CN116916920A - Microsphere formulations comprising lurasidone and methods of making and using the same - Google Patents

Abstract

Extended release microsphere formulations comprising lurasidone are provided. In one aspect, the microsphere formulation is characterized by a release of lurasidone in humans for a period of about 30 days. Methods of making the formulations and methods of using the formulations are also provided.

Description

Microsphere formulations comprising lurasidone and methods of making and using the same

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application No. 63267403 filed on 1-2-2021 and U.S. provisional patent application No. 63152943 filed on 24-2-2021, both of which are incorporated herein by reference in their entireties.

Background

Lurasidone (formula C) ₂₈ H ₃₆ N ₄ O ₂ S, S; CAS number 3675514-87-2), characterized by the following general structure:

is a known antipsychotic for the treatment of schizophrenia and depression in people with bipolar disorder. Lurasidone is currently available in the form of tablets (under the trade nameCommercially available) for oral administration. However, long-term maintenance therapy by this route is problematic because it can produce withdrawal symptoms due to the sharp rise and fall in plasma drug concentration after each administration. Patient compliance and potential for abuse are also disadvantages of this method of treatment.

Existing products for the treatment of schizophreniaIs a two week release microsphere formulation in which risperidone is microencapsulated in 75:25 poly (D, L-lactide-co-glycolide). However, some patients useSide effects may occur and another treatment regimen may be required.

Thus, there is a need for a sustained release microsphere formulation of encapsulated lurasidone, particularly a microsphere formulation having high drug loading, small particle size and low initial burst.

Disclosure of Invention

Microsphere formulations comprising lurasidone are provided. The microsphere formulation comprises polymeric microspheres, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere, and wherein the polymeric microsphere has a molecular weight of less than 25 μm (D ₅₀ ) Is a particle size of the particles. In one aspect, the microsphere formulation is characterized by at least 50% of the lurasidone released over a period of about 30 days (i.e., 10% of 30 days, or 27 days to 33 days) after injection into the subject. In another aspect, microsphere formulations are characterized in that they have a low initial burst, i.e., no more than 20% of the lurasidone is released within about 24 hours after injection into a subject. In another aspect, the microsphere formulation is sterilized by irradiation.

In one aspect, the microsphere formulation may be prepared 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 aspect, the method further comprises sterilizing the microsphere formulation by irradiation.

In one aspect, a method for treating schizophrenia and/or depression in a subject suspected of having bipolar disorder is provided. The method may comprise administering to a patient in need thereof a microsphere formulation prepared according to the methods described herein by intra-articular injection, intramuscular injection, or subcutaneous injection, wherein the formulation is administered to the patient on a dosing regimen of about every 30 days.

In another aspect, there is disclosed the use of a microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising: (i) lurasidone; and (ii) biodegradable polymers, wherein each polymerThe microspheres comprise lurasidone in an amount greater than 55% by weight of the polymeric microspheres, wherein the polymeric microspheres have an average particle size of less than 25 μm (D ₅₀ )。

In another aspect, there is provided a microsphere formulation comprising polymeric microspheres for use as a medicament for treating schizophrenia and/or depression in a subject suspected of having a bipolar disorder, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere, wherein the polymeric microsphere has an average particle size of less than 25 μm (D ₅₀ )。

In another aspect, a kit is provided, the kit comprising polymeric microspheres, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere, and wherein the polymeric microsphere has a molecular weight of less than 25 μm (D ₅₀ ) Is a particle size of the particles.

Brief description of the drawings

Fig. 1 is a schematic diagram depicting a process for preparing polymeric microspheres encapsulating lurasidone.

Fig. 2 is a microscope image of polymeric microspheres encapsulating lurasidone.

Fig. 3 is a graph showing the in vitro cumulative release of lurasidone over time from polymeric microspheres encapsulating lurasidone.

Fig. 4 is a graph showing the in vitro cumulative release of lurasidone over time from unirradiated and irradiated lurasidone-encapsulated polymeric microspheres.

Fig. 5 is a graph showing the in vitro cumulative release of lurasidone over time from unirradiated and irradiated lurasidone-encapsulated polymeric microspheres.

