WO2022187822A1 - Formulations de microsphères comprenant des inhibiteurs de btk et leurs procédés de fabrication et d'utilisation - Google Patents

Formulations de microsphères comprenant des inhibiteurs de btk et leurs procédés de fabrication et d'utilisation Download PDF

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WO2022187822A1
WO2022187822A1 PCT/US2022/070910 US2022070910W WO2022187822A1 WO 2022187822 A1 WO2022187822 A1 WO 2022187822A1 US 2022070910 W US2022070910 W US 2022070910W WO 2022187822 A1 WO2022187822 A1 WO 2022187822A1
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polymer
microsphere
lactide
microsphere formulation
btk inhibitor
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PCT/US2022/070910
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English (en)
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Michaela GILTNER
Rachel GALASKA
Tracy RICHEY
Mark Smith
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Oakwood Laboratories, Llc
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Priority to JP2023552544A priority Critical patent/JP2024508863A/ja
Priority to CA3210001A priority patent/CA3210001A1/fr
Priority to EP22764259.2A priority patent/EP4301345A1/fr
Priority to AU2022228489A priority patent/AU2022228489A1/en
Priority to KR1020237033397A priority patent/KR20230154222A/ko
Priority to MX2023010196A priority patent/MX2023010196A/es
Priority to CN202280014052.7A priority patent/CN116916893A/zh
Publication of WO2022187822A1 publication Critical patent/WO2022187822A1/fr
Priority to IL304654A priority patent/IL304654A/en
Priority to US18/459,831 priority patent/US20230404922A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/08—Simple coacervation, i.e. addition of highly hydrophilic material
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • B-cells account for up to 25% of all cells in some cancers.
  • BTK Bruton's Tyrosine Kinase
  • BTK inhibitors cause detachment of malignant B-cells from cancer sites into blood, which results in cell death.
  • BTK inhibition reduces the proliferation of malignant B-cells and decreases the survival of malignant B-cells.
  • Ibrutinib (chemical formula C25H24N6O2; CAS Number 936563-96-1), characterized by the general structure: is a BTK inhibitor. Ibrutinib, alone and in combination with other drugs, has been approved by the U.S. Food and Drug Administration (the “FDA”) 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.
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • Waldenstrom macroglobulinemia
  • SLL small lymphocytic lymphoma
  • relapsed/refractory marginal zone lymphoma in patients who require system
  • acalabrutinib approved for treatment of relapsed MCL
  • zanubrutinib approved for treatment of MCL
  • 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.
  • All of the currently approved BTK inhibitors are oral formulations.
  • Oral formulations may have several disadvantages.
  • oral formulations may require closely timed, successive dosages under the supervision of a physician.
  • some BTK inhibitors may have low and variable oral bioavailability.
  • ibrutinib may have an oral bioavailability of only 2.9% in the fasted state, but this can vary from patient to patient.
  • a need exists for a high-bioavailability formulation comprising a BTK inhibitor that may be administered by a long-acting, sustained release injection, without the need for patients to administer closely timed, successive dosages under supervision from their physician.
  • Microsphere formulations comprising a BTK inhibitor are provided.
  • the microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso).
  • the microsphere formulations are characterized in that they have a low initial burst release, that is, not more than 50% of the BTK inhibitor is released within about 4 hours of injection into a subject.
  • the microsphere formulations may be made by a method, the method comprising: (A) mixing: (i) the 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.
  • a method for treating cancer including a B-cell malignancy.
  • the method may comprise administering by intramuscular or subcutaneous injection to a patient in need thereof a microsphere formulation made according to the methods described herein.
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso), in the manufacture of a medicament for the treatment of cancer, including a B-cell malignancy.
  • Dso average particle size of less than 110 pm
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso), is provided for use as a medicament for the treatment of cancer, including a B-cell malignancy.
  • kits comprising polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso).
  • Figure 1 is a schematic depicting a method for making BTK inhibitor-encapsulated polymer microspheres.
  • Figure 2 is a graph showing in vitro cumulative ibrutinib release over time from ibrutinib-encapsulating polymer microspheres comprising a 50:50 poly (D,L-lactide-co-glycolide) (“PLGA”) as the biodegradable polymer.
