CN116916893A

CN116916893A - Microsphere formulations comprising BTK inhibitors and methods of making and using the same

Info

Publication number: CN116916893A
Application number: CN202280014052.7A
Authority: CN
Inventors: 米凯拉·吉尔特纳; 瑞秋·加拉斯卡; 特雷西·里奇; 马克·史密斯
Original assignee: Oakwood Laboratories LLC
Current assignee: Oakwood Laboratories LLC
Priority date: 2021-03-03
Filing date: 2022-03-02
Publication date: 2023-10-20
Also published as: WO2022187822A1; JP2024508863A; AU2022228489A1; IL304654A; EP4301345A1; KR20230154222A; CA3210001A1

Abstract

Extended release microsphere formulations comprising a BTK inhibitor are provided. In one aspect, the microsphere formulation is characterized by release of the BTTK inhibitor in humans for a period of about 7 days to about 28 days. Methods of making the formulations and methods of using the formulations are also provided.

Description

Microsphere formulations comprising BTK inhibitors and methods of making and using the same

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application No. 63156020 filed 3/2021, which is incorporated herein by reference in its entirety.

Background

In some cancers, B cells account for up to 25% of all cells. BTK inhibitors cause malignant B cells to shed from the cancer site into the blood by inhibiting bruton's tyrosine kinase ("BTK") involved in B cell receptor signaling, leading to cell death. Inhibition of BTK reduces proliferation of malignant B cells and reduces survival of malignant B-cells.

Ibrutinib (formula C) ₂₅ H ₂₄ N ₆ O ₂ The method comprises the steps of carrying out a first treatment on the surface of the CAS number 936563-96-1), characterized by the following general structure:

is a BTK inhibitor. Ibrutinib has been approved by the U.S. food and drug administration ("FDA") for the treatment of mantle cell lymphoma ("MCL"), chronic lymphocytic leukemia ("CLL"), waldenstrom's macroglobulinemia, small lymphocytic lymphoma ("SLL"), recurrent/refractory marginal zone lymphoma in patients who require systemic treatment and who have received at least one previous anti-CD 20 treatment, and graft versus host disease, among other diseases.

Two other BTK inhibitors have been approved by the united states food and drug administration: acartinib (approved for treatment of recurrent MCL) and zebutinib (approved for treatment of MCL). Several other drugs that inhibit BTK are undergoing clinical trials, including the treatment of evobutinib (evobertinib) for multiple sclerosis; ABBV-105 for systemic lupus erythematosus; non-nilotinib (fenebutinib) for use in rheumatoid arthritis, systemic lupus erythematosus and chronic idiopathic urticaria; GS-4059 for non-Hodgkin's lymphoma and/or CLL; sipidinib (Spebutinib) (AVL-292, CC-292); and HM71224 for autoimmune diseases.

All BTK inhibitors currently approved are oral formulations. Oral formulations may have several drawbacks. For example, oral formulations may require closely timed, continuous administration under the supervision of a physician. Furthermore, some BTK inhibitors may have low variable oral bioavailability. For example, ibrutinib may have an oral bioavailability of only 2.9% in the fasted state, but this may vary from patient to patient.

There is a need for a highly bioavailable formulation containing a BTK inhibitor that can be administered by long-acting sustained release injection without requiring the patient to administer the formulation continuously and precisely at regular time under the supervision of their physician.

Disclosure of Invention

Microsphere formulations comprising a BTK inhibitor are provided. The microsphere formulation comprises polymeric microspheres, each polymeric microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor of the drug loading, and wherein the polymeric microsphere has a molecular weight of less than 110 μm (D ₅₀ ) Is a particle size of the particles. In another aspect, microsphere formulations are characterized in that they have a low initial burst, i.e., release no more than 50% of the BTK inhibitor within about 4 hours after injection into a subject.

In one aspect, the microsphere formulation may be prepared by a method comprising: (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.

