Microsphere formulations containing BTK inhibitors and methods of making and using same

Abstract

Extended release microsphere formulations comprising a BTK inhibitor are provided. In one embodiment, the microsphere formulations are characterized in that the BTK inhibitor is released in vivo in humans over a period of about 7 to about 28 days. Methods of making and using the formulations are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 156,020, filed March 3, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] B cells account for up to 25% of all cells in some cancers. BTK inhibitors inhibit the Bruton's tyrosine kinase ("BTK") enzyme, which is involved in B cell receptor signaling, thereby causing the detachment of malignant B cells from the cancer site into the blood, resulting in cell death. BTK inhibition reduces malignant B cell proliferation and reduces malignant B cell survival.

[0003] General structure: [ka] Ibrutinib (chemical formula C 25 H 24 N6O2, CAS number 936563-96-1) is a BTK inhibitor. Ibrutinib has been approved by the U.S. Food and Drug Administration ("FDA"), alone and in combination with other drugs, for the treatment of mantle cell lymphoma ("MCL"), chronic lymphocytic leukemia ("CLL"), Waldenstrom's macroglobulinemia, small lymphocytic lymphoma ("SLL"), relapsed / refractory marginal zone lymphoma in patients who require systemic therapy and have received at least one prior anti-CD20-based therapy, and graft-versus-host disease, among other diseases.

[0004] Two other BTK inhibitors have been approved by the FDA: acalabrutinib (approved for the treatment of relapsed MCL) and zanubrutinib (approved for the treatment of MCL).Several other drugs that inhibit BTK are in clinical trials, including evobrutinib for multiple sclerosis, ABBV-105 for systemic lupus erythematosus, fenebrutinib for rheumatoid arthritis, systemic lupus erythematosus, and chronic spontaneous urticaria, GS-4059 for non-Hodgkin's lymphoma and / or CLL, spebrutinib (AVL-292, CC-292), and HM71224 for autoimmune diseases.

[0005] All currently approved BTK inhibitors are oral formulations. Oral formulations may have some drawbacks. For example, oral formulations may require strictly timed continuous dosing under medical supervision. In addition, some BTK inhibitors may have low and variable oral bioavailability. For example, ibrutinib may have only 2.9% oral bioavailability in the fasted state, which may vary from patient to patient.

[0006] There is a need for highly bioavailable formulations containing BTK inhibitors that may be administered by long-acting, sustained release injections without the need for patients to administer continuous, timed doses under medical supervision. Summary of the Invention

[0007] Microsphere formulations comprising a BTK inhibitor are provided. The microsphere formulations comprise polymeric microspheres, each polymeric microsphere comprising (i) a BTK inhibitor and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of 110 μm (D 50 In another embodiment, the microsphere formulation is characterized by having a low initial burst release, i.e., no more than 50% of the BTK inhibitor is released within about 4 hours of injection into a subject.

[0008] In one embodiment, the microsphere formulation may be produced by a process including: (A) mixing (i) a biodegradable polymer, (ii) a primary solvent, and (iii) a BTK inhibitor to form a dispersed phase; (B) mixing (i) water, and (ii) a surfactant to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.

[0009] In one embodiment, a method for treating cancer, including B-cell malignancies, is provided. The method may comprise administering the microsphere formulation produced according to the method described herein to a patient in need thereof by intramuscular or subcutaneous injection.

[0010] In another aspect, a microsphere formulation comprising polymeric microspheres in the manufacture of a medicament for the treatment of cancer, including B-cell malignancies, wherein each polymeric microsphere comprises (i) a BTK inhibitor and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, and wherein the polymeric microspheres have a diameter of less than 110 μm (D 50 The use of the above microsphere formulations having an average particle size of less than 100 μm is disclosed.

[0011] In another aspect, a microsphere formulation comprising polymeric microspheres for use as a medicament for the treatment of cancer, including B cell malignancies, wherein each polymeric microsphere comprises (i) a BTK inhibitor and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, and wherein the polymeric microspheres have a diameter of less than 110 μm (D 50 ) of the microsphere formulation.

[0012] In another aspect, a kit is provided, the kit comprising polymeric microspheres, each polymeric microsphere comprising (i) a BTK inhibitor and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of less than 110 μm (D 50 ) average particle size. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram showing a method for producing BTK inhibitor-encapsulated polymer microspheres.

