KR20230154222A - Microsphere preparations containing BTK inhibitors and methods for making and using the same - Google Patents

Abstract

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

Description

Microsphere preparations containing BTK inhibitors and methods for making and using the same

Cross-reference to related applications

This application claims priority from U.S. Provisional Patent Application No. 63/156,020, filed March 3, 2021, which is incorporated herein by reference in its entirety.

background technology

B-cells make up up to 25% of all cells in some cancers. By inhibiting the Bruton's Tyrosine Kinase (“BTK”) enzyme, which is involved in B-cell receptor signaling, BTK inhibitors cause malignant B-cells to segregate from the cancer site into the blood, resulting in cell death. BTK inhibition reduces the proliferation of malignant B-cells and reduces the survival of malignant B-cells.

Ibrutinib (formula C ₂₅ H ₂₄ N ₆ O ₂ ; CAS number 936563-96-1), characterized by the following general structure:

Ibrutinib, alone and in combination with other drugs, can be used to treat, among other diseases, mantle cell lymphoma (“MCL”), chronic lymphocytic leukemia (“CLL”), Waldenstrom’s macroglobulin Blood pressure ( 's macroglobulinemia, small lymphocytic lymphoma (“SLL”), relapsed/refractory marginal zone lymphoma in patients requiring systemic therapy and who have received at least one prior anti-CD20-based therapy, and It is approved by the US Food and Drug Administration (“FDA”) for the treatment of graft-versus-host disease.

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 include 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 currently approved BTK inhibitors are oral agents. Oral formulations may have several disadvantages. For example, oral formulations may require closely spaced sequential doses under the supervision of a physician. Additionally, some BTK inhibitors may have low and variable oral bioavailability. For example, ibrutinib may have an oral bioavailability of only 2.9% in the fasting state, but this may vary from patient to patient.

There is a need for highly bioavailability formulations containing BTK inhibitors that can be administered by long-acting sustained release injection without the need for patients to administer closely staggered sequential doses under physician supervision.

outline

Microsphere preparations comprising a BTK inhibitor are provided. The microsphere preparation includes polymeric microspheres, each polymeric microsphere containing (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size. In another aspect, the microsphere formulations are characterized as 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 the subject.

In one aspect, a microsphere formulation can be prepared by a method, which method comprises: (A) (i) a biodegradable polymer; (ii) primary solvent; and (iii) mixing a BTK inhibitor to form a dispersed phase; (B) (i) water; and (ii) mixing a surfactant to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.

In one aspect, a method of treating cancer, including B-cell malignancies, is provided. The method may include administering the microsphere preparation prepared according to the method described herein to a patient in need thereof by intramuscular or subcutaneous injection.

In another aspect, the use of a microsphere preparation comprising polymeric microspheres is disclosed in the manufacture of a medicament for the treatment of cancer, including B-cell malignancies, each polymeric microsphere comprising (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size.

In another aspect, a microsphere preparation is provided comprising polymeric microspheres for use as a medicament for the treatment of cancer, including B-cell malignancies, each polymeric microsphere comprising (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size.

In another aspect, a kit is provided, the kit 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 a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size.

Figure 1 is a schematic diagram showing a method for making BTK inhibitor-encapsulated polymer microspheres.
Figure 2 shows in vitro Ibrutinib over time from Ibrutinib-encapsulated polymer microspheres containing 50:50 poly(D,L-lactide-co-glycolide) ("PLGA") as a biodegradable polymer. This is a graph showing nip cumulative release.
Figure 3 shows the in vitro cumulative release of ibrutinib over time from ibrutinib-encapsulated polymer microspheres containing 75:25 PLGA as a biodegradable polymer with an intrinsic viscosity (“IV”) of 0.26 dL/g. This is a graph that represents
Figure 4 shows the in vitro cumulative release of Ibrutinib over time from Ibrutinib-encapsulated polymer microspheres comprising 75:25 PLGA as a biodegradable polymer with an IV of 0.41 dL/g to 0.70 dL/g. It's a graph.
Figure 5 is a graph showing the in vitro cumulative release of ibrutinib over time from ibrutinib-encapsulated polymer microspheres containing 85:15 PLGA as the biodegradable polymer.
Figure 6 is a graph showing the cumulative release of ibrutinib in vitro over time from ibrutinib-encapsulated polymer microspheres comprising poly(D,L-lactide) ("PLA") as a biodegradable polymer.

details

Microsphere preparations comprising a BTK inhibitor are provided. The microsphere preparation includes polymeric microspheres, each polymeric microsphere containing (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size. In another aspect, the microsphere formulations are characterized in that they have a low initial burst release, i.e., no more than 20% of the BTK inhibitor is released within about 24 hours of injection into the subject.