In one aspect, a method for treating cancer including a B cell malignancy is provided. The method may comprise administering to a patient in need thereof a microsphere formulation prepared according to the methods described herein by intramuscular or subcutaneous injection.

In another aspect, there is disclosed the use of a microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor of the drug loading, and wherein the polymeric microsphere has a molecular weight of less than 110 μm (D ₅₀ ) Is a particle size of the particles.

In another aspect, there is provided a microsphere formulation comprising polymeric microspheres, each polymeric microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor of the drug loading, and wherein the polymeric microsphere has a molecular weight of less than 110 μm (D ₅₀ ) Is a particle size of the particles.

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, wherein each polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor loaded, and wherein the polymeric microsphere has a loading of less than 110 μm (D ₅₀ ) Is a particle size of the particles.

Brief description of the drawings

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

Fig. 2 is a graph showing the cumulative release of ibrutinib in vitro over time from polymeric microspheres encapsulating ibrutinib, the polymeric microspheres comprising 50:50 poly (D, L-lactide-co-glycolide) ("PLGA") as biodegradable polymer.

FIG. 3 is a graph showing the cumulative release of ibrutinib in vitro over time from polymeric microspheres encapsulating ibrutinib comprising PLGA as a biodegradable polymer having an inherent viscosity ("IV") of 75:25 of 0.26 dL/g.

FIG. 4 is a graph showing the cumulative release of ibrutinib in vitro over time from polymeric microspheres encapsulating ibrutinib comprising PLGA having an IV of between 0.41dL/g and 0.70dL/g at 75:25 as biodegradable polymer.

Fig. 5 is a graph showing the cumulative release of ibrutinib in vitro over time from polymeric microspheres encapsulating ibrutinib, the polymeric microspheres comprising 85:15 PLGA as biodegradable polymer.

Fig. 6 is a graph showing the cumulative release of ibrutinib in vitro over time from polymeric microspheres encapsulating ibrutinib, the polymeric microspheres comprising poly (D, L-lactide) ("PLA") as biodegradable polymer.

Detailed Description

Microsphere formulations comprising a BTK inhibitor are provided. The microsphere formulation comprises polymeric microspheres, each polymeric microsphere comprising: (i) a BTK inhibitor; and (ii) a biodegradable polymer, wherein each polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor loaded, and wherein the polymeric microsphere has a loading of less than 110 μm (D ₅₀ ) Is a particle size of the particles. In another aspect, microsphere formulations are characterized in that they have a low initial burst, i.e., release no more than 20% of the BTK inhibitor within about 24 hours after injection into a subject.

BTK inhibitors

In one aspect, the BTK inhibitor is selected from the group comprising (consisting essentially of or consisting of): ibrutinib, acartinib, zebutinib, ibrutinib Wo Buti, ABBV-105, feibrutinib, GS-4059, or sapibutinib, or combinations thereof.

In one aspect, the composition consists essentially of ibrutinib. In one aspect, ibrutinib is provided 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 a solubility in water of <2.5mg/g. In one aspect, ibrutinib is characterized by a solubility in Dichloromethane (DCM) of >300mg/g. In one aspect, ibrutinib is characterized by a pKa of about 3.74.

BTK inhibitors may be in different polymorphs. Polymorphs may include hemihydrate, monohydrate, dihydrate, and other polymorphs 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 amorphous.

In one aspect where the BTK inhibitor comprises ibrutinib or another BTK inhibitor having similar solubility characteristics, a complex salt may be used to reduce solubility, such as, for example, palmitate, benzoate, toluene sulfonic acid, camphorsulfonic acid, or other salt complexes as would be readily appreciated by one of skill in the art.

Biodegradable polymers

In one aspect, the dispersed phase may comprise a biodegradable polymer, such as PLGA or PLA, although other suitable biodegradable polymers are contemplated. The biodegradable polymer may be hydrophobic or hydrophilic.