[0014] [Diagram 2] FIG. 1 is a graph showing in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres containing 50:50 poly(D,L-lactide-co-glycolide) (“PLGA”) as the biodegradable polymer.

[0015] [Diagram 3] FIG. 1 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres comprising 75:25 PLGA with an intrinsic viscosity ("IV") of 0.26 dL / g as the biodegradable polymer.

[0016] [Figure 4] FIG. 13 shows the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres comprising 75:25 PLGA with IV of 0.41 dL / g to 0.70 dL / g as the biodegradable polymer.

[0017] [Diagram 5] FIG. 1 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres containing 85:15 PLGA as the biodegradable polymer.

[0018] [Figure 6]FIG. 1 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres that include poly(D,L-lactide) (“PLA”) as the biodegradable polymer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Microsphere formulations comprising a BTK inhibitor are provided. The microsphere formulations comprise polymeric microspheres, each polymeric microsphere comprising (i) a BTK inhibitor and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of 110 μm (D 50 In another embodiment, the microsphere formulation is characterized by having a low initial burst release, i.e., no more than 20% of the BTK inhibitor is released within about 24 hours of injection into a subject.

[0020] In one embodiment, the microsphere formulation may be produced by a process including: (A) mixing (i) a biodegradable polymer, (ii) a primary solvent, and (iii) a BTK inhibitor to form a dispersed phase; (B) mixing (i) water, and (ii) a surfactant to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.

[0021] BTK inhibitors In one embodiment, the BTK inhibitor is selected from the group comprising, consisting essentially of, or consisting of ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ABBV-105, fenebrutinib, GS-4059, or spebrutinib, or a combination thereof.

[0022] In one embodiment, the composition consists essentially of ibrutinib. In one embodiment, ibrutinib is provided by ScinoPharm or MSN. In one embodiment, ibrutinib is hydrophobic. In one embodiment, ibrutinib is provided as a free base. In another embodiment, ibrutinib is provided as a pharma- ceutically acceptable salt. In one embodiment, ibrutinib is characterized by an aqueous solubility of less than 2.5 mg / g. In one embodiment, ibrutinib is characterized by a solubility in dichloromethane ("DCM") of greater than 300 mg / g. In one embodiment, ibrutinib is characterized by a pKa of about 3.74.

[0023] The BTK inhibitor may be in various polymorphic forms. The polymorphic forms may include hemihydrate, monohydrate, dihydrate, and other polymorphic forms known in the art. The salts may include hydrochloride, sulfate, acetate, phosphate, diphosphate, chloride, maleate, citrate, mesylate, nitrate, tartrate, gluconate, or other salts known in the art. In one embodiment, the BTK inhibitor is in an amorphous form.

[0024] In embodiments where the BTK inhibitor comprises ibrutinib or another BTK inhibitor with similar solubility characteristics, solubility may be reduced using complex salts, such as palmitate, benzoate, tosylate, camphorsulfonate, or other salt complexes that one of skill in the art could readily envision.

[0025] Biodegradable Polymers In one aspect, the dispersed phase may comprise a biodegradable polymer such as PLGA or PLA, although it is contemplated that other suitable biodegradable polymers may be used. The biodegradable polymer may be hydrophobic or hydrophilic.

[0026] In some embodiments, the biodegradable polymer comprises PLGA. In one embodiment, the PLGA comprises a lactide:glycolide ratio of 50:50, 75:25, or 85:15. In one embodiment, the PLGA is acid-terminated. In one embodiment, the PLGA is ester-terminated. In one embodiment, the PLGA has an IV of about 0.1 dL / g to about 0.8 dL / g, including about 0.1 dL / g to about 0.3 dL / g, about 0.16 dL / g to about 0.24 dL / g, about 0.2 dL / g to about 0.4 dL / g, about 0.4 dL / g to about 0.6 dL / g, about 0.6 dL / g to about 0.8 dL / g, about 0.20 dL / g, 0.26 dL / g, 0.41 dL / g, 0.56 dL / g, 0.66 dL / g, 0.7 dL / g, and any value or range between any two of these IV values.