Fig. 6 is a graph showing the in vitro cumulative release of lurasidone over time from unirradiated and irradiated lurasidone-encapsulated polymeric microspheres.

Fig. 7 is a graph showing the in vitro cumulative release of lurasidone over time from unirradiated and irradiated lurasidone-encapsulated polymeric microspheres.

Fig. 8 is a graph showing the in vitro cumulative release of lurasidone over time from non-irradiated lurasidone-encapsulated polymer microspheres.

Fig. 9 is a graph showing the in vitro cumulative release of lurasidone over time from irradiated lurasidone-encapsulated polymer microspheres.

Fig. 10 is a graph showing the results of pharmacokinetic studies in dogs using non-irradiated and irradiated polymeric microspheres encapsulating lurasidone.

Fig. 11 is a graph showing the in vitro cumulative release of lurasidone over time from polymeric microspheres encapsulating lurasidone.

Detailed Description

Microsphere formulations comprising lurasidone are provided. In one aspect, the microsphere formulation comprises polymeric microspheres, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere, and wherein the polymeric microsphere has a molecular weight of less than 25 μm (D ₅₀ ) Is a particle size of the particles. In one aspect, the microsphere formulation is characterized by release of lurasidone over a period of about 30 days.

In one aspect, the microsphere formulation may be prepared 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.

Lurasidone

In one aspect, the lurasidone is lurasidone hydrochloride supplied by Procos s.p.a. and has a specific hydrophobicity of log P _ow =5.6 (at 25 ℃), pka= 7.6,8.5, water solubility of 0.224mg/mL, solubility in dichloromethane of 24.43mg/g, and solubility in benzyl alcohol of 69.19mg/g.

Can be living thingsDegraded polymers

In one aspect, 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 other suitable biodegradable polymers are also contemplated. The biodegradable polymer may be hydrophobic or hydrophilic. In one aspect, the biodegradable polymer is hydrophobic. In another aspect, the inherent viscosity of the biodegradable polymer is from about 0.14dL/g to about 0.56dL/g, including from about 0.14dL/g to about 0.29dL/g, and including 0.19dL/g, 0.20dL/g, 0.21dL/g, 0.29dL/g, and 0.56dL/g. In one aspect, the biodegradable polymer comprises a Viatel manufactured by Ashland ^TM DLG 7502A, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.19 ("7502A"). In one aspect, the biodegradable polymer comprises a Viatel manufactured by Ashland ^TM DLG 7503A, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.29 ("7503A"). In one aspect, the biodegradable polymer comprises a polymer manufactured by Evonik Rohm GmbHRG 752H, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.21 dL/g ("752H"). In one aspect, the biodegradable polymer comprises a Viatel manufactured by Ashland ^TM DLG 7507A, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.56 ("7507A").

Disperse phase

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 to about 50 wt% of a co-solvent that optimizes the solubility of lurasidone in the primary solvent. In one aspect, the co-solvent may be Benzyl Alcohol (BA), dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, ethanol, N-methylpyrrolidone, ethyl acetate, or any other solvent that increases the solubility of lurasidone in a dispersed phase containing DCM. 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 2:about 1. During the preparation of the microspheres, the organic solvent is removed from the microspheres. If the microspheres meet the ICH guidelines, impurities: residual solvent guidelines Q3C (R8), current step 4 version, 2021, month 4, 22 ", the guidelines being incorporated herein by reference in their entirety, are" substantially free "of organic solvents.

Continuous phase

The dispersed phase may be combined with an aqueous continuous phase comprising water and optionally a buffer, a surfactant, or both.

In one aspect, 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 aspect, the buffer may be a phosphate buffer or a carbonate buffer. In one aspect, the buffer may be a 10mM phosphate buffer solution or carbonate buffer solution, and may be used to generate and maintain a system pH level of about 7.6.

The surfactant component may be present in the continuous phase in the water in an amount of from about 0.35 wt% to about 1.0 wt%. In one aspect, the surfactant component includes polyvinyl alcohol ("PVA") at a concentration of 0.35 wt.% in water.

