL. Blood samples were taken at 1, 3, 6, 24, 48, 96, 168, 264, 360, 480, 600, 720, 840, 960, 1080, 1200, 1320, 1440, 1560, and 1680 hours. Figure 10 is a graph showing the mean blood concentration of lurasidone (ng / mL) measured as a function of time for batch numbers 3, 3I, 4, 4I, 5, 5I, 6, and 6I.

[0068] Example 9 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 7 Following the general procedure described in Example 1 and illustrated in Figure 1, the DP was formed by dissolving 15 g of 7502A polymer (IV = 0.19 dL / g) in 133.3 g of DCM and 66.70 g of BA (DCM / BA (2:1)), then adding lurasidone (35 g) and mixing until completely dissolved. The DP was filtered and pumped at a flow rate of 25 mL / min into a Levitronix® BPS-i100 integrated pump system operating at 3,500 RPM. The CP containing 0.35% PVA (but no buffer) was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0069] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0070] Batch No. 7 was 16 μm (D 50 ), a drug loading of 63% (encapsulation efficiency=91% based on a target drug loading of 70%), and a molecular weight of 16.6 kDa. The microspheres contained no detectable residual DCM and 0.7 mg of residual BA. Figure 11 is a graph showing the in vitro cumulative lurasidone release over time from batch no. 7.

[0071] Example 10 - Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 8 Following the general procedure described in Example 1 and illustrated in Figure 1, a DP was formed by dissolving 3.0 g of 7507A polymer (IV = 0.56 dL / g) in 26.67 g of DCM and 13.33 g of BA (DCM / BA (2:1)), followed by adding lurasidone (7.0 g) and mixing until completely dissolved. The DP was filtered and pumped at a flow rate of 25 mL / min into a Levitronix® BPS-i100 integrated pump system operating at 3,500 RPM. The CP containing 0.35% PVA (but no buffer) was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0072] The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and a hollow fiber filter. The bulk suspension was recovered by filtration and lyophilized to yield a free-flowing powder.

[0073] Batch No. 8 is 18 μm (D 50 ), a drug loading of 59% (encapsulation efficiency=84% based on a target drug loading of 70%), and a molecular weight of 62.0 kDa. The microspheres contained no detectable residual DCM and 3.3 mg of residual BA. Figure 11 is a graph showing the in vitro cumulative lurasidone release over time from batch no. 8.

[0074] In use, the microspheres may be suspended in a diluent for administration (injection). The diluent may generally include a viscosity enhancer, a tonicity agent, and a surfactant. The viscosity enhancer may include carboxymethylcellulose-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 more. Generally, a viscosity of about 10 cps is suitable. However, a higher viscosity diluent may be preferred for larger microspheres to minimize settling of the microspheres in suspension.

[0075] A uniform microsphere suspension without particle settling results in a consistent delivered dose during drug administration by injection. To have the diluent's isotonicity, about 290 milliosmoles (mOsm), closer to the biological system, solutes such as mannitol, sodium chloride, or any other acceptable salt may be used. The diluent may also contain a buffer salt to maintain the pH of the composition. Typically, the pH is maintained near a physiologically relevant pH (pH about 7 to about 8) by adjusting the buffer content as needed.

[0076] The aspects disclosed herein are not intended to be exhaustive or limiting. Those skilled in the art will recognize that other aspects or modifications to the aspects may be made without departing from the spirit or scope of the present 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.

[0077] Unless otherwise specified, "a," "an," "the," "one or more of," and "at least one" are used interchangeably. The singular forms "a," "an," and "the" include their plurals. The recitation of numerical ranges by endpoints includes 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" means to include mixtures of the recited group.

[0078] Reference to the term "each" does not mean "all, without exception." For example, when referring to a microsphere formulation that includes polymeric microspheres, and "each polymeric microsphere" is said to have a particular API content, if there are 10 polymeric microspheres and two or more of the polymeric microspheres have the particular API content, then it is intended that a subset of the two or more polymeric microspheres meet the limitation.

[0079] The term "about" in connection with a number is merely shorthand and is intended to include ±10% of the number. This is true whether "about" is modifying an individual number or a number at either or both ends of a numerical range. In other words, "about 10" means 9 to 11. Similarly, "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.