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

In one aspect, the PLGA comprises a polymer made by Evonik502H, lactide: glycolide is a 50:50 acid-capped poly (D, L-lactide-co-glycolide), iv=0.20 ("502H"). In one aspect, the PLGA comprises a polymer manufactured by EvonikIs->502, lactide: glycolide is a 50:50 ester-capped poly (D, L-lactide-co-glycolide), iv=0.20 ("502"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DLG 7503A, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.26 ("7503A"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DLG 7503E, lactide: glycolide is a 75:25 ester-capped poly (D, L-lactide-co-glycolide), iv=0.26 ("7503E"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DLG 7505A, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.56 ("7505A"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DLG 7505E, lactide: glycolide is a 75:25 ester-capped poly (D, L-lactide-co-glycolide), iv=0.41 ("7505E"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DLG 7507A, lactide: glycolide is a 75:25 acid-capped poly (D, L-lactide-co-glycolide), iv=0.70 ("7507A"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DLG 7507E, lactide: glycolide is a 75:25 ester-terminated poly (D, L-lactide-co-glycolide), iv=0.66 ("7507E"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DL 8503A, lactide: glycolide is an 85:15 acid-terminated poly (D, L-lactide-co-glycolide), iv=0.24 ("8503A"). In one aspect, the PLGA comprises Viatel manufactured by Ashland ^TM DL 8503E, lactide: glycolide is an 85:15 ester-terminated poly (D, L-lactide-co-glycolide), iv=0.25 ("8503E").

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

In one aspect, the PLA comprises a Viatel manufactured by Ashland ^TM DL 02A, acid-capped poly (D, L-lactide), iv=0.16 ("DL 02A"). In one aspect, the PLA comprises a Viatel manufactured by Ashland ^TM DL 02E, ester-capped poly (L-lactide), iv=0.18 ("DL 02E"). In one aspect, the PLA comprises a Viatel manufactured by Ashland ^TM DL 03A, acid-capped poly (L-lactide), iv=0.32 ("DL 03A").

In one aspect, the biodegradable polymer is mixed with the BTK inhibitor to form microspheres that are injectable and formulated to release the BTK inhibitor to the patient over a predetermined release duration. In another aspect, the biodegradable polymer is used to encapsulate the BTK inhibitor into microspheres that are injectable and formulated to release the BTK inhibitor to a patient through a controlled release rate from the sphere over a predetermined release duration, or from different spheres at different times depending on particle size, thickness of the biodegradable polymer encapsulating the BTK inhibitor, molecular weight of the biodegradable polymer, polymer composition (such as comonomer ratio, end cap and drug loading, etc.), or a combination of these release influencing factors.

Disperse phase

In one aspect, the dispersed phase comprises a primary solvent. In one aspect, the primary solvent comprises DCM. The dispersed phase may also contain up to about 50 wt% of a co-solvent that is capable of optimizing the solubility of the BTK inhibitor in the primary solvent. In one aspect, 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. If the microspheres meet the ICH guidelines, impurities: residual solvent guidelines Q3C (R8), current step 4 version, 2021, month 4, 22 ", the guidelines being incorporated herein by reference in their entirety, are" substantially free "of organic solvents.

Continuous phase

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

In one aspect, a buffer may be added to the continuous phase to maintain the pH of the solution at about 7.0 to about 8.0. In one aspect, the buffer may be a phosphate buffer or a carbonate buffer. In one aspect, the buffer may be a 10mM phosphate or carbonate buffer solution and may be used to generate and maintain a system pH level of about 7.6.

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

In some aspects, the flow rate of the dispersed phase to the homogenizer may be from about 10mL/min to about 30mL/min, including about 20mL/min and about 25mL/min. In some aspects, the flow rate of the continuous phase to the homogenizer may be about 2L/min. Thus, in one aspect, the ratio of continuous phase to dispersed phase may be from about 66:1 to about 200:1, including about 100:1 and about 80:1. 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 ℃, about 37 ℃, about 35 ℃, about 30 ℃, about 25 ℃, about 20 ℃, about 15 ℃, about 10 ℃, about 5 ℃, about 0 ℃, and any range or value between any two of these temperature values.