In some aspects, the flow rate of the dispersed phase to the homogenizer may be from about 10mL/min to about 30mL/min, including about 20mL/min and about 25mL/min. In some aspects, the flow rate of the continuous phase to the homogenizer may be about 2L/min. Thus, in one aspect, the ratio of continuous phase to dispersed phase 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 ℃, about 37 ℃, about 35 ℃, about 30 ℃, about 25 ℃, about 20 ℃, about 15 ℃, about 10 ℃, about 5 ℃, about 0 ℃, and any range or value between any of these values.

Homogenizer

For the sake of brevity, and since the method is equally applicable to either method, the phrase "homogenizer" contemplates a system or apparatus capable of homogenizing the dispersed and continuous phases, the emulsified dispersed and continuous phases, or both, as 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 is described in, for example, U.S. Pat. No. 11167256The BPS-i100 integrated pump system is incorporated by reference herein in its entirety. In one aspect, the homogenizer is a membrane emulsifier. In one aspect, the homogenizer operates at an impeller speed of about 1000 to about 4000 Revolutions Per Minute (RPM), including about 1600RPM, about 2500RPM, and about 3500RPM.

Drug loading rate

The drug loading (in percent of drug to polymer ratio) of each polymeric microsphere can range from greater than 55 wt/wt% to about 70 wt/wt%, from about 60w 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%, greater than 60 wt/wt%.

Particle size

In one aspect, the polymeric microspheres may have an average particle size of 10 μm (D ₅₀ ) And 30 μm (D) ₅₀ ) And less than about 20 μm (D) ₅₀ ) Less than 25 μm (D) ₅₀ ) And at 14 μm (D ₅₀ ) And 25 μm (D) ₅₀ ) Between them.

Prolonged release

Microsphere formulations are characterized in that they have an in vivo release duration of about 30 days in humans. In one aspect, the microsphere formulation is characterized by 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 lurasidone released over a period of about 30 days of injection into a subject. For example, in one aspect, the microsphere formulation is characterized in that about 75% to 100% of the lurasidone is released over a period of about 30 days of injection into a subject. In another aspect, microsphere formulations are characterized in that they have a low initial burst, i.e., no more than about 20% of the lurasidone is released within about 24 hours after injection into a subject.

Therapeutic benefit

Possible conditions that may be treated using lurasidone microsphere formulations comprising lurasidone include schizophrenia and depression in bipolar disorder populations. In one aspect, microsphere formulations comprising lurasidone may be used to treat schizophrenia and depression, wherein the microsphere formulations are administered about once every 30 days.

In one aspect, a method of treating schizophrenia and/or depression in a subject suspected of having bipolar disorder is provided. The method may comprise administering to a patient in need thereof a microsphere formulation prepared according to the methods described herein by intra-articular injection, intramuscular injection, or subcutaneous injection, wherein the formulation is administered to the patient on a dosing regimen of about every 30 days.

In another aspect, there is disclosed the use of a microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere, wherein the polymeric microsphere has an average particle size of less than 25 μm (D ₅₀ )。

In another aspect, there is provided a microsphere formulation comprising polymeric microspheres for use as a medicament for treating schizophrenia and/or depression in a subject suspected of having bipolar disorder, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymerThe polymeric microspheres comprise lurasidone in an amount greater than 55% by weight of the polymeric microspheres, wherein the polymeric microspheres have an average particle size of less than 25 μm (D ₅₀ )。

In another aspect, a kit is provided, the kit comprising polymeric microspheres, each polymeric microsphere comprising: (i) lurasidone; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere, and wherein the polymeric microsphere has a molecular weight of less than 25 μm (D ₅₀ ) Is a particle size of the particles.

Examples

Example 1-general preparation of polymeric microspheres comprising lurasidone

Microsphere formation stage. Referring to fig. 1, a dispersed phase ("DP") 10 is formed by dissolving a polymer matrix (e.g., PLGA polymer) in an organic solvent system (e.g., DCM and BA) and then adding lurasidone for mixing until complete dissolution. DP 10 is filtered using a 0.2 μm sterilized PTFE or PVDF membrane filter (e.g., emflow, commercially available from Pall or sartoriosus ag) and pumped into a homogenizer 30, such as an in-line Silverson homogenizer (commercially available from Silverson Machines, waterside UK) or Levitronix i100 (as described in U.S. patent No. 11167256) at a defined flow rate. A continuous phase ("CP") 20 comprising water, surfactant and buffer is also pumped into the homogenizer 30 at a prescribed flow rate. The speed of the homogenizer 30 is typically fixed to achieve the desired polymer microsphere size distribution. A representative continuous "upstream" microsphere formation stage is described in U.S. patent No. 5945126, which is incorporated herein by reference in its entirety.