In one aspect, a microsphere preparation can be prepared by a method, which method comprises (A) (i) a biodegradable polymer; (ii) primary solvent; and (iii) mixing a BTK inhibitor to form a dispersed phase; (B) (i) water; and (ii) mixing a surfactant to form a continuous phase; and (C) combining the dispersed phase with the continuous phase in a homogenizer.

BTK inhibitor

In one aspect, the BTK inhibitor comprises ibrutinib, acalabrutinib, zanubrutinib, evobrutinib, ABBV-105, fenebrutinib, GS-4059, or spebrutinib, or a combination thereof; It consists essentially of, or is selected from the group consisting of.

In one aspect, the composition consists essentially of ibrutinib. In one aspect, ibrutinib is supplied by ScinoPharm or MSN. In one aspect, ibrutinib is hydrophobic. In one aspect, ibrutinib is supplied as the free base. In another aspect, ibrutinib is supplied as a pharmaceutically acceptable salt. In one aspect, ibrutinib is characterized by an aqueous solubility of less than 2.5 mg/g. In one aspect, ibrutinib is characterized by a solubility in dichloromethane (“DCM”) of greater than 300 mg/g. In one aspect, ibrutinib is characterized by a pKa of 3.74.

BTK inhibitors can be in various polymorphic forms. Polymorphic forms may include hemihydrate, monohydrate, dihydrate, and other polymorphic forms known in the art. Salts may include hydrochloride, sulfate, acetate, phosphate, diphosphate, chloride, maleate, citrate, mesylate, nitrate, tartrate, gluconate, or other salts known in the art. In one aspect, the BTK inhibitor is in an amorphous form.

In aspects where the BTK inhibitor comprises ibrutinib or another BTK inhibitor with similar solubility properties, for example, palmitate, benzoic acid, tosylic acid, camphor-sulfonic acid, or as readily envisioned by those skilled in the art. Complex salts such as other salt complexes may be used to reduce solubility.

biodegradable polymer

In one aspect, the dispersed phase may include a biodegradable polymer such as PLGA or PLA, although it is contemplated that other suitable biodegradable polymers may be used. Biodegradable polymers can be hydrophobic or hydrophilic.

In some aspects, the biodegradable polymer includes PLGA. In one aspect, the PLGA comprises a lactide:glycolide ratio of 50:50, 75:25, or 85:15. In one aspect, PLGA is acid-terminated. In one aspect, PLGA is ester-terminated. In one aspect, the PLGA has a weight of about 0.1 dL/g to about 0.8 dL/g, such as 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 , an IV of 0.66 dL/g, an IV of 0.7 dL/g, and any value or range between any two of these IV values.

In one aspect, PLGA is a 50:50 lactide:glycolide acid terminated poly(D,L-lactide-co-glycolide), Resomer® 502 H(", manufactured by Evonik, with IV = 0.20) 502 H"). In one aspect, PLGA is an ester terminated poly(D,L-lactide-co-glycolide) of 50:50 lactide:glycolide, Resomer® 502 ("502), manufactured by Evonik, with IV = 0.20. ") includes. In one aspect, PLGA is an acid terminated poly(D,L-lactide-co-glycolide) of 75:25 lactide:glycolide, manufactured by Ashland, Viatel™ DLG 7503 A ( "7503 A"). In one aspect, PLGA is an ester terminated poly(D,L-lactide-co-glycolide) of lactide:glycolide 75:25, manufactured by Ashland, with IV = 0.26, Viatel™ DLG 7503 E( "7503 E"). In one aspect, PLGA is an acid terminated poly(D,L-lactide-co-glycolide) of 75:25 lactide:glycolide, manufactured by Ashland, Viatel™ DLG 7505 A ( "7505 A"). In one aspect, PLGA is an ester terminated poly(D,L-lactide-co-glycolide) of lactide:glycolide 75:25, manufactured by Ashland, with IV = 0.41, Viatel™ DLG 7505 E( "7505 E"). In one aspect, PLGA is an acid terminated poly(D,L-lactide-co-glycolide) of 75:25 lactide:glycolide, manufactured by Ashland, Viatel™ DLG 7507 A ( "7507 A"). In one aspect, PLGA is an ester terminated poly(D,L-lactide-co-glycolide) of lactide:glycolide 75:25, manufactured by Ashland, with IV = 0.66, Viatel™ DLG 7507 E( "7507 E"). In one aspect, PLGA is an acid terminated poly(D,L-lactide-co-glycolide) of 85:15 lactide:glycolide, manufactured by Ashland, Viatel™ DL 8503 A ( "8503 A"). In one aspect, PLGA is an ester terminated poly(D,L-lactide-co-glycolide) of lactide:glycolide 85:15, Viatel™ DL 8503 E( "8503 E").