[0027] In one embodiment, the PLGA comprises Resomer® 502H, poly(D,L-lactide-co-glycolide), acid terminated, 50:50 lactide:glycolide ("502H") from Evonik, having an IV=0.20. In one embodiment, the PLGA comprises Resomer® 502, poly(D,L-lactide-co-glycolide), ester terminated, 50:50 lactide:glycolide ("502") from Evonik, having an IV=0.20. In one embodiment, the PLGA comprises Viatel™ DLG7503A, poly(D,L-lactide-co-glycolide), acid terminated, 75:25 lactide:glycolide ("7503A") from Ashland, having an IV=0.26. In one embodiment, the PLGA comprises Viatel™ DLG7503E, poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 75:25 ("7503E") manufactured by Ashland, having an IV=0.26. In one embodiment, the PLGA comprises Viatel™ DLG7505A, poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25 ("7505A") manufactured by Ashland, having an IV=0.56. In one embodiment, the PLGA comprises Viatel™ DLG7505E, poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 75:25 ("7505E") manufactured by Ashland, having an IV=0.41. In one embodiment, the PLGA comprises Viatel™ DLG7507A, poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25 ("7507A") manufactured by Ashland, having an IV=0.70. In one embodiment, the PLGA comprises Viatel™ DLG7507E, poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 75:25 ("7507E") manufactured by Ashland, having an IV=0.66. In one embodiment, the PLGA comprises Viatel™ DL8503A, poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 85:15 ("8503A") manufactured by Ashland, having an IV=0.24.In one embodiment, the PLGA comprises Viatel™ DL8503E from Ashland, poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 85:15 ("8503E"), having an IV=0.25.

[0028] In some embodiments, the biodegradable polymer is PLA. In one embodiment, the PLA is acid terminated. In one embodiment, the PLA is ester terminated. In one embodiment, the PLA has an IV of about 0.1 dL / g to about 0.4 dL / g, including about 0.16 dL / g, about 0.18 dL / g, and about 0.32 dL / g, and any value or range between any two of these IV values.

[0029] In one embodiment, the PLA comprises Viatel™ DL02A, poly(D,L-lactide), acid terminated ("DL02A") from Ashland, having an IV=0.16. In one embodiment, the PLA comprises Viatel™ DL02E, poly(L-lactide), ester terminated ("DL02E") from Ashland, having an IV=0.18. In one embodiment, the PLA comprises Viatel™ DL03A, poly(L-lactide), acid terminated ("DL03A") from Ashland, having an IV=0.32.

[0030] In one embodiment, a biodegradable polymer is mixed with the BTK inhibitor to form a microsphere, which is injectable and formulated to release the BTK inhibitor to a patient over an intended release duration. In another embodiment, a biodegradable polymer is used to encapsulate the BTK inhibitor in a microsphere, which is injectable and formulated to release the BTK inhibitor to a patient over an intended release duration by a controlled release rate from the spheres, or by release from different spheres at different times based on particle size, thickness of the biodegradable polymer encapsulating the BTK inhibitor, molecular weight of the biodegradable polymer, polymer composition, e.g., comonomer ratio, end capping, and drug loading, or a combination of such release influencing factors.

[0031] dispersed phase In one embodiment, the dispersed phase comprises a primary solvent. In one embodiment, the primary solvent comprises DCM. The dispersed phase may also comprise up to about 50% by weight of a co-solvent that can optimize the solubility of the BTK inhibitor in the primary solvent. In one embodiment, the co-solvent may be benzyl alcohol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, ethanol, N-methylpyrrolidone, ethyl acetate, or any other solvent that increases the solubility of the BTK inhibitor in the dispersed phase containing DCM. The microspheres are "essentially free" of organic solvent if they meet the criteria set forth in "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.

[0032] Continuous Phase The dispersed phase may be combined with an aqueous continuous phase that comprises water and optionally a buffer, a surfactant, or both.

[0033] 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.

[0034] 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.

[0035] 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. Larger batches may require higher flow rates.

[0036] The continuous phase may be provided at room temperature or above or below room temperature, in 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 value or range between any two of these temperature values.

[0037] 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, for example, as described 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 or static mixer. In one embodiment, the homogenizer operates at an impeller speed of about 1,000 to about 4,000 revolutions per minute ("RPM"), including about 2,000 RPM, about 3,000 RPM, and any value or range between any two of these RPM values.