  • PLGA poly (D,L-lactide-co-glycolide)
  • Figure 3 is a graph showing in vitro cumulative ibrutinib release over time from ibrutinib-encapsulating polymer microspheres comprising a 75:25 PLGA with an inherent viscosity (“IV”) of 0.26 dL/g as the biodegradable polymer.
  • Figure 4 is a graph showing in vitro cumulative ibrutinib release over time from ibrutinib-encapsulating polymer microspheres comprising a 75:25 PLGA with IVs between 0.41 dL/g and 0.70 dL/g as the biodegradable polymer.
  • Figure 5 is a graph showing in vitro cumulative ibrutinib release over time from ibrutinib-encapsulating polymer microspheres comprising an 85:15 PLGA as the biodegradable polymer.
  • Figure 6 is a graph showing in vitro cumulative ibrutinib release over time from ibrutinib-encapsulating polymer microspheres comprising a poly(D,L-lactide) (“PL A”) as the biodegradable polymer.
  • PL A poly(D,L-lactide)
  • Microsphere formulations comprising a BTK inhibitor are provided.
  • the microsphere formulations comprise polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso).
  • the microsphere formulations are characterized in that they have a low initial burst release, that is, not more than 20% of the BTK inhibitor is released within about 24 hours of injection into a subject.
  • the microsphere formulations may be made by a method, the method comprising: (A) mixing: (i) the 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.
  • 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 combinations thereof.
  • the composition consists essentially of ibrutinib.
  • the ibrutinib is supplied by ScinoPharm or MSN.
  • the ibrutinib is hydrophobic.
  • the ibrutinib is supplied as a free base.
  • the ibrutinib is supplied as a pharmaceutically acceptable salt.
  • the ibrutinib is characterized by an aqueous solubility of ⁇ 2.5 mg/g.
  • the ibrutinib is characterized by a solubility in dichloromethane (“DCM”) of >300 mg/g.
  • DCM dichloromethane
  • the ibrutinib is characterized by a pKa of about 3.74.
  • the BTK inhibitor may be in various polymorphic forms.
  • Polymorphic forms may include hemihydrates, monohydrates, dihydrates, and other polymorphic forms as known in the art.
  • Salts may include hydrochloride, sulfate, acetate, phosphate, diphosphate, chloride, maleate, citrate, mesylate, nitrate, tartrate, gluconate, or other salts as known in the art.
  • the BTK inhibitor is in an amorphous form.
  • a complex salt may be used to decrease solubility, such as, for example, palmitate, benzoic acid, tosylic acid, camphor-sulfonic acid, or other salt complexes as one of skill in the art can readily envision.
  • the dispersed phase may include a biodegradable polymer, such as a PLGA or a PLA, although it is contemplated that other suitable biodegradable polymers may be used.
  • the biodegradable polymer may be hydrophobic or hydrophilic.
  • the biodegradable polymer comprises a PLGA.
  • the PLGA comprises a lactide:glycolide ratio of 50:50, 75:25, or 85:15.
  • the PLGA is acid-terminated.
  • the PLGA is ester-terminated.
  • the PLGA has an IV of from about 0.1 dL/g to about 0.8 dL/g, including from about 0.1 dL/g to about 0.3 dL/g, from about 0.16 dL/g to about 0.24 dL/g, from about 0.2 dL/g to about 0.4 dL/g, from about 0.4 dL/g to about 0.6 dL/g, from 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 those IV values.
  • the biodegradable polymer is a PLA.
  • the PLA is acid- terminated.
  • the PLA is ester-terminated.
  • the PLA has an IV of between about 0.1 dL/g and 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 those IV values.
  • the biodegradable polymer is mixed with the BTK inhibitor to form microspheres, which are injectable and formulated to release the BTK inhibitor to the patient over the intended duration of release.
  • the biodegradable polymer is used to encapsulate the BTK inhibitor into microspheres, which are injectable and formulated to release the BTK inhibitor to the patient over the intended duration of release, via a controlled rate of release from the spheres, or release from different spheres at different times based upon particle size, thickness of the biodegradable polymer encapsulating the BTK inhibitor, molecular weight of the biodegradable polymer, polymer composition such as co-monomer ratio, end-cap, and drug load, or combinations of such release-affecting factors.