In some aspects, the biodegradable polymer is PLA. In one aspect, PLA is acid-terminated. In one aspect, PLA is ester-terminated. In one aspect, PLA has an IV of about 0.1 dL/g to about 0.4 dL/g, such as about 0.16 dL/g, about 0.18 dL/g, and about 0.32 dL/g, and any two of these IV values. It has an arbitrary value or range of .

In one aspect, the PLA includes Viatel™ DL 02 A (“DL 02 A”), an acid terminated poly(D,L-lactide), manufactured by Ashland, with IV = 0.16. In one aspect, the PLA includes Viatel™ DL 02 E (“DL 02 E”), an ester terminated poly(L-lactide), manufactured by Ashland, with IV = 0.18. In one aspect, the PLA includes Viatel™ DL 03 A (“DL 03 A”), an acid terminated poly(L-lactide) manufactured by Ashland, with IV = 0.32.

In one aspect, a biodegradable polymer is mixed with a BTK inhibitor to form microspheres, which are injectable and formulated to release the BTK inhibitor to the patient over the intended release period. In another aspect, a biodegradable polymer is used to encapsulate a BTK inhibitor into microspheres, which are injectable and vary in size, such as particle size, thickness of the biodegradable polymer encapsulating the BTK inhibitor, molecular weight of the biodegradable polymer, and comonomer ratio. Release from the spheres, or through controlled rates of release from different spheres at different times, over the intended release period, based on the polymer composition, end-cap, and drug load, or a combination of factors that affect such release. It is formulated to release the BTK inhibitor into the patient over time.

dispersed phase

In one aspect, the dispersed phase includes a primary solvent. In one aspect, the primary solvent includes DCM. The dispersed phase may also include up to about 50% by weight of a cosolvent, which can optimize the solubility of the BTK inhibitor in the primary solvent. In one aspect, the cosolvent increases the solubility of the BTK inhibitor in the disperse phase containing benzyl alcohol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, acetonitrile, ethanol, N-methyl pyrrolidone, ethyl acetate, or DCM. It may be any other solvent. If the microspheres meet the standards set forth in "ICH Harmonized Guideline, Impurities: Guideline for Residual Solvents Q3C(R8), Current Step 4 version dated 22 April 2021," which is incorporated by reference in its entirety “Essentially free” of organic solvents.

Continuous Award

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

In one aspect, a buffering agent may be added to the continuous phase to maintain the pH of the solution between about 7.0 and about 8.0. In one aspect, the buffering agent may be a phosphate buffer or a carbonate buffer. In one aspect, the buffering agent may be a 10 mM phosphate or carbonate buffer solution and may be used to bring about 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. In one aspect, the surfactant component includes polyvinyl alcohol (“PVA”) at a concentration of 0.35% by weight in water.

In some aspects, the dispersed phase flow rate to the homogenizer can be from about 10 mL/min to about 30 mL/min, such as about 20 mL/min and about 25 mL/min. In some aspects, the continuous phase flow rate to the homogenizer can be about 2 L/min. Accordingly, in one aspect, the continuous phase:disperse phase ratio may be from about 66:1 to about 200:1, such as about 100:1 and about 80:1. Larger scale batches may require higher flow rates.

