Erdafitinib formulations and osmotic systems for intravesical administration

Abstract

Provided herein are solid pharmaceutical compositions comprising the L-lactate salt of erdafitinib, processes for making such formulations, and drug delivery systems comprising such formulations, including systems for intravesical administration.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 311,855, filed February 18, 2022, the disclosure of which is incorporated by reference in its entirety herein.

[0002] (Reference to Electronic Sequence Listing) The electronic sequence listing (761662002140seqlisting.xml, size: 53,009 bytes, and creation date: February 15, 2023) is incorporated herein by reference in its entirety. [Background technology]

[0003] The present disclosure is generally in the field of pharmaceutical formulations and drug-device combination products, and more specifically, relates to erdafitinib-based formulations and systems for intravesical administration of such formulations.

[0004] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is a potent pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. Erdafitinib has been found to inhibit FGFR phosphorylation and signaling and reduce cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib has demonstrated antitumor activity in FGFR-expressing cell lines and in xenograft models derived from tumor types, including bladder cancer.

[0005] Erdafitinib (BALVERSA®) is currently available as a film-coated tablet for oral administration and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that harbors susceptible fibroblast growth factor receptor FGFR3 or FGFR2 genetic alterations and has progressed during or after at least one prior line of platinum-containing chemotherapy, including neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

[0006] No. 10,898,482 to Broggini and WO 2020 / 201138 to De Porre describe certain erdafitinib formulations and methods of treatment.

[0007] Examples of intravesical drug delivery systems are described in U.S. Patent No. 8,679,094 to Cima et al., U.S. Patent No. 9,017,312 to Lee et al., U.S. Patent No. 9,107,816 to Lee et al., and U.S. Patent No. 9,457,176 to Lee et al. In some embodiments, the intravesical system includes a water-permeable housing defining a drug reservoir lumen containing a solid or semi-solid drug formulation, and release of the drug in vivo occurs when water from the bladder diffuses into the drug reservoir lumen to solubilize the drug, and then the osmotic pressure built up within the drug reservoir lumen releases the solubilized drug from the drug reservoir lumen through a release opening.

[0008] U.S. Patent No. 10,286,199 to Lee et al. discloses a system in which a drug is released from a housing, the housing being made of a first wall structure and a hydrophilic second wall structure, the first wall structure being impermeable to the drug and the second wall structure being permeable to the drug. U.S. Patent No. 10,894,150 to Lee also discloses a system in which a drug is released from a housing, the housing being made of a first wall structure that is impermeable to the drug and a second wall structure that is permeable to the drug. Summary of the Invention [Means for solving the problem]

[0009] In one aspect, provided herein is an intravesical drug delivery system comprising an elongate body configured for intravesical insertion into a patient, and a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharma- ceutically acceptable salt thereof, in particular the L-lactate salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine). In some embodiments, the drug delivery system is configured to be osmotically driven to release erdafitinib from one or more openings in the elongate body. In some embodiments, erdafitinib is present as mono-L-lactate salt. In some embodiments, the elongate body comprises a biocompatible elastomer. In some embodiments, the biocompatible elastomer comprises a silicone or a thermoplastic polyurethane. In some embodiments, the biocompatible elastomer comprises a silicone. In some embodiments, the biocompatible elastomer comprises a platinum-cured silicone elastomer. In some embodiments, at least one of the one or more openings of the elongate body is located in a sidewall of the elongate body. In some embodiments, at least one of the one or more openings of the elongate body is located in a first end and / or an opposing second end of the elongate body. In some embodiments, the drug delivery system has a single opening located in a sidewall of the elongate body at a location between the first end and the opposing second end of the elongate body. In some embodiments, the one or more openings have a diameter of about 100 μm to about 200 μm. In some embodiments, the one or more openings have a diameter of about 150 μm.

[0010] In some embodiments, the drug delivery system is configured to release erdafitinib by osmotic pressure through one or more openings in the elongate body. In some embodiments, the elongate body comprises an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed. In some embodiments, the annular wall structure has a thickness of about 0.1 mm to about 0.5 mm. In some embodiments, the annular wall structure has a thickness of about 0.2 mm.