  • the dispersed phase comprises a primary solvent.
  • the primary solvent comprises DCM.
  • the dispersed phase may also include up to about 50% by weight of a co-solvent capable of optimizing the solubility of the BTK inhibitor in the primary solvent.
  • the co-solvent may be benzyl alcohol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, acetonitrile, ethanol, N-methyl pyrrolidone, ethyl acetate, or any other solvent that increases the solubility of the BTK inhibitor in the dispersed phase containing DCM.
  • 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. Larger scale batches may require higher flow rates.
  • 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 value or range between any two of those temperature values.
  • Homogenizer a homogenizer
  • 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 or a static mixer.
  • the homogenizer runs 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 those RPM values.
  • RPM revolutions per minute
  • the drug load of each polymer microsphere in a drug to polymer ratio may be greater than 40 wt/wt%, including from about 40 wt/wt% to about 70 wt/wt%, from about 45 wt/wt% to about 70 wt/wt%, from about 45 wt/wt% to about 65 wt/wt%, from 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 loads.
  • the drug load may be as low as 20 wt/wt%.
  • the polymer microspheres may have an average particle size of less than 110 pm (D50), including between about 30 pm (D50) and about 60 pm (D50), between about 30 pm
  • average particle sizes may be as large as 150-200 pm.
  • the microsphere formulations are characterized in that they have an in vivo duration of release of less than about 7 days in humans. In one aspect, the microsphere formulations are characterized in that they have an in vivo duration of release of between about 7 days to about 14 days in humans. In one aspect, the microsphere formulations are characterized in that they have an in vivo duration of release of between about 14 days to about 28 days in humans. In one aspect, the microsphere formulations are characterized in that they have an in vivo duration of release of about 28 days in humans. In one aspect, the microsphere formulations are characterized in that they have an in vivo duration of release of greater than about 28 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 BTK inhibitor is released within ⁇ 7, 7-14, 14-28, or >28 days (as described in the preceding paragraph) of injection into a subject.
  • the microsphere formulations are characterized in that about 75% to 100% of the BTK inhibitor is released over the designated period after 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 BTK inhibitor is released within about 24 hours of injection into a subject.
  • a further aspect includes a sustained release injectable formulation of ibrutinib that is pharmacologically comparable 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.
  • Another aspect includes a method of treating a human patient for MCL, CLL/SLL, and other diseases or conditions that may be treated by the BTK inhibitors.
  • the method may comprise providing an injectable form of ibrutinib in a dosage strength that is pharmacologically comparable to 70 mg, 140 mg, 280 mg, 420 mg, and 560 mg per day orally, the injectable form with a duration of continuous release such that patient compliance is assured, the medical consequences of missing a dose or doses are avoided, and the pharmacokinetic profile is improved as compared with the oral dosage form.
  • Possible conditions that may be treated using the microsphere formulations comprising a BTK inhibitor include cancer, including B-cell malignancies, including MCL, CCL, and SLL.
  • B-cell malignancy may be treated using the microsphere formulations comprising a BTK inhibitor, wherein the microsphere formulations are administered about every ⁇ 7, 7-14, 14- 28, or >28 days.
  • a method for treating cancer including a B-cell malignancy.
  • the method may comprise administering by intramuscular or subcutaneous injection to a patient in need thereof a microsphere formulation made according to the methods described herein.
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso), in the manufacture of a medicament for the treatment of cancer, including a B-cell malignancy.
  • Dso average particle size of less than 110 pm
  • a microsphere formulation comprising polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso), is provided for use as a medicament for the treatment of cancer, including a B-cell malignancy.
  • kits comprising polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the BTK inhibitor of greater than 40% by weight of the polymer microsphere, and wherein the polymer microspheres have an average particle size of less than 110 pm (Dso).
  • Example 1 General preparation of polymer microspheres comprising a BTK inhibitor
  • 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 the addition of the BTK inhibitor with mixing until completely dissolved.
  • the DP 10 is filtered using a 0.2 pm sterilizing PTFE or PVDF membrane filter (such as EMFLON, commercially available from Pall or SartoriousAG) and pumped into a homogenizer 30 at a defined flow rate.