Microsphere treatment stage. The formed or forming microspheres exit the homogenizer 30 and enter a solvent removal vessel ("SRV") 40. During microsphere formation, water may be added to the SRV 40 to minimize the solvent level in the aqueous medium. After the DP 10 is exhausted, the flow rates of CP 20 and water are stopped and the washing step is started. Solvent removal was achieved using a water wash and a hollow fiber filter (commercially available as HFF from cytova) 50. A representative "downstream" microsphere processing stage is described in U.S. patent No. 6270802, which is incorporated herein by reference.

The washed microspheres were collected and freeze-dried in a lyophilizer (Virtis) to remove any moisture. The resulting microspheres were free flowing off-white lump powder.

Example 2 preparation of Polymer microspheres encapsulating lurasidone-batch 1

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 400g 752H polymer (iv=0.21 dL/g) in 4000g DCM and 2000g BA (DCM/BA (2:1)) and then adding lurasidone (600 g) to mix until complete dissolution. DP was filtered and pumped inBPS-i100 integrates a pump system that operates at 3000 RPM. CP containing 0.35% PVA and phosphate buffer (ph=7.6) was also pumped into the homogenizer at the specified flow rate.

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder. The average particle diameter of the obtained microspheres was 9.2 (D ₅₀ ) The drug loading is 66.7%.

Example 3 preparation of Polymer microspheres encapsulating lurasidone-batch 2

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 400g 752H polymer (iv=0.21 dL/g) in 4000g DCM and 2000g BA (DCM/BA (2:1)) and then adding lurasidone (600 g) to mix until complete dissolution. DP was filtered and pumped into operation at 4000RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA and phosphate buffer (ph=7.6) was also pumped into the homogenizer at the specified flow rate.

Formed or being formedThe microspheres leave the homogenizer and enter the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder. The average particle diameter of the obtained microspheres was 14.8 (D ₅₀ ) The drug loading is 65.5%.

Fig. 2 is a microscope image of a polymeric microsphere encapsulated with lurasidone of lot 2.

Fig. 3 is a graph comparing the cumulative release of lurasidone from lot 1 and lot 2 over time.

Example 4 preparation of Polymer microspheres encapsulating lurasidone-batch 3 and 3I

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 120g of 7502A polymer (iv=0.20 dL/g) in 800g of DCM and 400g of BA (DCM/BA (2:1)) and then adding lurasidone (180 g) to mix until complete dissolution. DP was filtered and pumped at a flow rate of 25ml/min to run at 2500RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA and 10mM phosphate buffer (ph=7.6) was also pumped into the homogenizer (CP: dp=80:1) at a flow rate of 2L/min.

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder.

A portion of the powder was subjected to gamma irradiation of 25kGy at ambient temperature. The average particle diameter of the unirradiated fraction (batch 3) was 22 μm (D ₅₀ ) The drug loading was 60.4 wt% and the molecular weight was 16.9kDa. The average particle diameter of the irradiated fraction (batch 3I) was 21. Mu.m (D ₅₀ ) The drug loading was 60.2 wt% and the molecular weight was 15.8kDa.

Fig. 4 is a graph comparing the in vitro cumulative release of lurasidone over time for lot 3 and lot 3I. Fig. 4 shows that lot 3 and lot 3I have low initial burst and that sterilization of the polymeric microspheres by irradiation does not adversely affect the release profile of the microsphere formulation.

Example 5 preparation of Polymer microspheres encapsulating lurasidone-lots 4 and 4I

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 120g of 7502A polymer (iv=0.20 dL/g) in 800g of DCM and 400g of BA (DCM/BA (2:1)) and then adding lurasidone (180 g) to mix until complete dissolution. DP was filtered and pumped at a flow rate of 25ml/min to run at 3500RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA and 10mM phosphate buffer (ph=7.6) was also pumped into the homogenizer (CP: dp=80:1) at a flow rate of 2L/min.

