Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5089—Processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• Lurasidone (chemical formula C28H36N4O2S; CAS Number 367514-87-2), characterized by the general structure: is a known antipsychotic medication used to treat schizophrenia and depression in people with bipolar disorder. Lurasidone is currently orally administered with a tablet (commercially available under the trade name Latuda®). However, long term maintenance treatment through this route is problematic, as it creates withdrawal symptoms due to the steep rise and drop of the drug concentrations in plasma after each dose. Patient compliance and the potential for abuse are also drawbacks for this method of treatment.
• Risperdal® Consta® An existing product for the treatment of schizophrenia, Risperdal® Consta®, is a two- week release microsphere formulation wherein risperidone is micro-encapsulated in Poly(D,L- lactide-co-glycolide), 75:25.
• Risperdal® Consta® some patients experience side effects from using Risperdal® Consta® and may require another treatment option.
• Microsphere formulations comprising lurasidone are provided.
• the microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso).
• the microsphere formulations are characterized in that at least 50% of the lurasidone is released over a period of about 30 days (i.e., ⁇ 10% of 30 days or 27 days to 33 days) of injection into a subject.
• the microsphere formulations are characterized in that they have a low initial burst release, that is, not more than 20% of the lurasidone is released within about 24 hours of injection into a subject.
• the microsphere formulations are sterilized by irradiation.
• the microsphere formulations may be made by a method, the method comprising: (A) mixing: (i) the 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.
• the method further comprises sterilizing the microsphere formulations by irradiation.
• a method for treating schizophrenia and/or depression in a subject suspected of having bipolar disorder may comprise administering by intra-articular, intramuscular, or subcutaneous 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 days.
• a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso), in the manufacture of a medicament for the treatment of schizophrenia and/or depression in a subject suspected of having bipolar disorder.
• Dso mih
• a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso), is provided for use as a medicament for the treatment of schizophrenia and/or depression in a subject suspected of having bipolar disorder.
• kits comprising polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso).
• Figure 1 is a schematic depicting a method for making lurasidone-encapsulated polymer microspheres.
• Figure 2 is a microscope image of lurasidone-encapsulating polymer microspheres.
• Figure 3 is a graph showing in vitro cumulative lurasidone release over time from lurasidone-encapsulating polymer microspheres.
• Figure 4 is a graph showing in vitro cumulative lurasidone release over time from non- irradiated and irradiated lurasidone-encapsulating polymer microspheres.
• Figure 5 is a graph showing in vitro cumulative lurasidone release over time from non- irradiated and irradiated lurasidone-encapsulating polymer microspheres.
• Figure 6 is a graph showing in vitro cumulative lurasidone release over time from non- irradiated and irradiated lurasidone-encapsulating polymer microspheres.
• Figure 7 is a graph showing in vitro cumulative lurasidone release over time from non- irradiated and irradiated lurasidone-encapsulating polymer microspheres.
• Figure 8 is a graph showing in vitro cumulative lurasidone release over time from non- irradiated lurasidone-encapsulating polymer microspheres.
• Figure 9 is a graph showing in vitro cumulative lurasidone release over time from irradiated lurasidone-encapsulating polymer microspheres.
• Figure 10 is a graph showing results of a pharmacokinetics study in dogs using non- irradiated and irradiated lurasidone-encapsulating polymer microspheres.
• Figure 11 is a graph showing in vitro cumulative lurasidone release over time from lurasidone-encapsulating polymer microspheres.
• Microsphere formulations comprising lurasidone are provided.
• the microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso).
• the microsphere formulations are characterized in that the lurasidone is released over a period of about 30 days.
• the microsphere formulations may be made by a method, the method comprising: (A) mixing: (i) the 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.
• the dispersed phase may include a biodegradable polymer, such as poly (D,L-lactide-co-glycolide) (“PLGA”), a poly(L-lactide) (“PLA”), or a poly(D,L-lactide) (“PLDA”), although it is contemplated that other suitable biodegradable polymers may be used.
• PLGA poly (D,L-lactide-co-glycolide)
• PLA poly(L-lactide)
• PLDA poly(D,L-lactide)
• the biodegradable polymer may be hydrophobic or hydrophilic. In one aspect, the biodegradable polymer is hydrophobic.
• the biodegradable polymer has an inherent viscosity of about 0.14 dL/g to about 0.56 dL/g, including from about 0.14 dL/g to about 0.29 dL/g, and including 0.19 dL/g, 0.20 dL/g, 0.21 dL/g, 0.29 dL/g, and 0.56 dL/g.
• the dispersed phase comprises a primary solvent.
• the primary solvent comprises dichloromethane (DCM).