  • a continuous phase (“CP”) 20 comprising water, surfactant, and, optionally, a 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. See, e.g., U.S. Patent No. 9,017,715, which is incorporated by reference herein in its entirety.
  • SRV solvent removal vessel
  • 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.
  • Example 2 Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising a 50:50 PLGA - Batch Nos. 1 and 2 (“Group A”)
  • the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,000 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.
  • Batch No. 1 had an average particle size of 36 pm (Dso), a drug load of 47.6 wt%, and a molecular weight of 17.6 kDa.
  • the microspheres contained residual DCM of 3.0%.
  • Batch No. 2 had an average particle size of 44 pm (Dso), a drug load of 47.8 wt%, and a molecular weight of 17.7 kDa.
  • the microspheres contained residual DCM of 3.0%.
  • Table 1 The parameters and results are shown tabularly in Table 1:
  • Figure 2 is a graph showing in vitro cumulative ibrutinib release over time from the Group A ibrutinib-encapsulating polymer microspheres.
  • Example 3 Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising a 75:25 PLGA with a low polymer IV - Batch Nos. 3. 4. 6. 7. and 11 (“Group B”)
  • the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,000 RPM (Batch Nos. 3, 4, 6, and 7) or 2,000 RPM (Batch No. 11).
  • 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.
  • Batch No. 3 had an average particle size of 39 pm (Dso), a drug load of 48.2 wt%, and a molecular weight of 29.4 kDa.
  • the microspheres contained residual DCM of 3.1%.
  • Batch No. 4 had an average particle size of 35 pm (Dso), a drug load of 48.9 wt%, and a molecular weight of 25.5 kDa.
  • the microspheres contained residual DCM of 2.1%.
  • Batch No. 6 had an average particle size of 34 pm (Dso), a drug load of 60.6 wt%, and a molecular weight of 31.0 kDa.
  • the microspheres contained residual DCM of 2.7%.
  • Figure 3 is a graph showing in vitro cumulative ibrutinib release over time from the Group B ibrutinib-encapsulating polymer microspheres.
  • Example 4 Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising a 75:25 PLGA with a high polymer IV - Batch Nos. 5. 12. 13. and 14 (“Group C”)
  • 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.
  • Batch No. 5 had an average particle size of 53 pm (Dso), a drug load of 47.5 wt%, and a molecular weight of 66.4 kDa.
  • the microspheres contained residual DCM of 4.1%.
  • Batch No. 12 had an average particle size of 47 pm (Dso), a drug load of 51.2 wt%, and a molecular weight of 49.8 kDa.
  • the microspheres contained residual DCM of 0.8%.
  • Batch No. 13 had an average particle size of 52 pm (Dso), a drug load of 62.2 wt%, and a molecular weight of 87.7 kDa.
  • the microspheres contained residual DCM of 1.3%.
  • Figure 4 is a graph showing in vitro cumulative ibrutinib release over time from the Group C ibrutinib-encapsulating polymer microspheres.
  • Example 5 Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising an 85:15 PLGA - Batch Nos. 18 and 19 (“Group D”)
  • the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at 3,000 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.
  • Batch No. 18 had an average particle size of 36 pm (Dso), a drug load of 49.8 wt%, and a molecular weight of 22.7 kDa.
  • the microspheres contained residual DCM of 0.5%.
  • Batch No. 19 had an average particle size of 35 pm (Dso), a drug load of 49.2 wt%, and a molecular weight of 25.8 kDa.
  • the microspheres contained residual DCM of 0.3%.
  • Figure 5 is a graph showing in vitro cumulative ibrutinib release over time from the Group D ibrutinib-encapsulating polymer microspheres.
  • Example 6 Preparation of Ibrutinib-Encapsulated Polymer Microspheres Comprising a PLA - Batch Nos. 8 9 10 16 and 17 (“Group E”1
  • the DP was filtered and pumped at a flow rate of 25 mL/min into a Levitronix® BPS-ilOO integrated pump system operating at either 3,000 RPM (Batch Nos. 8, 9, 10, and 16) or 2,000 RPM (Batch No. 17).
  • 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.
  • Batch No. 8 had an average particle size of 32 pm (Dso), a drug load of 51.7 wt%, and a molecular weight of 12.0 kDa.