Claims

1. 1. A microsphere formulation comprising: Each polymeric microsphere comprises: Lurasidone, A biodegradable polymer; the biodegradable polymer comprises poly(lactide) ("PLA") or poly(lactide-co-glycolide) ("PLGA") having an intrinsic viscosity of 0.14 dL / g±10% to 0.56 dL / g±10%; each polymeric microsphere comprises a drug loading of lurasidone of greater than 55% by weight of said polymeric microsphere; The polymer microspheres have a diameter of 25 μm (D ５０ ) an average particle size of less than 1000 μm.

2. 2. The microsphere formulation of claim 1, wherein the lurasidone comprises lurasidone HCl.

3. The microsphere formulation of claim 1 , wherein the biodegradable polymer comprises acid-terminated PLGA.

4. 10. The microsphere formulation of claim 1, wherein each polymeric microsphere has a lurasidone drug loading of 55% to 70% ±10% by weight of the polymeric microsphere.

5. The microsphere formulation of claim 1, wherein the polymeric microspheres have a particle size of 14 μm±10% to 25 μm±10% (D 50 ).

6. The microsphere formulation of claim 1, wherein the biodegradable polymer has an intrinsic viscosity of 0.14 dL / g ± 10% to 0.21 dL / g ± 10%.

7. The microsphere formulation of claim 1, wherein the biodegradable polymer has an intrinsic viscosity of 0.14 dL / g ± 10% to 0.29 dL / g ± 10%.

8. The microsphere formulation of claim 1 , wherein the polymeric microspheres are irradiated.

9. 2. The microsphere formulation of claim 1, wherein 75%±10% to 100% of the lurasidone is released over a period of 30 days±10% of injection into a subject, but no more than 20%±10% of the lurasidone is released within 24 hours±10% of injection into a subject.

10. A pharmaceutical composition comprising the microsphere formulation of claim 1.

11. 11. A pharmaceutical composition according to claim 10 for use in the treatment of schizophrenia and / or depression.

12. A microsphere formulation comprising: Each polymeric microsphere comprises: an active pharmaceutical ingredient consisting of lurasidone HCl; A biodegradable polymer; the biodegradable polymer comprises acid-terminated poly(lactide-co-glycolide) ("PLGA") having an intrinsic viscosity of 0.14 dL / g±10% to 0.56 dL / g±10%; each polymeric microsphere having a drug loading of lurasidone of 55% to 70% ± 10% by weight of said polymeric microsphere; said polymeric microspheres having a particle size of 14 μm±10% (D 50 ) to 25 μm (D 50 ); The microsphere formulation is characterized in that 75%±10% to 100% of the lurasidone is released over a period of 30 days±10% of injection into a subject, but no more than 20%±10% of the lurasidone is released within 24 hours±10% of injection into a subject.

13. The microsphere formulation of claim 12, wherein the biodegradable polymer has an intrinsic viscosity of 0.14 dL / g ± 10% to 0.21 dL / g ± 10%.

14. The microsphere formulation of claim 12, wherein the biodegradable polymer has an intrinsic viscosity of 0.14 dL / g ± 10% to 0.29 dL / g ± 10%.

15. The microsphere formulation of claim 12, wherein the polymeric microspheres are irradiated.

16. A pharmaceutical composition comprising the microsphere formulation of claim 12.

17. A pharmaceutical composition as described in claim 16 for use in the treatment of schizophrenia and / or depression.

18. A kit comprising: Each polymeric microsphere comprises: (i) lurasidone, (ii) a biodegradable polymer; and Including, Each polymeric microsphere comprises a drug loading of lurasidone of greater than 55% by weight of said polymeric microsphere, said polymeric microspheres having a diameter of 25 μm (D ５０ The above kit, wherein the average particle size is less than 100 μm.

19. The kit of claim 18, wherein the biodegradable polymer comprises acid-terminated poly(lactide-co-glycolide).

20. 20. The kit of claim 18, wherein each polymeric microsphere has a lurasidone drug loading of 55% to 70% ± 10% by weight of the polymeric microsphere.

21. The kit of claim 18 , wherein the polymeric microspheres are irradiated.

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