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder.

A portion of the powder was subjected to gamma irradiation of 25kGy at ambient temperature. The average particle diameter of the unirradiated fraction (lot 4) was 15 μm (D ₅₀ ) The drug loading was 60.5 wt% and the molecular weight was 16.9kDa. The average particle diameter of the irradiated fraction (batch 4I) was 15 μm (D ₅₀ ) The drug loading was 60.0 wt% and the molecular weight was 15.9kDa.

Fig. 5 is a graph comparing the in vitro cumulative release of lurasidone over time for lot 4 and lot 4I. Fig. 5 shows that lot 4 and lot 4I have low initial burst and that sterilization of the polymeric microspheres by irradiation does not adversely affect the release profile of the microsphere formulation.

Example 6 preparation of Polymer microspheres encapsulating lurasidone-batches 5 and 5I

Following the general procedure described in example 1 and shown in fig. 1, the polymer was prepared by dissolving 120g of 7503A polymer (iv=0.29 dL/g) in 800g of DCM and 400g of BA (DCM/BA (2:1))Lurasidone (180 g) was then added and mixed until completely dissolved, forming DP. DP was filtered and pumped at a flow rate of 25ml/min to run at 3500RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA and 10mM phosphate buffer (ph=7.6) was also pumped into the homogenizer (CP: dp=80:1) at a flow rate of 2L/min.

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder.

A portion of the powder was subjected to gamma irradiation of 25kGy at ambient temperature. The average particle diameter of the unirradiated fraction (batch 5) was 18 μm (D ₅₀ ) The drug loading was 58.7 wt% and the molecular weight was 29.9kDa. The average particle diameter of the irradiated fraction (batch 5I) was 18 μm (D ₅₀ ) The drug loading was 58.8 wt% and the molecular weight was 27.2kDa.

Fig. 6 is a graph comparing the in vitro cumulative release of lurasidone over time for batch 5 and batch 5I. Fig. 6 shows that lot 5 and lot 5I have low initial burst and that sterilization of the polymeric microspheres by irradiation does not adversely affect the release profile of the microsphere formulation.

Example 7 preparation of Polymer microspheres encapsulating lurasidone-batches 6 and 6I

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 120g 752H polymer (iv=0.21 dL/g) in 800g DCM and 400g BA (DCM/BA (2:1)) and then adding lurasidone (180 g) to mix until complete dissolution. DP filtration was carried out by pumping at a flow rate of 25ml/min into a vacuum pump operated at 3500RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA and 10mM phosphate buffer (ph=7.6) was also pumped into the homogenizer (CP: dp=80:1) at a flow rate of 2L/min.

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder.

A portion of the powder was subjected to gamma irradiation of 25kGy at ambient temperature. The average particle diameter of the unirradiated fraction (batch 6) was 16 μm (D ₅₀ ) The drug loading was 59.4 wt% and the molecular weight was 15.6kDa. The average particle diameter of the irradiated fraction (batch 6I) was 16 μm (D ₅₀ ) The drug loading was 60.1 wt% and the molecular weight was 14.9kDa.

Fig. 7 is a graph comparing the in vitro cumulative release of lurasidone over time for lot 6 and lot 6I. Fig. 7 shows that lot 6 and lot 6I have low initial burst and that sterilization of the polymeric microspheres by irradiation does not adversely affect the release profile of the microsphere formulation.

Fig. 8 is a graph comparing the in vitro cumulative release of lurasidone over time for lot 3, lot 4, lot 5, and lot 6. Fig. 9 is a graph comparing the in vitro cumulative release of lurasidone over time for batches 3, 4, 5 and 6.