[0011] In some embodiments, the drug delivery system further comprises a first end plug disposed at a first end of the annular wall structure and a second end plug disposed at a second end of the annular wall structure. In some embodiments, the one or more openings of the elongate body of the drug delivery system comprise a single opening in the annular wall structure, and the elongate body is configured to release erdafitinib through the opening. In some embodiments, the elongate body is configured to release erdafitinib through a microchannel temporarily formed in one or both end regions of the annular wall structure. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day, particularly 1 mg / day to 10 mg / day of erdafitinib free base equivalent. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 6 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day to 4 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 4 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day. In some embodiments, the system is configured to release erdafitinib in a zero order release profile. In some embodiments, the system is configured to release erdafitinib for up to about 30 days. In some embodiments, the system is configured to release erdafitinib for up to about 90 days. In some embodiments, the system comprises 500 mg of erdafitinib (free base equivalent).

[0012] In some embodiments, the drug delivery system is elastically deformable between a relatively straightened deployed configuration suitable for insertion through the patient's urethra into the patient's bladder and a retained configuration suitable for retaining the system in the bladder. In some embodiments, the system is elastically deformable and comprises a tube having two opposing free ends that are directed away from each other when the system is in the low profile deployed configuration and directed toward each other when the system is in the relatively expanded retained configuration. In some embodiments, the system comprises an elastically deformable elongated body having two opposing free ends that are within the confines of a bi-elliptical expanded retained configuration. In some embodiments, the elongated body further comprises a retaining frame lumen. In some embodiments, the system further comprises a nitinol wire disposed in the retaining frame lumen.

[0013] In another aspect, provided herein is a pharmaceutical composition or a drug delivery system comprising the pharmaceutical composition, the pharmaceutical composition comprising a lactate salt of erdafitinib, particularly erdafitinib L-lactate, and at least one pharmaceutical excipient. In some embodiments, the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. In some embodiments, the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

[0014] In some embodiments, the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof, In some embodiments, the binder is present in the drug formulation at a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

[0015] In some embodiments, the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, or a combination thereof. In some embodiments, the diluent (filler) is present in the drug formulation at a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight.

[0016] In some embodiments, the glidant comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, hi some embodiments, the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1%, about 0.1% to about 0.5%, or about 0.25% by weight.

[0017] In some embodiments, the lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol. In some embodiments, the lubricant comprises magnesium stearate or sodium stearyl fumarate. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5% by weight.

[0018] In some embodiments, the pharmaceutical composition or the drug delivery system comprising the pharmaceutical composition comprises an intragranular composition or intragranular fraction and an extragranular composition or extragranular fraction. In some embodiments, the intragranular composition or fraction comprises erdafitinib or a pharmaceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, for example, erdafitinib L-lactate. In some embodiments, the intragranular composition or fraction comprises erdafitinib or a pharmaceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, for example, erdafitinib L-lactate, and at least one intragranular excipient, and the extragranular composition or fraction comprises at least one extragranular excipient. In some embodiments, the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient. In some embodiments, the at least one intragranular excipient comprises an intragranular binder. In some embodiments, the intragranular binder comprises hydroxypropyl methylcellulose. In some embodiments, the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. In some embodiments, the extragranular binder comprises vinylpyrrolidone-vinyl acetate. In some embodiments, the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. In some embodiments, the extragranular glidant comprises or is colloidal silicon dioxide (hydrophilic). In some embodiments, the extragranular lubricant comprises magnesium stearate or sodium stearyl fumarate or polyethylene glycol. In some embodiments, the extragranular lubricant comprises magnesium stearate or sodium stearyl fumarate. In some embodiments, the extragranular lubricant comprises or is magnesium stearate. In some embodiments, the at least one extragranular excipient comprises a filler and a binder, particularly microcrystalline cellulose and vinylvinylpyrrolidone-vinyl acetate, particularly in a weight:weight ratio of filler to binder of 1:1.

[0019] In some embodiments, the pharmaceutical composition, or drug delivery system comprising the pharmaceutical composition, comprises erdafitinib L-lactate at a concentration of 60% to 91% by weight. In some embodiments, the pharmaceutical composition, or drug delivery system comprising the pharmaceutical composition, comprises erdafitinib L-lactate at a concentration of 60% to 80% by weight. In some embodiments, erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight.

[0020] In some embodiments, the pharmaceutical composition, or the drug delivery system comprising the pharmaceutical composition, comprises erdafitinib L-lactate in the form of a plurality of mini-tablets. In some embodiments, the pharmaceutical composition is in the form of about 10 to about 100 mini-tablets. In some embodiments, the pharmaceutical composition comprises a mini-tablet having a total length of about 14.5 cm to about 15 cm, and / or the (b) formulation comprises a mini-tablet having a weight of about 920 mg to about 965 mg. In some embodiments, the pharmaceutical composition comprises a mini-tablet having a total length of about 14.5 cm to about 15 cm, and / or the (b) formulation comprises a mini-tablet having a weight of about 920 mg to about 950 mg.