The continuous phase may be provided at room temperature, above or below room temperature. In some aspects, the continuous phase is 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 2 Any value or range between these temperature values may be provided.

homogenizer

For simplicity, and because the methods are equally applicable to either, the phrase "homogenizer" refers to a system or device capable of homogenizing dispersed and continuous phases, or emulsifying dispersed and continuous phases, or both. With this in mind, such systems and devices are known in the art. For example, in one aspect, the homogenizer is an in-line Silverson homogenizer (commercially available from Silverson Machines, Waterside, England), or, e.g., U.S. Patent No. 11,167,256, which is incorporated herein by reference in its entirety. The Levitronix® BPS-i100 integrated pump system used as described in In one aspect, the homogenizer is a membrane emulsifier or static mixer. In one aspect, the homogenizer operates with an impeller speed of about 1,000 to about 4,000 revolutions per minute (RPM), such as about 2,000 RPM, about 3,000 RPM, and any value or range between any two of these RPM values.

drug load

The drug load of each polymer microsphere, expressed as a percent drug to polymer ratio, is greater than 40 wt/wt%, such as from about 40 wt/wt% to about 70 wt/wt%, from 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 two of these drug loadings. It can be any value or range in between.

It is contemplated that in some specific aspects, drug loading may be as low as 20 wt/wt%.

particle size

In one aspect, the polymer microspheres are less than 110 μm (D ₅₀ ), such as about 30 μm (D ₅₀ ) to about 60 μm (D ₅₀ ), about 30 μm (D ₅₀ ) to about 50 μm (D ₅₀ ), About 35 μm (D ₅₀ ) to about 60 μm (D ₅₀ ), about 45 μm (D ₅₀ ) to about 60 μm (D ₅₀ ), about 30 μm (D ₅₀ ), about 35 μm (D ₅₀ ), about 40 μm(D ₅₀ ), about 45 μm(D ₅₀ ), about 50 μm(D ₅₀ ), about 55 μm(D ₅₀ ), about 60 μm(D ₅₀ ), less than about 60 μm(D ₅₀ ), and any It can have an average particle size of any value or range between two of these average particle sizes.

In some specific aspects, it is contemplated that the average particle size may be as large as 150 μm to 200 μm.

extended release

In one aspect, the microsphere formulation is characterized as having an in vivo release period of less than about 7 days in humans. In one aspect, the microsphere formulation is characterized as having an in vivo release period in humans of about 7 days to about 14 days. In one aspect, the microsphere formulation is characterized as having an in vivo release period of about 14 days to about 28 days in humans. In one aspect, the microsphere formulation is characterized as having an in vivo release period of about 28 days in humans. In one aspect, the microsphere formulation is characterized as having an in vivo release period in humans greater than about 28 days.

In one aspect, the microsphere preparation contains at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the BTK inhibitor, and any of the ranges between these values. characterized in that it is released over a period of less than 7 days, 7 to 14 days, 14 to 28 days, or more than 28 days (as described in the previous paragraph) upon injection into the subject. For example, in one aspect, the microsphere formulation is characterized in that about 75% to 100% of the BTK inhibitor is released over a defined period of time following injection into the subject. In another aspect, the microsphere formulations are characterized in that they have a low initial burst release, i.e., no more than about 20% of the BTK inhibitor is released within about 24 hours of injection into the subject.

Additional aspects include oral doses of 70 mg, 140 mg, 280 mg, 420 mg, and 560 mg in sustained-release injectable formulations releasing over approximately 7, 14, 21, or 28 days, and pharmacologically. Includes a similar sustained-release injectable formulation of ibrutinib.

Another aspect includes methods of treating human patients for MCL, CLL/SLL, and other diseases or conditions that can be treated by BTK inhibitors. The method may include providing an injectable form of ibrutinib at dosage strengths that are pharmacologically similar to 70 mg, 140 mg, 280 mg, 420 mg, and 560 mg per day orally, has a duration of continuous release so that patient compliance is ensured, the medical consequences of missing a dose or doses are avoided, and the pharmacokinetic profile is improved compared to oral dosage forms.

therapeutic benefits

Possible conditions that can be treated using microsphere preparations containing BTK inhibitors include cancers, including B-cell malignancies, including MCL, CCL, and SLL. In one aspect, B-cell malignancies can be treated using a microsphere preparation comprising a BTK inhibitor, wherein the microsphere preparation is administered for less than about 7 days, 7 to 14 days, 14 to 28 days, or 28 days. Administered more than once a day.

In one aspect, a method of treating cancer, including B-cell malignancies, is provided. The method may include administering the microsphere preparation prepared according to the method described herein to a patient in need thereof by intramuscular or subcutaneous injection.

In another aspect, the use of a microsphere preparation comprising polymeric microspheres is disclosed in the manufacture of a medicament for the treatment of cancer, including B-cell malignancies, each polymeric microsphere comprising (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size.