Examples 8-lot 3, lot 3I, lot 4I, lot 5I, lot 6 and lot 6I in dogs Pharmacokinetic studies

The pharmacokinetic profile of lurasidone following subcutaneous injection of a dose of sustained release lurasidone formulation in dogs was studied. These dogs received the indicated batches at a 10mg/kg dose of lurasidone at a concentration of 100 mg/mL. Blood samples were taken at time points of 1 hour, 3 hours, 6 hours, 24 hours, 48 hours, 96 hours, 168 hours, 264 hours, 360 hours, 480 hours, 600 hours, 720 hours, 840 hours, 960 hours, 1080 hours, 1200 hours, 1320 hours, 1440 hours, 1560 hours and 1680 hours. FIG. 10 is a graph showing measured average blood concentration (ng/mL) of lurasidone for lot 3, lot 3I, lot 4I, lot 5I, lot 6, and lot 6I as a function of time.

Example 9 preparation of Polymer microspheres encapsulating lurasidone-batch 7

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 15g 7502A polymer (iv=0.19 dL/g) in 133.3g DCM and 66.70g BA (DCM/BA (2:1)) followed by mixing with lurasidone (35 g) until complete dissolution. DP was filtered and pumped at a flow rate of 25ml/min to run at 3500RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA (but no buffer) was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder.

The average particle diameter of the 7 th batch was 16 μm (D ₅₀ ) The drug loading was 63% (91% encapsulation efficiency based on 70% of the target drug loading) and the molecular weight was 16.6kDa. Fig. 11 is a graph showing the in vitro cumulative release of lurasidone over time for batch 7.

Example 10 preparation of Polymer microspheres encapsulating lurasidone-batch 8

Following the general procedure described in example 1 and shown in fig. 1, DP was formed by dissolving 3.0g 7507A polymer (iv=0.56 dL/g) in 26.67g DCM and 13.33g BA (DCM/BA (2:1)) and then adding lurasidone (7.0 g) to mix until complete dissolution. DP was filtered and pumped at a flow rate of 25ml/min to run at 3500RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA (but no buffer) was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

The formed or forming microspheres leave the homogenizer into the SRV. Deionized water was added to the SRV. Solvent removal was achieved using water washing and hollow fiber filters. A large amount of suspension was collected by filtration and freeze-dried to obtain a free-flowing powder.

The average particle diameter of the 8 th batch was 18. Mu.m (D ₅₀ ) The drug loading was 59% (84% encapsulation efficiency based on 70% of the target drug loading) and the molecular weight was 62.0kDa. Fig. 11 is a graph showing the in vitro cumulative release of lurasidone over time for batch 8.

In use, the microspheres may be suspended in a diluent for administration (injection). The diluent may generally contain a thickener, a penetrant, and a surfactant. The thickener may include sodium carboxymethyl cellulose (CMC-Na) or other suitable compounds. The appropriate viscosity grade and appropriate concentration of CMC-Na may be selected to achieve a diluent viscosity of 3cp or higher. In general, a viscosity of about 10cp is suitable; however, for larger microspheres, a higher viscosity diluent may be preferred to minimize sedimentation of the microspheres in suspension.

A uniform microsphere suspension without particle settling will produce a consistent dosage during injection administration. To bring the permeability of the diluent closer to that of the biological system, a solute of about 290 milliosmoles (mOsm) may be used, such as mannitol, sodium chloride, or any other acceptable salt. The diluent may also contain a buffer salt to maintain the pH of the composition. Typically, the pH is maintained near physiologically relevant pH (pH about 7 to about 8) by adjusting the buffer content as needed.

The aspects disclosed herein are not intended to be exhaustive or limiting. Those skilled in the art will recognize that other aspects and modifications may be made to the present aspects without departing from the spirit or scope of the present application. Aspects of the disclosure, as generally described herein and shown in the drawings, may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are contemplated herein.

Unless otherwise indicated, "a", "an", "the", "one or more", and "at least one" are used interchangeably. The singular forms "a", "an" and "the" include plural referents. 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," "including," and "containing" are intended to be equivalent and open-ended. The phrase "consisting essentially of … …" means that the composition or method can include additional ingredients and/or steps, provided that 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 groups.

When the term "each" is referred to, it does not mean "each" without exception. For example, if a microsphere formulation comprising polymeric microspheres is mentioned, and "each polymeric microsphere" is stated as having a specific API content, if there are 10 polymeric microspheres, and two or more polymeric microspheres have a specific API content, then a subset of two or more polymeric microspheres is intended to meet this limitation.