[0021] In some embodiments, the pharmaceutical composition comprising erdafitinib L-lactate is in the form of a tablet having a hardness of at least about 100 N. In some embodiments, the tablet has a hardness of about 150 N to about 250 N. In some embodiments, The tablet has a hardness of about 175N to about 225N. In some embodiments, the tablet has a thickness of about 3.2mm to about 3.6mm. In some embodiments, the tablet is a mini-tablet in the form of a solid cylinder having a cylindrical axis, a cylindrical side surface, a circular end surface perpendicular to the cylindrical axis, a diameter of the circular end surface, and a length along the cylindrical side surface. In some embodiments, the length of the mini-tablet exceeds the diameter of the mini-tablet, providing a mini-tablet with an aspect ratio (length:diameter) of more than 1:1. In some embodiments, the mini-tablet has a diameter of 1.0mm to 3.2mm, or 1.5mm to 3.1mm. In some embodiments, the mini-tablet has a diameter of 2.5mm to 2.7mm. In some embodiments, the mini-tablet has a length of 3.0mm to 3.5mm. In some embodiments, the mini-tablet has a mass of 22mg to 24mg.

[0022] In another aspect, a process for making the pharmaceutical composition in the form of a tablet is provided, comprising: (a) preparing an intragranular solid composition comprising erdafitinib L-lactate and at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition. In some embodiments, (a) the at least one intragranular pharmaceutical excipient comprises at least one intragranular binder, and (b) the at least one extragranular pharmaceutical excipient comprises an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant. In some embodiments, the intragranular solid composition is prepared by a fluid bed granulation process. In some embodiments, the at least one intragranular binder comprises hydroxypropyl methylcellulose. In some embodiments, the at least one extragranular binder comprises vinylpyrrolidone-vinyl acetate (PVP VA). In some embodiments, the at least one extragranular filler (diluent) comprises microcrystalline cellulose. In some embodiments, the extragranular filler (diluent) further comprises a second extragranular filler (diluent) comprising silicified microcrystalline cellulose. In some embodiments, the extragranular glidant comprises or is colloidal silicon dioxide (hydrophilic). In some embodiments, the extragranular lubricant comprises or is magnesium stearate. In some embodiments, the extragranular lubricant comprises sodium stearyl fumarate. In some embodiments, the extragranular lubricant comprises polyethylene glycol. In some embodiments, the at least one extragranular excipient comprises a filler and a binder, particularly microcrystalline cellulose and vinyl vinylpyrrolidone-vinyl acetate, particularly where the weight:weight ratio of filler to binder is 1:1. In some embodiments, the ejection force is less than about 1000N. [Brief description of the drawings]