In another aspect, a microsphere preparation is provided comprising polymeric microspheres for use as a medicament for the treatment of cancer, including B-cell malignancies, each polymeric microsphere comprising (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size.

In another aspect, a kit is provided, the kit 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 a BTK inhibitor greater than 40% by weight of the polymer microsphere, and the polymer microspheres have an average particle size of less than 110 μm (D ₅₀ ). It has size.

Example

Example 1 - General preparation of polymer microspheres containing BTK inhibitors

Microsphere formulation step. Referring to Figure 1, the dispersed phase ("DP") 10 is formed by dissolving a polymer matrix (e.g., PLGA or PLA polymer) in an organic solvent system (e.g., DMC) followed by mixing the BTK inhibitor until completely dissolved. It is formed by adding DP (10) is filtered using a 0.2 μm sterile PTFE or PVDF membrane filter (e.g., EMFLON, commercially available from Pall or SatoriousAG) and pumped at a defined flow rate into the homogenizer (30). A continuous phase (“CP”) 20 comprising water, surfactant, and optionally a buffer is also pumped at a defined flow rate to the homogenizer 30. The speed of the homogenizer 30 is generally fixed to achieve the desired polymer microsphere size distribution. Representative sequential “upstream” microsphere formation steps are described in U.S. Pat. No. 5,945,126, which is incorporated herein by reference in its entirety.

Microsphere processing steps. The formed or forming microspheres exit the homogenizer (30) and enter the solvent removal conduit (“SRV”) (40). Water may be added to SRV 40 during microsphere formation to minimize solvent levels in the aqueous medium. See, for example, U.S. Patent No. 9,017,715, which is incorporated herein by reference in its entirety. After DP 10 is exhausted, CP 20 and water flow are stopped and the cleaning step is initiated. Solvent removal is achieved using a water wash and a hollow fiber filter (commercially available as HFF from Cytiva) (50). Representative “downstream” microsphere processing steps are described in U.S. Pat. No. 6,270,802, which is incorporated herein by reference in its entirety.

Washed microspheres are recovered and freeze-dried in a freeze dryer (Virtis) to remove any moisture. The resulting microspheres are a free-flowing off-white bulk powder.

Example 2 - Ibrutinib-Encapsulated Polymer Microspheres Comprising 50:50 PLGA - Batch No. Manufacturing of 1 and 2 (“Group A”)

Following the general procedure described in Example 1 and illustrated in Figure 1, 2.5 g of 502 H polymer (Batch No. 1) or 502 polymer (Batch No. 2) (IV = 0.20 dL/g) was mixed with 11.67 g of DCM. DP was formed by dissolving and then adding ibrutinib (2.5 g) with mixing until completely dissolved. DP was filtered and pumped at a flow rate of 25 mL/min with a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM. CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L/min (CP:DP = 80:1).

The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using a water wash and a hollow fiber filter. The bulk suspension was recovered through filtration and lyophilized to obtain a free-flowing powder.

Batch No. 1 had an average particle size of 36 μm (D ₅₀ ), a drug loading of 47.6 wt%, and a molecular weight of 17.6 kDa. 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. Microspheres contained 3.0% residual DCM. Parameters and results are tabulated in Table 1:

Figure 2 is a graph showing in vitro cumulative release of ibrutinib over time from Group A ibrutinib-encapsulated polymer microspheres.

Example 3 - Ibrutinib-Encapsulated Polymer Microspheres Comprising 75:25 PLGA with Low Polymer IV - Batch No. Preparation of 3, 4, 6, 7, and 11 (“Group B”)

Following the general procedure described in Example 1 and illustrated in Figure 1, 2.5 g (Batch No. 3, 4, and 11), 2.0 g (Batch No. 6), or 1.5 g (Batch No. 7) of 7503 Polymer A (Batch No. 3, 6, 7, and 11) or 7502 Polymer E (Batch No. 6) (IV = 0.26 dL/g) was dissolved in 11.67 g of DCM, followed by ibrutinib (16.67 g). Mix sufficient to provide DP weight (i.e., 2.5 g for batches No. 3, 4, and 11; 3.0 g for batch No. 6; and 3.5 g for batch No. 7) until completely dissolved. DP was formed by adding it while doing so. DP was filtered and pumped at a flow rate of 25 mL/min with 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). . CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L/min (CP:DP = 80:1).