[0038] Drug burden The drug loading of each polymeric microsphere in terms of drug to polymer ratio, expressed as a percentage, may be greater than 40 wt / wt%, including about 40 wt / wt% to about 70 wt / wt%, about 45 wt / wt% to about 70 wt / wt%, about 45 wt / wt% to about 65 wt / wt%, about 50 wt / wt% to about 65 wt / wt%, greater than 50 wt / wt%, and any value or range between any two of those drug loadings.

[0039] It is contemplated that in some particular embodiments, the drug loading may be as low as 20 wt / wt%.

[0040] particle size In one embodiment, the polymer microspheres have a diameter of about 30 μm (D 50 ) ~ approx. 60 μm (D 50 ), approximately 30 μm (D 50 ) ~ approx. 50 μm (D 50 ), approximately 35 μm (D 50 ) ~ approx. 60 μm (D 50 ), approximately 45 μm (D 50 ) ~ approx. 60 μm (D 50 ), approximately 30 μm (D 50 ), approximately 35 μm (D 50 ), approximately 40 μm (D 50 ), approximately 45 μm (D 50 ), approximately 50 μm (D 50 ), approximately 55 μm (D 50 ), approximately 60 μm (D 50 ), approximately 60 μm (D 50 ) and any value or range between any two of these average particle sizes. 50 ) average particle size.

[0041] It is contemplated that in some particular embodiments, the average particle size may be as large as 150-200 μm.

[0042] extended release In one embodiment, the microsphere formulation is characterized by having an in vivo release duration in humans of less than about 7 days. In one embodiment, the microsphere formulation is characterized by having an in vivo release duration in humans of about 7 days to about 14 days. In one embodiment, the microsphere formulation is characterized by having an in vivo release duration in humans of about 14 days to about 28 days. In one embodiment, the microsphere formulation is characterized by having an in vivo release duration in humans of about 28 days. In one embodiment, the microsphere formulation is characterized by having an in vivo release duration in humans of more than about 28 days.

[0043] 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 BTK inhibitor within <7, 7-14, 14-28, or >28 days (as described in the previous paragraph) of injection into a subject. For example, in one embodiment, the microsphere formulation is characterized by releasing about 75%-100% of the BTK inhibitor over a specified period of time after 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 BTK inhibitor is released within about 24 hours of injection into a subject.

[0044] Further embodiments include sustained release injectable formulations of ibrutinib that are pharmacologically equivalent to oral doses of 70 mg, 140 mg, 280 mg, 420 mg, and 560 mg in sustained release injectable formulations that release over approximately 7, 14, 21, or 28 days.

[0045] Another embodiment includes a method of treating a human patient for MCL, CLL / SLL, and other diseases or conditions that may be treated by a BTK inhibitor. The method may include providing an injectable form of ibrutinib orally at pharmacologically equivalent dosage strengths of 70 mg, 140 mg, 280 mg, 420 mg, and 560 mg per day, where the injectable form has a continuous release duration such that patient compliance is ensured, medical consequences of missing one or more doses are avoided, and the pharmacokinetic profile is improved compared to the oral dosage form.

[0046] Therapeutic Benefits Potential conditions that may be treated using a microsphere formulation comprising a BTK inhibitor include cancers, including B cell malignancies, including MCL, CCL, and SLL. In one embodiment, B cell malignancies may be treated using a microsphere formulation comprising a BTK inhibitor, where the microsphere formulation is administered about every <7, 7-14, 14-28, or >28 days.

[0047] In one embodiment, a method for treating cancer, including B-cell malignancies, is provided. The method may comprise administering the microsphere formulation produced according to the method described herein to a patient in need thereof by intramuscular or subcutaneous injection.

[0048] In another aspect, a microsphere formulation comprising polymeric microspheres in the manufacture of a medicament for the treatment of cancer, including B-cell malignancies, wherein each polymeric microsphere comprises (i) a BTK inhibitor and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, and wherein the polymeric microspheres have a diameter of less than 110 μm (D 50 The use of the above microsphere formulations having an average particle size of less than 100 μm is disclosed.

[0049] In another aspect, a microsphere formulation comprising polymeric microspheres for use as a medicament for the treatment of cancer, including B cell malignancies, wherein each polymeric microsphere comprises (i) a BTK inhibitor and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, and wherein the polymeric microspheres have a diameter of less than 110 μm (D 50 ) of the microsphere formulation.