[0023] The detailed description is described with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. Elements and / or components shown in the drawings are not necessarily drawn to scale. [Figure 1A] FIG. 1 is a plan view of one embodiment of a drug delivery system in a coiled retention configuration according to the present disclosure. [Figure 1B] 1B is a cross-sectional view of one embodiment of the drug delivery system shown in FIG. 1A taken along line BB. [Diagram 2] 1 is a schematic diagram of the operation of one embodiment of an osmotic drug delivery system according to the present disclosure. [Diagram 3] FIG. 1 is a perspective view of one embodiment of a mini-tablet form of a drug formulation according to the present disclosure. [Figure 4] Figure 1 shows single dose erdafitinib exposure in plasma from nude rats bearing subcutaneous or orthotopic UM-UC-1 tumors. Exposure levels were measured in plasma from nude rats bearing naive orthotopic bladder or scUM-UC-1 tumors. Rats were dosed with a single IVES (1 hour infusion) or po dose of erdafitinib at the dose levels shown. Individual data points are shown and the mean is represented by the horizontal line at each time point. IVES, intravesical; PO or po, oral; sc, subcutaneous. [Diagram 5]Figure 1 shows the effect of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors. Nude rat UM-UC-1 orthotopic bladder tumors were administered a single dose of vehicle or the indicated dose levels of erdafitinib IVES (1 hour infusion) or po, and individual pERK and total ERK levels were measured. pERK and total ERK levels are reported as ratios to the mean vehicle group at the corresponding time point (pERK / ERK), except for the 120 hour time point, where values ​​were normalized to the 48 hour vehicle group. Individual data points are shown and the mean is represented by the horizontal line at each time point. N=2-6 / group; ERK, extracellular signal-regulated kinase; IVES, intravesical; pERK, phosphorylated extracellular signal-regulated kinase; PO or po, oral. [Figure 6] Shown is the size of orthotopic bladder UC tumor examples versus control bladders at day 14 after implantation. Formalin was used to fix tissue samples after necropsy. UC, urothelial carcinoma; NBTII, rat Nara bladder tumor No. 2 cells; T24, human bladder cancer cells. [Figure 7] FIG. 1 is a schematic diagram of a perfusion experiment in athymic rats with UM-UC-1 implanted within the bladder wall. [Figure 8] Figure 1 shows the percentage change in body weight of bladder-cannulated athymic rats bearing orthotopic UM-UC-1 bladder tumors. Graph values ​​are expressed as the mean ± SEM of 10-13 animals in each group. Concentrations shown in the figure index are nominal target urinary concentrations. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by two-way ANOVA followed by Bonferroni multiple comparison test. There was no statistically significant difference when the percentage change in body weight of erdafitinib (0.5, 1.0, and 5.0 μg / mL) treatment groups was compared with the percentage change in body weight of the vehicle control group. SEM, standard error of the mean. [Figure 9]The mean percentage tumor weight reduction after taking into account the tumor-free bladder weight is shown. Values ​​(groups 1-4) are expressed as the mean ± SEM of 10-13 animals in each group. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by one-way ANOVA followed by Dunnett's multiple comparison test. Conc, concentration; SEM, standard error of the mean. [Figure 10] Figure 1 shows the percentage change in body weight of bladder-cannulated athymic nude rats bearing orthotopic RT-112 bladder tumors. Values ​​are expressed as the mean ± SEM of 2-14 animals in each group. Concentrations indicated in the figure index are nominal target urinary concentrations. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by two-way ANOVA followed by Bonferroni multiple comparison test. There were no statistically significant differences when the percentage change in body weight of erdafitinib (0.5, 1.0, and 5.0 μg / mL)-treated groups was compared with the percentage change in body weight of the vehicle control group, except for group 4 at day 11 (*p<0.05). SEM, standard error of the mean. [Figure 11] Figure 1 shows the effect of intravesical erdafitinib exposure on tumor growth as determined by change in total bladder weight in athymic rats bearing orthotopic RT-112 bladder tumors. Values ​​(groups 1-5) are expressed as the mean ± SEM of 2-14 animals in each group. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by one-way ANOVA followed by Dunnett's multiple comparison test. *p<0.05. Conc, concentration; SEM, standard error of the mean; ns, not significant. [Figure 12A] Plasma (FIG. 12A) and bladder (FIG. 12B) concentrations of erdafitinib in rats after bladder irrigation are shown. Bladder irrigation with erdafitinib solution (0.1 mg / mL, 0.1 mL / hr, cumulative dose of 0.72 mg) was performed for 72 hours. Concentrations are expressed as mean daily urinary concentration in ng / mL. [Figure 12B]Plasma (FIG. 12A) and bladder (FIG. 12B) concentrations of erdafitinib in rats after bladder irrigation are shown. Bladder irrigation with erdafitinib solution (0.1 mg / mL, 0.1 mL / hr, cumulative dose of 0.72 mg) was performed for 72 hours. Concentrations are expressed as mean daily urinary concentration in ng / mL. [Figure 13] Average erdafitinib urinary concentrations in pigs after intravesical infusion of erdafitinib at a constant rate of 12.5 mL / h for 6 consecutive days for 2 animals and 8 consecutive days for 3 animals. Total voided urine was collected at 24-h intervals over 6 or 8 days. Conc., concentration; SD, standard deviation. [Figure 14] Figure 1 shows the mean erdafitinib plasma concentrations in pigs after intravesical infusion of erdafitinib at a constant rate of 12.5 mL / h for 6 consecutive days for 2 animals and 8 consecutive days for 3 animals. Blood samples were taken daily on study days 1-8. SD, standard deviation. [Figure 15] Screening results for material permeability are shown: O is permeable, Δ is virtually impermeable, × is impermeable. a High variability between replicates. [Figure 16A] 1 shows a schematic of an osmotic system design with an orifice + end plug. FIGURE 1 provides a cross-sectional side view of one embodiment of a device with a pre-formed sidewall orifice and two constraining end plugs. [Figure 16B] 1 shows a schematic of an osmotic system design with an orifice + end plug. FIG provides a top view of one embodiment of a device with a pre-formed sidewall orifice and two constraining end plugs. [Figure 16C] 1 shows a schematic of an osmotic system design with an orifice + end plug. FIGURE 1 provides a cross-sectional side view of an end portion of one embodiment of a device with a constraining end plug and a microchannel formed through the end plug. [Figure 17]Figure 2 shows the IVR (in vitro release) profile of prototype 4, osmolarity (orifice + end plugs), 0.2 mm wall, erdafitinib L-lactate, tablet (20% by weight water insoluble excipients). Erda, erdafitinib; IVR, in vitro release; SU, simulated urine; FBE, free base equivalent. [Figure 18] IVR profile for prototype 5, Osmolarity (Orifice + End Plugs), 0.2 mm Wall, Erdafitinib L-Lactate, Tablet (Water Soluble Excipients). Erda, Erdafitinib, IVR, In Vitro Release, SU, Simulated Urine, FBE, Free Base Equivalent. [Figure 19] The mean urinary concentration versus time profiles in minipigs for prototypes 4-5 are summarized. [Figure 20A] FIG. 20A shows the solubility of erdafitinib L-lactate as a function of pH in water at 37° C. with the pH adjusted using HCl / NaOH solution (FIG. 20A), and the solubility mg / mL of erdafitinib L-lactate as a function of pH in simulated urine at 37° C. (FIG. 20B). [Figure 20B] FIG. 20A shows the solubility of erdafitinib L-lactate as a function of pH in water at 37° C. with the pH adjusted using HCl / NaOH solution (FIG. 20A), and the solubility mg / mL of erdafitinib L-lactate as a function of pH in simulated urine at 37° C. (FIG. 20B). [Figure 21] 1 shows an outline of the synthesis reaction of erdafitinib mono-L-lactate (JNJ-42756493-AFK) from erdafitinib series (JNJ-42756493-AAA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In some embodiments, erdafitinib solid formulations are provided that contain high concentrations of erdafitinib and are designed for intravesical drug delivery and controlled and extended drug release when placed in the bladder.In some embodiments, the solid erdafitinib formulations are further adapted for large-scale manufacturing and are further adapted to provide the structural and chemical integrity of solid formulations, particularly tablets, when used in intravesical drug delivery systems.Improved intravesical drug delivery systems and drug delivery methods are also provided.In certain embodiments, the system is configured for intravesical insertion and sustained drug delivery, and is preferably configured to provide a zero-order release rate of therapeutically effective amounts of drugs, particularly erdafitinib.