The term "about" used in connection with a number is a simple shorthand and is intended to include + -10% of the number. This is true whether the "about" modifies an independent number or a number at one or both ends of a range of numbers. In other words, "about 10" means from 9 to 11. Likewise, "about 10 to about 20" refers to 9 to 22 and 11 to 18. Without the term "about," exact numbers are referred to. In other words, "10" is 10.

Claims (20)

1. A microsphere formulation comprising:

polymeric microspheres, each polymeric microsphere comprising:

lurasidone; and

a biodegradable polymer which can be used as a carrier,

wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere and

wherein the polymer microspheres have an average particle size of less than 25 [ mu ] m (D ₅₀ )。

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

3. The microsphere formulation of claim 1, wherein the biodegradable polymer comprises an acid-terminated poly (D, L-lactide-co-glycolide).

4. The microsphere formulation of claim 1, wherein the biodegradable polymer comprises lactide: glycolide is an acid-terminated poly (D, L-lactide-co-glycolide) of about 75:25.

5. The microsphere formulation of claim 1, wherein the drug loading of lurasidone per polymeric microsphere is from 55% to about 70% by weight of the polymeric microsphere.

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

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

8. Microsphere formulation according to claim 1 for use in the treatment of schizophrenia and/or depression.

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

10. A process for preparing a microsphere formulation according to claim 1, the process comprising the steps of:

(i) At a solvent ratio of about 2: in the presence of an organic solvent system of about 1 methylene chloride and benzyl alcohol, the lurasidone is reacted with a comonomer comprising a comonomer ratio of about 75: about 25 of the biodegradable polymer of the acid-terminated poly (D, L-lactide-co-glycolide) is contacted to form a dispersed phase;

(ii) Combining the dispersed phase with a continuous phase comprising water and a surfactant in a homogenizer to form an emulsion;

(iii) Removing the organic solvent from the emulsion to form a microsphere formulation that is substantially free of organic solvent; and

(iv) Freeze-drying the substantially organic solvent-free microsphere formulation.

11. The method of claim 10, wherein the surfactant comprises polyvinyl alcohol.

12. The method of claim 10, wherein the surfactant comprises polyvinyl alcohol, and wherein the concentration of polyvinyl alcohol in the aqueous phase prior to the combining is about 0.35 wt%.

13. The method of claim 10, wherein the continuous phase further comprises a buffer.

14. The method of claim 10, wherein the continuous phase further comprises a buffer, and wherein the buffer is a phosphate buffer having a pH between about 7 and about 8.

15. A kit comprising:

polymeric microspheres, each polymeric microsphere comprising:

(i) Lurasidone; and

(ii) A biodegradable polymer which can be used as a carrier,

wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere and wherein the polymeric microsphere has an average particle size of less than 25 μm (D ₅₀ )。

16. The kit of claim 15, wherein the biodegradable polymer comprises lactide: glycolide is an acid-terminated poly (D, L-lactide-co-glycolide) of about 75:25.

17. The kit of claim 15, wherein the drug loading of lurasidone per polymeric microsphere is from 55% to about 70% by weight of the polymeric microsphere.

18. The kit of claim 15, wherein the polymeric microspheres are irradiated.

19. A method for treating schizophrenia and/or depression in a subject suspected of having bipolar disorder, the method comprising:

administering to the subject a microsphere formulation by intra-articular injection, intramuscular injection, or subcutaneous injection in a dosing regimen of about every 30 days, the microsphere formulation comprising:

polymeric microspheres, each polymeric microsphere comprising:

(1) Lurasidone; and

(2) A biodegradable polymer which can be used as a carrier,

wherein each polymeric microsphere comprises lurasidone in an amount greater than 55% by weight of the polymeric microsphere and

wherein the polymer microspheres have an average particle size of less than 25 [ mu ] m (D ₅₀ )。

20. The method according to claim 19, wherein:

the biodegradable polymer comprises lactide: glycolide is about 75:about 25 acid-capped poly (D, L-lactide-co-glycolide); and is also provided with

The lurasidone loading of each polymeric microsphere is from 55% to about 70% by weight of the polymeric microsphere.