Homogenizer

For the sake of brevity, and since the method is equally applicable to either method, the phrase "homogenizer" contemplates a system or apparatus capable of homogenizing the dispersed and continuous phases, the emulsified dispersed and continuous phases, or both, as known in the art. For example, in one aspect, the homogenizer is an in-line Silverson homogenizer (commercially available from Silverson Machines, waterside UK) or is described in, for example, U.S. Pat. No. 11167256The BPS-i100 integrated pump system is incorporated by reference herein in its entirety. In one aspect, the homogenizer is a membrane emulsifier or a static mixer. In one aspect, the homogenizer operates at an impeller speed of about 1000 to about 4000 revolutions per minute ("RPM"), including about 2000RPM, about 3000RPM, and any value or range between any two of these RPM values.

Drug loading rate

The drug loading (in percent of drug to polymer) of each polymeric microsphere may be greater than 40 wt/wt%, including 40 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 these drug loading rates.

In some particular aspects, it is contemplated that the drug loading may be as low as 20 weight/weight%.

Particle size

In one aspect, the polymeric microspheres may have an average particle size of less than 110 μm (D ₅₀ ) Including at about 30 μm (D ₅₀ ) And about 60 μm (D) ₅₀ ) Between about 30 μm (D) ₅₀ ) And about 50 μm (D) ₅₀ ) Between about 35 μm (D) ₅₀ ) And about 60 μm (D) ₅₀ ) Between about 45 μm (D) ₅₀ ) And about 60 μm (D) ₅₀ ) Between 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 value or range between any two of these average particle sizes.

In some particular aspects, average particle sizes up to 150 μm to 200 μm are contemplated.

Prolonged release

In one aspect, microsphere formulations are characterized in that they have a duration of release in humans of less than about 7 days. In one aspect, microsphere formulations are characterized by their duration of release in humans from about 7 days to about 14 days. In one aspect, microsphere formulations are characterized by their duration of release in humans between about 14 days and about 28 days. In one aspect, microsphere formulations are characterized by their duration of release in humans of about 28 days. In one aspect, microsphere formulations are characterized by their duration of release in humans of greater than about 28 days.

In one aspect, the microsphere formulation is characterized by release of the BTK inhibitor within <7 days, 7 days to 14 days, 14 days to 28 days, or >28 days (as described above) after injection into the subject of 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 the foregoing values. For example, in one aspect, the microsphere formulation is characterized by about 75% to 100% of the BTK inhibitor released within a specified time after injection into a subject. In another aspect, microsphere formulations are characterized in that they have a low initial burst, i.e., release no more than about 20% of the BTK inhibitor within about 24 hours after injection into a subject.

Further aspects include sustained release injection formulations of ibrutinib having a pharmacological equivalent oral dosages of 70mg, 140mg, 280mg, 420mg and 560mg, the sustained release injection formulations having a release time of about 7 days, 14 days, 21 days or 28 days.

Another aspect includes methods of treating MCL, CLL/SLL and other diseases or conditions treatable by BTK inhibitors in human patients. The method may include providing an injectable form of ibrutinib having a dosage strength pharmacologically equivalent to 70mg, 140mg, 280mg, 420mg and 560mg administered orally per day, the injectable form having a sustained release duration to ensure patient compliance, avoid missing one or more doses of medical consequences, and having improved pharmacokinetic profile as compared to an oral dosage form.

Therapeutic benefit

Possible disorders that can be treated using microsphere formulations comprising BTK inhibitors include cancers, including B cell malignancies, including MCL, CCL, and SLL. In one aspect, a microsphere formulation comprising a BTK inhibitor can be used to treat a B cell malignancy, wherein the microsphere formulation is administered about once every <7 days, 7 days to 14 days, 14 days to 28 days, or >28 days.

In another aspect, there is provided a microsphere formulation 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 polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor loaded, and wherein the polymeric microsphere has a loading of less than 110 μm (D ₅₀ ) Is a particle size of the particles.