The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using a water wash and a hollow fiber filter. The bulk suspension was recovered through filtration and lyophilized to obtain a free-flowing powder.

Batch No. 3 had an average particle size of 39 μm (D ₅₀ ), a drug loading of 48.2% by weight, 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% by weight, and a molecular weight of 25.5 kDa. 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% by weight, 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% by weight, and a molecular weight of 30.1 kDa. Microspheres contained 1.5% residual DCM. Batch No. 11 had an average particle size of 61 μm (D ₅₀ ), a drug loading of 51% by weight, and a molecular weight of 28.9 kDa. Microspheres contained 1.4% residual DCM. Parameters and results are tabulated in Table 2:

Figure 3 is a graph showing in vitro cumulative release of ibrutinib over time from Group B ibrutinib-encapsulated polymer microspheres.

Example 4 - Ibrutinib-Encapsulated Polymer Microspheres Comprising 75:25 PLGA with High Polymer IV - Batch No. Preparation of 5, 12, 13, and 14 (“Group C”)

Following the general procedure described in Example 1 and illustrated in Figure 1, 2.5 g (Batch Nos. 5 and 12) or 2.0 g (Batch No. 13 and 14) of 7505 A polymer (Batch No. 5) (IV = 0.56 dL/g), 7505 E Polymer (Batch No. 12) (IV = 0.41 dL/g), 7507 A Polymer (Batch No. 13) (IV = 0.7 dL/g), or 7507 E Polymer (Batch No. 14) (IV = 0.66 dL/g) was dissolved in 11.67 g of DCM, followed by ibrutinib (sufficient to give a DP weight of 16.67 g, i.e. 2.5 g for batches Nos. 5 and 12; and batches DP was formed by adding 3.0 g for Nos. 13 and 14) with mixing until completely dissolved. DP was filtered and pumped at a flow rate of 25 mL/min with a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM. CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L/min (CP:DP = 80:1).

The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using a water wash and a hollow fiber filter. The bulk suspension was recovered through filtration and lyophilized to obtain a free-flowing powder.

Batch No. 5 had an average particle size of 53 μm (D ₅₀ ), a drug loading of 47.5% by weight, 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% by weight, and a molecular weight of 49.8 kDa. 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% by weight, 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. Parameters and results are tabulated in Table 3:

Figure 4 is a graph showing in vitro cumulative release of ibrutinib over time from Group C ibrutinib-encapsulated polymer microspheres.

Example 5 - Ibrutinib-Encapsulated Polymer Microspheres Comprising 85:15 PLGA - Batch No. Manufacturing of 18 and 19 (“Group D”)

Following the general procedure described in Example 1 and illustrated in Figure 1, 2.5 g of 8503 A polymer (Batch No. 18) (IV = 0.24 dL/g) or 8503 E polymer (Batch No. 19) (IV = 0.25 dL/g) was dissolved in 11.67 g of DCM, followed by the addition of ibrutinib (2.5 g) with mixing until completely dissolved. DP was filtered and pumped at a flow rate of 25 mL/min with a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM. CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L/min (CP:DP = 80:1).

The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using a water wash and a hollow fiber filter. The bulk suspension was recovered through filtration and lyophilized to obtain a free-flowing powder.

Batch No. 18 had an average particle size of 36 μm (D ₅₀ ), a drug loading of 49.8 wt%, and a molecular weight of 22.7 kDa. 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% by weight, and a molecular weight of 25.8 kDa. Microspheres contained 0.3% residual DCM. The parameters and results are tabulated in Table 4:

Figure 5 is a graph showing in vitro cumulative release of ibrutinib over time from Group D ibrutinib-encapsulated polymer microspheres.

Example 6 - Ibrutinib-Encapsulated Polymer Microspheres Comprising PLA - Batch No. Preparation of 8, 9, 10, 16, and 17 (“Group E”)

Following the general procedure described in Example 1 and illustrated in Figure 1, 2.5 g (Batch No. 8, 9, 16 and 17) or 2.0 g (Batch No. 10) of DL 02 A polymer (Batch No. 8 and 17) (IV = 0.16 dL/g), DL 02 E polymer (Batch No. 9 and 10) (IV = 0.18 dL/g), or DL 03 A polymer (Batch No. 16) (IV = 0.32 dL/g ) was dissolved in 11.67 g of DCM, followed by ibrutinib (sufficient to give a DP weight of 16.67 g, i.e., 2.5 g for batches No. 8, 9, 16, and 17; and for batch No. 10). DP was formed by adding 3.0 g) with mixing until completely dissolved. DP was filtered and pumped at a flow rate of 25 mL/min with a Levitronix® BPS-i100 integrated pump system operating at 3,000 RPM (Batch No. 8, 9, 10, and 16) or 2,000 RPM (Batch No. 17). . CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2 L/min (CP:DP = 80:1).