[0050] In another aspect, a kit is provided, the kit comprising polymeric microspheres, each polymeric microsphere comprising (i) a BTK inhibitor and (ii) a biodegradable polymer, each polymeric microsphere comprising a drug loading of the BTK inhibitor of greater than 40% by weight of the polymeric microsphere, the polymeric microspheres having a diameter of less than 110 μm (D 50 ) average particle size.

[0051] example Example 1 - General preparation of polymeric microspheres containing BTK inhibitors Microsphere-forming phase. With reference to FIG. 1, a dispersed phase ("DP") 10 is formed by dissolving a polymer matrix (such as a PLGA or PLA polymer) in an organic solvent system (such as DCM), followed by addition of a BTK inhibitor 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 into a homogenizer 30 at a prescribed flow rate. A continuous phase ("CP") 20, which includes water, surfactant, and optionally a buffer, is also pumped into the homogenizer 30 at a prescribed flow rate. The speed of the homogenizer 30 is generally fixed to achieve a desired polymer microsphere size distribution. An exemplary continuous "upstream" microsphere-forming phase is described in U.S. Pat. No. 5,945,126, which is incorporated herein by reference in its entirety.

[0052] 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. See also U.S. Pat. No. 9,017,715, which is incorporated herein by reference in its entirety. 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. Pat. No. 6,270,802, which is incorporated herein by reference in its entirety.

[0053] 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.

[0054] Example 2 - Preparation of Ibrutinib-Encapsulated Polymer Microspheres with 50:50 PLGA - Batch Nos. 1 and 2 ("Group A") Following the general procedure described in Example 1 and illustrated in Figure 1, DP was formed by dissolving 2.5 g of either 502H polymer (batch no. 1) or 502 polymer (batch no. 2) (IV = 0.20 dL / g) in 11.67 g of DCM, then adding ibrutinib (2.5 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 3,000 RPM. The CP with 0.35% PVA 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] Batch No. 1 is 36 μm (D 50 ), a drug loading of 47.6 wt%, and a molecular weight of 17.6 kDa. The microspheres contained 3.0% residual DCM. Batch No. 2 had an average particle size of 44 μm (D 50 ), a drug loading of 47.8 wt%, and a molecular weight of 17.7 kDa. The microspheres contained 3.0% residual DCM. The parameters and results are tabulated in Table 1. [Table 1]

[0057] FIG. 2 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres of Group A.

[0058] Example 3 - Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising 75:25 PLGA with Low Polymer IV - Batch Nos. 3, 4, 6, 7, and 11 ("Group B") Following the general procedure described in Example 1 and illustrated in Figure 1, DPs were formed by dissolving 2.5 g (Batch Nos. 3, 4, and 11), 2.0 g (Batch No. 6), or 1.5 g (Batch No. 7) of either 7503A polymer (Batch Nos. 3, 6, 7, and 11) or 7502E polymer (Batch No. 6) (IV = 0.26 dL / g) in 11.67 g of DCM, followed by addition of ibrutinib (enough to provide a DP weight of 16.67 g, i.e., 2.5 g for Batch Nos. 3, 4, and 11, 3.0 g for Batch No. 6, and 3.5 g for Batch No. 7) and mixing until completely dissolved. The DPs were filtered and pumped into a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM (Batch Nos. 3, 4, 6, and 7) or 2,000 RPM (Batch No. 11) at a flow rate of 25 mL / min. CP containing 0.35% PVA 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] Batch No. 3 was 39 μm (D 50 ), a drug loading of 48.2 wt%, and a molecular weight of 29.4 kDa. The microspheres contained 3.1% residual DCM. Batch No. 4 had an average particle size of 35 μm (D 50 ), a drug loading of 48.9 wt%, and a molecular weight of 25.5 kDa. The microspheres contained 2.1% residual DCM. Batch No. 6 had an average particle size of 34 μm (D 50 ), a drug loading of 60.6 wt%, and a molecular weight of 31.0 kDa. The microspheres contained 2.7% residual DCM. Batch No. 7 had an average particle size of 30 μm (D 50 ), a drug loading of 65.6 wt%, and a molecular weight of 30.1 kDa. The microspheres contained 1.5% residual DCM. Batch No. 11 had an average particle size of 61 μm (D 50 ), a drug loading of 51 wt%, and a molecular weight of 28.9 kDa. The microspheres contained 1.4% residual DCM. The parameters and results are tabulated in Table 2. [Table 2]

[0061] FIG. 3 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres of Group B.