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, wherein each polymeric microsphere comprises greater than 40% by weight of the polymeric microsphere of the BTK inhibitor of the drug loading, and wherein the polymeric microsphere has a molecular weight of less than 110 μm (D ₅₀ ) Is a particle size of the particles.

Examples

Example 1-general preparation of polymeric microspheres containing BTK inhibitor

Microsphere formation stage. Referring to fig. 1, a dispersed phase ("DP") 10 is formed by dissolving a polymer matrix (e.g., PLGA or PLA polymer) in an organic solvent system (e.g., DCM) and then adding the BTK inhibitor to mix until completely dissolved. DP 10 is filtered using a 0.2 μm sterile PTFE or PVDF membrane filter (such as emflown, commercially available from Pall or sartorius ag) and pumped into homogenizer 30 at a prescribed flow rate. A continuous phase ("CP") 20 comprising water, surfactant and optionally buffer is also pumped into the homogenizer 30 at a prescribed flow rate. The speed of the homogenizer 30 is typically fixed to achieve the desired polymer microsphere size distribution. A representative continuous "upstream" microsphere formation stage is described in U.S. patent No. 5945126, which is incorporated herein by reference in its entirety.

Microsphere treatment stage. The formed or forming microspheres exit the homogenizer 30 and enter a solvent removal vessel ("SRV") 40. During microsphere formation, water may be added to the SRV 40 to minimize the solvent level in the aqueous medium. See, for example, U.S. patent No. 9017715, which is incorporated by reference herein in its entirety. After the DP 10 is exhausted, the flow rates of CP 20 and water are stopped and the washing step is started. Solvent removal was achieved using a water wash and a hollow fiber filter (commercially available as HFF from cytova) 50. A representative "downstream" microsphere processing stage is described in U.S. patent No. 6270802, which is incorporated herein by reference in its entirety.

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

Example 2-preparation of polymeric microspheres containing 50:50PLGA encapsulated ibrutinib-lots 1 and 2 ("A) Group')

DP was formed following the general procedure described in example 1 and shown in fig. 1 by dissolving 2.5g of 502H polymer (lot 1) or 502 polymer (lot 2) (iv=0.20 dL/g) in 11.67g of DCM and then adding ibrutinib (2.5 g) to mix until completely dissolved. After filtration of the DP, the DP was pumped at a flow rate of 25ml/min to a speed of 3000RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

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

The average particle size of run 1 was 36 μm (D50), the drug loading was 47.6 wt.% and the molecular weight was 17.6kDa. The microspheres contained 3.0% residual DCM. The average particle diameter of the 2 nd batch was 44. Mu.m (D ₅₀ ) The drug loading was 47.8 wt% and the molecular weight was 17.7kDa. The microspheres contained 3.0% residual DCM. Parameters and results are shown in table 1 in the form of a list:

TABLE 1

Fig. 2 is a graph showing the in vitro cumulative release of ibrutinib over time from group a encapsulated polymeric microspheres.

Example 3-preparation of polymer micro-encapsulated ibrutinib comprising 75:25 PLGA with low polymer IV Ball-lot 3, lot 4, lot 6, lot 7 and lot 11 ("group B")

DP was formed following the general procedure described in example 1 and shown in fig. 1 by dissolving 2.5g (lot 3, lot 4 and lot 11), 2.0g (lot 6) or 1.5g (lot 7) 7503A polymer (lot 3, lot 6, lot 7 and lot 11) or 7502E polymer (lot 6) (iv=0.26 dL/g) in 11.67g of DCM followed by adding ibrutinib (sufficient to provide a DP weight of 16.67g, i.e. lot 3, lot 4 and lot 11 of 2.5g; lot 6 of 3.0g; lot 7 of 3.5 g) until completely dissolved. DP was filtered and pumped at a flow rate of 25ml/minBPS-i100 integrated pump system, the pump systemThe system was run at 3000RPM (lot 3, lot 4, lot 6 and lot 7) or 2000RPM (lot 11). CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