• the dispersed phase may also include up to about 50% by weight of a co-solvent capable of optimizing the solubility of lurasidone in the primary solvent.
• 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 lurasidone in the dispersed phase containing DCM.
• the primary solvent comprises DCM
• the co-solvent comprises BA.
• the ratio of DCM to BA is about 2: about 1.
• the organic solvent is removed from the microspheres during their preparation. A microsphere is “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.
• the dispersed phase may be combined with an aqueous continuous phase that comprises water and, optionally, a buffer, a surfactant, or both.
• the buffer may be added to the continuous phase to maintain a pH of the solution of about 7.0 to about 8.0.
• the buffer may be a phosphate buffer or a carbonate buffer.
• the buffer may be a 10 mM phosphate or carbonate buffer solution and may be used to create and maintain a system pH level of about 7.6.
• 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.
• the surfactant component comprises polyvinyl alcohol (“PVA”) in a concentration of 0.35% by weight in water.
• the dispersed phase flow rate to the homogenizer may be from about 10 mL/min to about 30 mL/min, including about 20 mL/min and about 25 mL/min. In some aspects, the continuous phase flow rate to the homogenizer may be about 2 L/min. Thus, in one aspect, the continuous phase: dispersed phase ratio may be from about 66:1 to about 200:1, including about 100:1 and about 80:1.
• 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 values.
• 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.
• 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.
• the homogenizer is a membrane emulsifier.
• the homogenizer runs 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.
• the drug load of each polymer microsphere in a drug to polymer ratio 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%.
• the polymer microspheres may have an average particle size between 10 mih (p5o) and 30 mih (Dso), less than about 20 mih (Dso), less than 25 mih (Dso), and between 14 mih (p5o) and 25 mih (Dso). Extended Release
• the microsphere formulations are characterized in that they have an in vivo duration of release of about 30 days in humans.
• the microsphere formulations are characterized in that 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 those values, of the lurasidone is released over a period of about 30 days of injection into a subject.
• the microsphere formulations are characterized in that about 75% to 100% of the lurasidone is released over a period of about 30 days of injection into a subject.
• the microsphere formulations are characterized in that they have a low initial burst release, that is, not more than about 20% of the lurasidone is released within about 24 hours of injection into a subject.
• Possible conditions that may be treated using the lurasidone microsphere formulations comprising lurasidone include schizophrenia and depression in people with bipolar disorder.
• schizophrenia and depression may be treated using the microsphere formulations comprising lurasidone, wherein the microsphere formulations are administered about every 30 days.
• a method for treating schizophrenia and/or depression in a subject suspected of having bipolar disorder may comprise administering by intra-articular, intramuscular, or subcutaneous 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 days.
• a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso), in the manufacture of a medicament for the treatment of schizophrenia and/or depression in a subject suspected of having bipolar disorder.
• Dso mih
• a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 mih (Dso), is provided for use as a medicament for the treatment of schizophrenia and/or depression in a subject suspected of having bipolar disorder.
• kits comprising polymer microspheres, each polymer microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of lurasidone of greater than 55% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 25 pm (D50).
• Example 1 General preparation of polymer microspheres comprising lurasidone
• 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 the addition of lurasidone with mixing until completely dissolved.
• a polymer matrix such as a PLGA polymer
• an organic solvent system such as DCM and BA
• 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, such as an in-line Silverson Homogenizer (commercially available from Silverson Machines, Waterside UK) or a Levitronix ilOO (as described in U.S. Patent No. 11,167,256), at a defined flow rate.
• a continuous phase (“CP”) 20 comprising water, surfactant, and buffer 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.
• 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. After the DP 10 has been exhausted, the CP 20 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. [0043] The washed microspheres are collected and freeze-dried in a lyophilizer (Virtis) to remove any moisture.
• a lyophilizer Virtual lyophilizer
• Example 2 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 1
• the DP was filtered and pumped into a Levitronix® BPS-ilOO integrated pump system operating at 3,000 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• the resulting microspheres had an average particle size of 9.2 (Dso) and a drug load of 66.7%.
• Example 3 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 2
• the DP was filtered and pumped into a Levitronix® BPS-ilOO integrated pump system operating at 4,000 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• the resulting microspheres had an average particle size of 14.8 (Dso) and a drug load of 65.5%.
• Figure 2 is a microscope image of lurasidone-encapsulating polymer microspheres from Batch No. 2.
• Figure 3 is a graph comparing the cumulative lurasidone release over time from Batch No. 1 versus Batch No. 2.
• Example 4 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 3 & 31
• the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 2,500 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• a portion of the powder was subjected to 25 kGy gamma irradiation under ambient temperature.