[0062] Example 4 - Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising 75:25 PLGA with High Polymer IV - Batch Nos. 5, 12, 13, and 14 ("Group C") Following the general procedure described in Example 1 and illustrated in FIG. 1, DPs were formed by dissolving 2.5 g (Batch Nos. 5 and 12) or 2.0 g (Batch Nos. 13 and 14) of either the 7505A polymer (Batch No. 5) (IV=0.56 dL / g), 7505E polymer (Batch No. 12) (IV=0.41 dL / g), 7507A polymer (Batch No. 13) (IV=0.7 dL / g), or 7507E polymer (Batch No. 14) (IV=0.66 dL / g) in 11.67 g DCM, followed by the addition of ibrutinib (sufficient to provide a DP weight of 16.67 g, i.e., 2.5 g for Batch Nos. 5 and 12, and 3.0 g for Batch Nos. 13 and 14) and mixing until completely dissolved. The DP was filtered and pumped into a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM at a flow rate of 25 mL / min. The CP with 0.35% PVA 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] Batch No. 5 is 53 μm (D 50 ), a drug loading of 47.5 wt%, and a molecular weight of 66.4 kDa. The microspheres contained 4.1% residual DCM. Batch No. 12 had an average particle size of 47 μm (D 50 ), a drug loading of 51.2 wt%, and a molecular weight of 49.8 kDa. The microspheres contained 0.8% residual DCM. Batch No. 13 had an average particle size of 52 μm (D 50 ), a drug loading of 62.2 wt%, and a molecular weight of 87.7 kDa. The microspheres contained 1.3% residual DCM. Batch No. 14 had an average particle size of 53 μm (D 50), a drug loading of 61.0 wt%, and a molecular weight of 90.8 kDa. The microspheres contained 1.3% residual DCM. The parameters and results are tabulated in Table 3. [Table 3]

[0065] FIG. 4 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres of Group C.

[0066] Example 5-85: Preparation of Ibrutinib-Encapsulated Polymer Microspheres with 15 PLGA - Batch Nos. 18 and 19 ("Group D") Following the general procedure described in Example 1 and illustrated in Figure 1, DP was formed by dissolving 2.5 g of either 8503A polymer (batch no. 18) (IV = 0.24 dL / g) or 8503E polymer (batch no. 19) (IV = 0.25 dL / g) in 11.67 g of DCM, then adding ibrutinib (2.5 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 3,000 RPM. The CP with 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0067] 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.

[0068] Batch No. 18 is 36 μm (D 50 ), a drug loading of 49.8 wt%, and a molecular weight of 22.7 kDa. The microspheres contained 0.5% residual DCM. Batch No. 19 had an average particle size of 35 μm (D 50), a drug loading of 49.2 wt%, and a molecular weight of 25.8 kDa. The microspheres contained 0.3% residual DCM. The parameters and results are tabulated in Table 4. [Table 4]

[0069] FIG. 5 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymeric microspheres of Group D.

[0070] Example 6 - Preparation of Ibrutinib-Encapsulated Polymer Microspheres with PLA - Batch Nos. 8, 9, 10, 16, and 17 ("Group E") Following the general procedure described in Example 1 and illustrated in FIG. 1, DPs were formed by dissolving 2.5 g (Batch Nos. 8, 9, 16, and 17) or 2.0 g (Batch No. 10) of either DL02A polymer (Batch Nos. 8 and 17) (IV=0.16 dL / g), DL02E polymer (Batch Nos. 9 and 10) (IV=0.18 dL / g), or DL03A polymer (Batch No. 16) (IV=0.32 dL / g) in 11.67 g DCM, followed by addition of ibrutinib (sufficient to provide a DP weight of 16.67 g, i.e., 2.5 g for Batch Nos. 8, 9, 16, and 17, and 3.0 g for Batch No. 10) 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 either 3,000 RPM (batch numbers 8, 9, 10, and 16) or 2,000 RPM (batch number 17). The CP with 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L / min (CP:DP = 80:1).

[0071] 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.