The average particle diameter of batch 3 was 39 μm (D ₅₀ ) The drug loading was 48.2 wt% and the molecular weight was 29.4kDa. The microspheres contained 3.1% residual DCM. The average particle diameter of the 4 th batch was 35 μm (D ₅₀ ) The drug loading was 48.9 wt% and the molecular weight was 25.5kDa. The microspheres contained 2.1% residual DCM. The average particle diameter of the 6 th batch was 34. Mu.m (D ₅₀ ) The drug loading was 60.6 wt% and the molecular weight was 31.0kDa. The microspheres contained 2.7% residual DCM. The average particle diameter of the 7 th batch was 30. Mu.m (D ₅₀ ) The drug loading was 65.6 wt% and the molecular weight was 30.1kDa. The microspheres contained 1.5% residual DCM. The average particle diameter of the 11 th batch was 61. Mu.m (D ₅₀ ) The drug loading was 51 wt% and the molecular weight was 28.9kDa. The microspheres contained 1.4% residual DCM. Parameters and results are shown in table 2 in tabular form:

TABLE 2

Fig. 3 is a graph showing the in vitro cumulative release of ibrutinib over time from group B encapsulated polymeric microspheres.

Example 4-preparation of polymer micro-encapsulated ibrutinib comprising 75:25 PLGA with high polymer IV Ball-lot 5, lot 12, lot 13 and lot 14 ("group C")

Following the general procedure described in example 1 and shown in fig. 1, the polymerization was carried out by mixing 2.5g (lot 5 and lot 12) or 2.0g (lot 13 and lot 14) 7505A polymer (lot 5) (iv=0.56 dL/g), 7505E polymer (lot 12) (iv=0.41 dL/g), 7507A polymer(13) (iv=0.7 dL/g) or 7507E polymer (14) (iv=0.66 dL/g) was dissolved in 11.67g DCM and ibrutinib (sufficient to provide a DP weight of 16.67g, i.e. batches 5 and 12 were 2.5g; batches 13 and 14 were 3.0 g) was then added and mixed until complete dissolution to form DP. DP was filtered and pumped at a flow rate of 25ml/min to run at 3000RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

The average particle diameter of the 5 th batch was 53. Mu.m (D ₅₀ ) The drug loading was 47.5 wt% and the molecular weight was 66.4kDa. The microspheres contained 4.1% residual DCM. The average particle diameter of the 12 th batch was 47. Mu.m (D ₅₀ ) The drug loading was 51.2 wt% and the molecular weight was 49.8kDa. The microspheres contained 0.8% residual DCM. The average particle diameter of the 13 th batch was 52. Mu.m (D ₅₀ ) The drug loading was 62.2 wt% and the molecular weight was 87.7kDa. The microspheres contained 1.3% residual DCM. The average particle diameter of the 14 th batch was 53. Mu.m (D ₅₀ ) The drug loading was 61.0 wt% and the molecular weight was 90.8kDa. The microspheres contained 1.3% residual DCM. Parameters and results are shown in table form in table 3:

TABLE 3 Table 3

Fig. 4 is a graph showing the in vitro cumulative release of ibrutinib over time from group C encapsulated polymeric microspheres.

Example 5-preparation of polymeric microspheres of encapsulated ibrutinib comprising 85:15 PLGA-lot 18 and 19 ("group D")

DP was formed following the general procedure described in example 1 and shown in fig. 1 by dissolving 2.5g of 8503A polymer (batch 18) (iv=0.24 dL/g) or 8503E polymer (batch 19) (iv=0.25 dL/g) in 11.67g of DCM and then adding ibrutinib (2.5 g) and mixing until completely dissolved. DP was filtered and pumped at a flow rate of 25ml/min to run at 3000RPMBPS-i100 integrates a pump system. CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

The average particle diameter of the 18 th batch was 36. Mu.m (D ₅₀ ) The drug loading was 49.8 wt% and the molecular weight was 22.7kDa. The microspheres contained 0.5% residual DCM. The average particle diameter of the 19 th batch was 35 μm (D ₅₀ ) The drug loading was 49.2 wt% and the molecular weight was 25.8kDa. The microspheres contained 0.3% residual DCM. Parameters and results are shown in table form in table 4:

TABLE 4 Table 4

Fig. 5 is a graph showing the in vitro cumulative release of ibrutinib over time from group D encapsulated polymeric microspheres.