• the non-irradiated portion (Batch No. 3) had an average particle size of 22 mih (Dso), a drug load of 60.4 wt%, and a molecular weight of 16.9 kDa.
• the irradiated portion (Batch No. 31) had an average particle size of 21 mih (Dso), a drug load of 60.2 wt%, and a molecular weight of 15.8 kDa.
• Figure 4 is a graph comparing in vitro cumulative lurasidone release over time from Batch Nos. 3 and 31.
• Figure 4 demonstrates that Batch Nos. 3 and 31 have a low initial burst release, and that the release profile of the microsphere formulation is not adversely impacted by sterilization of the polymer microspheres via irradiation.
• Example 5 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 4 & 41
• the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,500 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• a portion of the powder was subjected to 25 kGy gamma irradiation under ambient temperature.
• the non-irradiated portion (Batch No. 4) had an average particle size of 15 mih (Dso), a drug load of 60.5 wt%, and a molecular weight of 16.9 kDa.
• the irradiated portion (Batch No. 41) had an average particle size of 15 mih (Dso), a drug load of 60.0 wt%, and a molecular weight of 15.9 kDa.
• Figure 5 is a graph comparing in vitro cumulative lurasidone release over time from Batch Nos. 4 and 41.
• Figure 5 demonstrates that Batch Nos. 4 and 41 have a low initial burst release, and that the release profile of the microsphere formulation is not adversely impacted by sterilization of the polymer microspheres via irradiation.
• Example 6 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 5 & 51
• the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,500 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• a portion of the powder was subjected to 25 kGy gamma irradiation under ambient temperature.
• the non-irradiated portion (Batch No. 5) had an average particle size of 18 mih (Dso), a drug load of 58.7 wt%, and a molecular weight of 29.9 kDa.
• the irradiated portion (Batch No. 51) had an average particle size of 18 mih (Dso), a drug load of 58.8 wt%, and a molecular weight of 27.2 kDa.
• Figure 6 is a graph comparing in vitro cumulative lurasidone release over time from Batch Nos. 5 and 51.
• Figure 6 demonstrates that Batch Nos. 5 and 51 have a low initial burst release, and that the release profile of the microsphere formulation is not adversely impacted by sterilization of the polymer microspheres via irradiation.
• Example 7 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch Nos. 6 & 61
• the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,500 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• a portion of the powder was subjected to 25 kGy gamma irradiation under ambient temperature.
• the non-irradiated portion (Batch No. 6) had an average particle size of 16 mih (Dso), a drug load of 59.4 wt%, and a molecular weight of 15.6 kDa.
• the irradiated portion (Batch No. 61) had an average particle size of 16 mih (Dso), a drug load of 60.1 wt%, and a molecular weight of 14.9 kDa.
• Figure 7 is a graph comparing in vitro cumulative lurasidone release over time from Batch Nos. 6 and 61.
• Figure 7 demonstrates that Batch Nos. 6 and 61 have a low initial burst release, and that the release profile of the microsphere formulation is not adversely impacted by sterilization of the polymer microspheres via irradiation.
• Figure 8 is a graph comparing in vitro cumulative lurasidone release over time from Batch Nos. 3, 4, 5, and 6.
• Figure 9 is a graph comparing in vitro cumulative lurasidone release over time from Batch Nos. 31, 41, 51, and 61.
• Example 8 Pharmacokinetics Study in Dogs of Batch Nos. 3. 3T 4. 4 T 5. 5T 6. and 61 [0067] The pharmacokinetic profile of lurasidone following a subcutaneously injected dose of time-released lurasidone formulation in dogs was studied. The dogs received a 10 mg/kg dose of the indicated Batch No., having a lurasidone concentration of 100 mg/mL. Blood samples were collected at 1, 3, 6, 24, 48, 96, 168, 264, 360, 480, 600, 720, 840, 960, 1080, 1200, 1320, 1440, 1560, and 1680 hour timepoints.
• Figure 10 is a graph showing the measured mean blood concentration (ng/mL) of lurasidone as a function of time for Batches Nos. 3, 31, 4, 41, 5, 51, 6, and 61.
• the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,500 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• Figure 11 is a graph showing in vitro cumulative lurasidone release over time from Batch No. 7.
• Example 10 Preparation of Lurasidone-Encapsulated Polymer Microspheres - Batch No. 8
• the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,500 RPM.
• 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 collected via filtration and lyophilized to obtain a free-flowing powder.
• Figure 11 is a graph showing in vitro cumulative lurasidone release over time from Batch No. 8.
• 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.
• CMC-Na carboxymethyl cellulose-sodium
• 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 to minimize the settling of microspheres in the suspension.
• each it is not meant to mean “each and every, without exception.”
• 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.

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