[0072] Batch No. 8 was 32 μm (D 50 ), a drug loading of 51.7 wt%, and a molecular weight of 12.0 kDa. The microspheres contained 0.4% residual DCM. Batch No. 9 had an average particle size of 29 μm (D 50 ), a drug loading of 51.8 wt%, and a molecular weight of 11.7 kDa. The microspheres contained 0.1% residual DCM. Batch No. 10 had an average particle size of 29 μm (D 50 ), a drug loading of 64.2 wt%, and a molecular weight of 11.7 kDa. The microspheres contained 0.2% residual DCM. Batch No. 16 had an average particle size of 40 μm (D 50 ), a drug loading of 48.9 wt%, and a molecular weight of 30.1 kDa. The microspheres contained 0.6% residual DCM. Batch No. 17 had an average particle size of 49 μm (D 50 ), a drug loading of 50.2 wt%, and a molecular weight of 12.4 kDa. The microspheres contained 0.8% residual DCM. The parameters and results are tabulated in Table 5. [Table 5]

[0073] FIG. 6 is a graph showing the in vitro cumulative ibrutinib release over time from ibrutinib-encapsulated polymer microspheres of Group E.

[0074] In use, the microspheres may be suspended in a diluent for administration (injection). The diluent may generally include a thickening agent, a tonicity agent, and a wetting agent. The thickening agent 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 BTK inhibitor content, if there are 10 polymeric microspheres and two or more of the polymeric microspheres have the particular BTK inhibitor 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: (i) ibrutinib, (ii) a biodegradable polymer; and Including, each polymeric microsphere comprises a drug loading of ibrutinib of greater than 20% by weight of said polymeric microsphere; The polymer microspheres have a diameter of 110 μm (D ５０ ) an average particle size of less than 1000 μm.

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

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

4. The microsphere formulation of claim 1 , wherein the biodegradable polymer is acid terminated.

5. The microsphere formulation of claim 1 , wherein the biodegradable polymer is ester-terminated.

6. 2. The microsphere formulation of claim 1, wherein the biodegradable polymer has an intrinsic viscosity of about 0.2 dL / g to 0.6 dL / g.

7. 2. The microsphere formulation of claim 1, wherein the biodegradable polymer has an intrinsic viscosity of about 0.1 dL / g to 0.4 dL / g.

8. 2. The microsphere formulation of claim 1, wherein each polymer microsphere comprises a drug loading of ibrutinib of greater than 40% by weight of the polymer microsphere.

9. The polymer microspheres have a diameter of about 30 μm (D ５０ ) ~ approx. 60 μm (D ５０ 2. The microsphere formulation of claim 1 having a particle size of about 1000 nm to about 1000 nm.

10. 2. The microsphere formulation of claim 1, wherein about 75%-100% of the ibrutinib is released over a period of about 7-28 days after injection into a subject, but about 20% or less of the ibrutinib is released within about 24 hours after injection into a subject.

11. A pharmaceutical composition comprising a microsphere formulation according to any one of claims 1 to 10.

12. 12. The microsphere formulation of claim 11 for use in the treatment of B-cell malignancies.

13. 1. A method for producing a microsphere formulation, comprising: (i) contacting ibrutinib with a biodegradable polymer comprising poly(D,L-lactide-co-glycolide) having a comonomer ratio of about 50:50 to 85:15 and an intrinsic viscosity of about 0.2 dL / g to 0.6 dL / g or poly(D,L-lactide) having an intrinsic viscosity of about 0.1 dL / g to 0.4 dL / g in the presence of an organic solvent system 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 essentially free of organic solvent; (iv) subjecting the substantially organic solvent-free microsphere formulation to a drying process; The above method.

14. A kit comprising: Each polymeric microsphere comprises: (i) ibrutinib, (ii) a biodegradable polymer comprising poly(D,L-lactide-co-glycolide) having an intrinsic viscosity of about 0.2 dL / g to 0.6 dL / g or poly(D,L-lactide) having an intrinsic viscosity of about 0.1 dL / g to 0.4 dL / g; Including, Each polymeric microsphere comprises a drug loading of ibrutinib of greater than 40% by weight of said polymeric microsphere, said polymeric microsphere having a diameter of about 30 μm (D ５０ ) ~ approx. 60 μm (D ５０ The above kit, wherein the average particle size of the particles is 100%.

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