Example 6-preparation of polymeric microspheres of encapsulated ibrutinib comprising PLA-lot 8, 9, 10, 16 Batch and batch 17 ("group E")

By mixing 2.5g (lot 8, lot 9, lot 16 and lot 17) or 2.0g (lot 10) DL 02A polymer (lot 8 and lot 17) (iv=0.16 DL/g), DL 02E polymer (lot 9 and lot 10) (iv=018 DL/g) orDL 03A polymer (lot 16) (iv=0.32 DL/g) was dissolved in 11.67g DCM and ibrutinib (sufficient to provide a DP weight of 16.67g, i.e. lot 8, 9, 16, and 17 of 2.5g; lot 10 of 3.0 g) was then mixed until complete dissolution to form DP. DP was filtered and pumped at a flow rate of 25ml/minBPS-i100 integrates a pump system that operates at 3000RPM (lot 8, 9, 10, and 16) or 2000RPM (lot 17). CP containing 0.35% PVA was also pumped into the homogenizer at a flow rate of 2L/min (CP: dp=80:1).

The average particle diameter of the 8 th batch was 32. Mu.m (D ₅₀ ) The drug loading was 51.7 wt% and the molecular weight was 12.0kDa. The microspheres contained 0.4% residual DCM. The average particle diameter of the 9 th batch was 29. Mu.m (D ₅₀ ) The drug loading was 51.8 wt% and the molecular weight was 11.7kDa. The microspheres contained 0.1% residual DCM. The average particle diameter of batch 10 was 29. Mu.m (D ₅₀ ) The drug loading was 64.2 wt% and the molecular weight was 11.7kDa. The microspheres contained 0.2% residual DCM. The average particle diameter of the 16 th batch was 40. Mu.m (D ₅₀ ) The drug loading was 48.9 wt% and the molecular weight was 30.1kDa. The microspheres contained 0.6% residual DCM. The average particle diameter of the 17 th batch was 49. Mu.m (D ₅₀ ) The drug loading was 50.2 wt% and the molecular weight was 12.4kDa. The microspheres contained 0.8% residual DCM. Parameters and results are shown in table 5 in tabular form:

TABLE 5

Fig. 6 is a graph showing the in vitro cumulative release of ibrutinib over time from group E encapsulated polymeric microspheres.

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

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

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

Unless otherwise indicated, "a", "an", "the", "one or more", and "at least one" are used interchangeably. The singular forms "a", "an" and "the" include plural referents. The recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). The terms "comprising," "including," and "containing" are intended to be equivalent and open-ended. The phrase "consisting essentially of … …" means that the composition or method can include additional ingredients and/or steps, provided that the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method. The phrase "selected from the group consisting of … …" is meant to include mixtures of the listed groups.

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

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

Claims

1. A microsphere formulation comprising:

polymeric microspheres, each polymeric microsphere comprising:

(i) BTK inhibitors; and

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

wherein each polymeric microsphere comprises a BTK inhibitor at a drug loading of greater than 40 wt% of the polymeric microsphere, and

wherein the polymer microspheres have an average particle size of less than 110 [ mu ] m (D ₅₀ )。

2. The microsphere formulation of claim 1, wherein the BTK inhibitor comprises ibrutinib.

3. Microsphere formulation according to claim 1 or 2, wherein the biodegradable polymer comprises poly (D, L-lactide-co-glycolide).