The formed or forming microspheres exited the homogenizer and entered the SRV. Deionized water was added to the SRV. Solvent removal was achieved using a water wash and a hollow fiber filter. The bulk suspension was recovered through filtration and lyophilized to obtain a free-flowing powder.

Batch No. 8 had an average particle size of 32 μm (D ₅₀ ), a drug loading of 51.7 wt%, and a molecular weight of 12.0 kDa. 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. 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% by weight, and a molecular weight of 11.7 kDa. 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% by weight, and a molecular weight of 30.1 kDa. 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% by weight, and a molecular weight of 12.4 kDa. Microspheres contained 0.8% residual DCM. The parameters and results are tabulated in Table 5:

Figure 6 is a graph showing in vitro cumulative release of ibrutinib over time from Group E ibrutinib-encapsulated polymer microspheres.

In use, the microspheres may be suspended in a diluent for administration (injection). Diluents generally may contain thickening agents, isotonic agents, and wetting agents. Thickeners may include carboxymethyl cellulose-sodium (CMC-Na) or other suitable compounds. A suitable viscosity grade and suitable concentration of CMC-Na can be selected such that the diluent has a viscosity of 3 cps or more. Typically, a viscosity of about 10 cps is suitable; Higher viscosity diluents may be desirable for larger microspheres to minimize settling of the microspheres in suspension.

A homogeneous microsphere suspension without particle precipitation will result in a constant delivered dose during drug administration by injection. To bring the isotonicity of the diluent closer to that of biological systems, about 290 milliosmol (mOsm) of solute, such as mannitol, sodium chloride, or any other acceptable salt, can be used. The diluent may also contain buffering salts to maintain the pH of the composition. Typically, the pH is maintained near a physiologically appropriate pH (pH about 7 to about 8) by adjusting the buffer content as needed.

Aspects disclosed herein are not intended to be exclusive or limiting. Those skilled in the art will recognize that other aspects or modifications may be made to this aspect without departing from the spirit or scope of the invention. As generally described herein and illustrated in the drawings, aspects of the present disclosure can be arranged, replaced, combined, separated and designed in a wide variety of configurations, all of which are contemplated herein.

Unless otherwise specified, the terms “a”, “an”, “the”, “one or more” and “at least one” are used interchangeably. The singular indefinite articles (“a”, “an”) and definite articles (“the”) include their plural forms. Recitation of a range of numbers by endpoints includes all numbers included 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 non-limiting. The phrase “consisting essentially of” allows a composition or method to include additional ingredients and/or steps only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method. It means there is. The phrase “selected from a group consisting of” is meant to include mixtures of the listed groups.

When the term “each” is mentioned, it is not intended to mean “each and every without exception.” For example, if you are referring to a microsphere preparation comprising polymer microspheres and say "each polymer microsphere" has a specific BTK inhibitor content, then there are 10 polymer microspheres and at least 2 polymer microspheres have a specific BTK inhibitor content. It is intended that a subset of two or more polymer microspheres will meet the limits, provided they have an inhibitor content.

The term "about" related to a number is simply abbreviated and is intended to include ±10% of the number. This applies regardless of whether “about” modifies an independent number or a number at one or both ends of a range of numbers. That is, “about 10” means 9 to 11. Likewise, “about 10 to about 20” considers 9 to 22 and 11 to 18. If the term “about” is absent, the exact number is intended. In other words, “10” means 10.