  • the microspheres contained residual DCM of 0.4%.
  • Batch No. 9 had an average particle size of 29 pm (Dso), a drug load of 51.8 wt%, and a molecular weight of 11.7 kDa.
  • the microspheres contained residual DCM of 0.1%.
  • Batch No. 10 had an average particle size of 29 pm (Dso), a drug load of 64.2 wt%, and a molecular weight of 11.7 kDa.
  • the microspheres contained residual DCM of 0.2%.
  • Figure 6 is a graph showing in vitro cumulative ibrutinib release over time from the Group E ibrutinib-encapsulating polymer microspheres.
  • the microspheres may be suspended in a diluent for administration (injection).
  • the diluent may generally contain a thickening agent, a tonicity agent, and a wetting agent.
  • 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.
  • diluent 290 milliosmole (mOsm), 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 around a physiologically relevant pH by adjusting the buffer content as needed (pH about 7 to about 8).
  • 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 BTK inhibitor content, if there are 10 polymer microspheres, and two or more of the polymer microspheres have the particular BTK inhibitor content, then that subset of two or more polymer microspheres is intended to meet the limitation.

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Abstract

L'invention concerne des formulations de microsphères à libération prolongée comprenant un inhibiteur de BTK. Dans un aspect, les formulations de microsphères sont caractérisées en ce que l'inhibiteur de BTK est libéré in vivo chez les êtres humains sur une période d'environ 7 à environ 28 jours. L'invention porte également sur des procédés de fabrication et d'utilisation de ces formulations.
PCT/US2022/070910 2021-03-03 2022-03-02 Formulations de microsphères comprenant des inhibiteurs de btk et leurs procédés de fabrication et d'utilisation WO2022187822A1 (fr)

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JP2023552544A JP2024508863A (ja) 2021-03-03 2022-03-02 Ｂｔｋ阻害剤を含むミクロスフェア製剤ならびにその製造方法および使用方法
CA3210001A CA3210001A1 (fr) 2021-03-03 2022-03-02 Formulations de microspheres comprenant des inhibiteurs de btk et leurs procedes de fabrication et d'utilisation
EP22764259.2A EP4301345A1 (fr) 2021-03-03 2022-03-02 Formulations de microsphères comprenant des inhibiteurs de btk et leurs procédés de fabrication et d'utilisation
AU2022228489A AU2022228489A1 (en) 2021-03-03 2022-03-02 Microsphere formulations comprising btk inhibitors and methods for making and using the same
KR1020237033397A KR20230154222A (ko) 2021-03-03 2022-03-02 Btk 억제제를 포함하는 마이크로스피어 제제 및 이의 제조 및 사용 방법
MX2023010196A MX2023010196A (es) 2021-03-03 2022-03-02 Formulaciones de microesferas que comprenden inhibidores de btk y metodos para fabricar y usar las mismas.
CN202280014052.7A CN116916893A (zh) 2021-03-03 2022-03-02 包含btk抑制剂的微球制剂及其制备和使用方法
IL304654A IL304654A (en) 2021-03-03 2023-07-23 Nanosphere formulations containing btk inhibitors, methods for their preparation and use
US18/459,831 US20230404922A1 (en) 2021-03-03 2023-09-01 Microsphere formulations comprising btk inhibitors and methods for making and using the same

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160317453A1 (en) * 2013-03-15 2016-11-03 Oakwood Laboratories LLC High drug load buprenorphine microspheres and method of producing same
US20180028537A1 (en) * 2014-08-07 2018-02-01 Pharmacyclics Llc Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160317453A1 (en) * 2013-03-15 2016-11-03 Oakwood Laboratories LLC High drug load buprenorphine microspheres and method of producing same
US20180028537A1 (en) * 2014-08-07 2018-02-01 Pharmacyclics Llc Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M D BLANCO , R L SASTRE, C TEIJÓN, R OLMO, J M TEIJÓN: "5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characterization and drug release.", JOURNAL OF MICROENCAPSULATION, vol. 22, no. 6, September 2005 (2005-09-01), pages 671 - 682, XP009539781, DOI: 10.1080/02652040500161990 *

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