4. A microsphere formulation according to any one of claims 1 to 3, wherein the biodegradable polymer comprises poly (D, L-lactide-co-glycolide) having a lactide to glycolide ratio of 50:50.

5. A microsphere formulation according to any one of claims 1 to 3, wherein the biodegradable polymer comprises poly (D, L-lactide-co-glycolide) having a lactide to glycolide ratio of 75:25.

6. A microsphere formulation according to any one of claims 1 to 3, wherein the biodegradable polymer comprises poly (D, L-lactide-co-glycolide) having a lactide to glycolide ratio of 85:15.

7. Microsphere formulation according to claim 1 or 2, wherein the biodegradable polymer comprises poly (D, L-lactide).

8. The microsphere formulation according to any one of the preceding claims, wherein the biodegradable polymer is acid-terminated.

9. The microsphere formulation 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 to 6, 8 or 9, wherein the inherent viscosity of the biodegradable polymer is between about 0.2dL/g and 0.6 dL/g.

11. The microsphere formulation of any one of claims 1, 2, 7, 8 or 9, wherein the inherent viscosity of said biodegradable polymer is between about 0.1dL/g and 0.4 dL/g.

12. The microsphere formulation of any one of the preceding claims, wherein each polymeric microsphere comprises about 45% to about 65% by weight of the polymeric microsphere of the BTK inhibitor of drug loading.

13. The microsphere formulation according to any one of the preceding claims, wherein the average particle size of the polymeric microspheres is about 30 μιη (D ₅₀ ) To about 60 μm (D) ₅₀ )。

14. The microsphere formulation of any one of the preceding claims, wherein about 75% to 100% of the BTK inhibitor is released over a period of time between about 7 days and 28 days of injection into a subject, but no more than about 20% of the BTK inhibitor is released over about 24 hours of injection into the subject.

15. A pharmaceutical composition comprising a microsphere formulation according to any one of the preceding claims.

16. Microsphere formulation according to any one of the preceding claims for use in the treatment of B cell malignancies.

17. A method of preparing a microsphere formulation, the method comprising the steps of:

(i) Contacting a BTK inhibitor with a biodegradable polymer comprising poly (D, L-lactide-co-glycolide) in a comonomer ratio of between about 50:50 and 85:15 and an inherent viscosity of between about 0.2dL/g and 0.6dL/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 that is substantially free of organic solvent; and

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

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 wherein the polyvinyl alcohol concentration in the aqueous phase prior to the combining is about 0.35 wt%.

20. A method of preparing a microsphere formulation, the method comprising the steps of:

(i) Contacting a BTK inhibitor with a biodegradable polymer comprising poly (D, L-lactide) having an inherent viscosity of between about 0.1dL/g and 0.4dL/g in the presence of an organic solvent system to form a dispersed phase;

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

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 wherein the polyvinyl alcohol concentration in the aqueous phase prior to the combining is about 0.35 wt%.

23. A kit comprising:

polymeric microspheres, each polymeric microsphere comprising:

(i) Ibrutinib; and

(ii) A biodegradable polymer having an inherent viscosity of between about 0.2dL/g and 0.6dL/g comprising poly (D, L-lactide-co-glycolide),

wherein each polymer is micro-sizedThe spheres comprise ibrutinib at a drug loading of about 45% to about 65% by weight of the polymeric microspheres, and wherein the polymeric microspheres have an average particle size of about 30 μm (D ₅₀ ) To about 60 μm (D) ₅₀ )。

24. A method of treating a B cell malignancy, the method comprising:

administering to the subject a microsphere formulation by intramuscular injection or subcutaneous injection in a dosing regimen of about every 7 days to about every 28 days, the microsphere formulation comprising:

(i) Ibrutinib; and

wherein each polymeric microsphere comprises from about 45% to about 65% by weight of the polymeric microsphere of ibrutinib having a drug loading, and wherein the polymeric microsphere has an average particle size of about 30 μm (D ₅₀ ) To about 60 μm (D) ₅₀ )。