Claims (24)

A microsphere preparation comprising polymeric microspheres, comprising:
Each polymer microsphere is
(i) BTK inhibitor; and
(ii) biodegradable polymers
Including,
Each polymer microsphere comprises a drug load of a BTK inhibitor greater than 40% by weight of the polymer microsphere,
Microsphere preparation, wherein the polymeric microspheres have an average particle size of less than 110 μm (D ₅₀ ). The microsphere formulation of claim 1 , wherein the BTK inhibitor comprises ibrutinib. 3. Microsphere preparation according to claim 1 or 2, wherein the biodegradable polymer comprises poly(D,L-lactide-co-glycolide). 4. Microspheres according to any one of claims 1 to 3, wherein the biodegradable polymer comprises poly(D,L-lactide-co-glycolide) with a lactide:glycolide ratio of 50:50. Jeje. 4. Microspheres according to any one of claims 1 to 3, wherein the biodegradable polymer comprises poly(D,L-lactide-co-glycolide) with a lactide:glycolide ratio of 75:25. Jeje. 4. Microspheres according to any one of claims 1 to 3, wherein the biodegradable polymer comprises poly(D,L-lactide-co-glycolide) with a lactide:glycolide ratio of 85:15. Jeje. 3. Microsphere preparation according to claim 1 or 2, wherein the biodegradable polymer comprises poly(D,L-lactide). 8. The microsphere preparation according to any one of claims 1 to 7, wherein the biodegradable polymer is acid-terminated. 8. The microsphere preparation according to any one of claims 1 to 7, wherein the biodegradable polymer is ester-terminated. 10. The microsphere formulation of any one of claims 1-6, 8, or 9, wherein the biodegradable polymer has an intrinsic viscosity of about 0.2 dL/g to 0.6 dL/g. 10. The microsphere formulation of claim 1, 2, 7, 8, or 9, wherein the biodegradable polymer has an intrinsic viscosity of about 0.1 dL/g to 0.4 dL/g. . 12. The microsphere preparation of any one of claims 1-11, wherein each polymer microsphere comprises a drug load of a BTK inhibitor from about 45% to about 65% by weight of the polymer microsphere. 13. The microsphere preparation of any one of claims 1 to 12, wherein the polymeric microspheres have an average particle size of about 30 μm (D ₅₀ ) to about 60 μm (D ₅₀ ). The method of any one of claims 1 to 13, wherein about 75% to 100% of the BTK inhibitor is released over a period of about 7 to 28 days after injection into the subject, but no more than about 20% of the BTK inhibitor is released into the subject. A microsphere formulation, characterized in that it is released within about 24 hours of injection into the body. A pharmaceutical composition comprising the microsphere preparation of any one of claims 1 to 14. 15. Microsphere preparation according to any one of claims 1 to 14, for use in the treatment of B-cell malignancies. A method of preparing a microsphere preparation, the method comprising:
(i) the BTK inhibitor is mixed with poly(D,L-lactide-co) 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 in the presence of an organic solvent system. forming a dispersed phase by contacting it with a biodegradable polymer containing -glycolide);
(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 preparation that is essentially free of organic solvent; and
(iv) subjecting the microsphere preparation substantially free of organic solvent to a drying process.
Method, including. 18. The method of claim 17, wherein the surfactant comprises polyvinyl alcohol. 19. The method of claim 17 or 18, wherein the surfactant comprises polyvinyl alcohol and the polyvinyl alcohol concentration in the aqueous phase prior to combination is about 0.35% by weight. A method of preparing a microsphere preparation, the method comprising:
(i) contacting the BTK inhibitor with a biodegradable polymer comprising 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 preparation that is essentially free of organic solvent; and
(iv) subjecting the microsphere preparation substantially free of organic solvent to a drying process.
Method, including. 21. The method of claim 20, wherein the surfactant comprises polyvinyl alcohol. 22. The method of claim 20 or 21, wherein the surfactant comprises polyvinyl alcohol and the polyvinyl alcohol concentration in the aqueous phase prior to combination is about 0.35% by weight. A kit comprising polymer microspheres,
Each polymer microsphere is
(i) ibrutinib; and
(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.
Including,
Each polymer microsphere comprises a drug load of ibrutinib from about 45% to about 65% by weight of the polymer microsphere, and the polymer microspheres are about 30 μm (D ₅₀ ) to about 60 μm (D ₅₀ ). Kit, with average particle size. A method for treating a B-cell malignancy, the method comprising:
administering the microsphere formulation to the subject by intramuscular or subcutaneous injection on a dosing schedule of about every 7 days to about every 28 days,
The microsphere preparation is
(i) ibrutinib; and
(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.
Including,
Each polymer microsphere comprises a drug load of ibrutinib from about 45% to about 65% by weight of the polymer microsphere, and the polymer microspheres are about 30 μm (D ₅₀ ) to about 60 μm (D ₅₀ ). Method having an average particle size.