[0025] To utilize this administration route, erdafitinib formulations and release systems adapted for intravesical drug delivery are described herein.When formulated in solid form and administered in a suitable intravesical drug delivery system, such formulations can provide controlled drug release rates and extended drug release profiles.Furthermore, systems are provided that can deliver erdafitinib at effective release rates for localized treatment of bladder cancer.

[0026] In certain embodiments, the drug delivery system described herein is a drug-device combination consisting of a device component, particularly an intravesical device, and a drug component, particularly an erdafitinib formulation, e.g., an erdafitinib tablet.

[0027] Erdafitinib formulations and tablets In one aspect, erdafitinib lactate is disclosed, particularly erdafitinib L-lactate, particularly erdafitinib mono-L-lactate.This is useful, for example, in the local delivery / administration of erdafitinib to patients.In an embodiment, a pharmaceutical composition is provided, comprising erdafitinib lactate, particularly erdafitinib L-lactate, and one or more excipients.In an embodiment, the pharmaceutical composition is in the form of a tablet, particularly a mini-tablet.

[0028] In one aspect, the present disclosure provides an erdafitinib formulation suitable for use in the disclosed intravesical drug delivery system, particularly an erdafitinib tablet.In particular, a drug tablet is provided that includes a salt form of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine).After the drug delivery system is inserted into the bladder, the drug is released from the system into the bladder.In one aspect, for example, the drug delivery system can operate as an osmotic pump, which provides a continuous release of drug into the bladder over an extended period of time as the drug is released from the tablet in the system.

[0029] In order to increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, the drug tablet may have a relatively high erdafitinib content by weight. This relatively high weight fraction of erdafitinib in the drug tablet is accompanied by a reduced or low weight fraction of excipients that may be required for tablet manufacturing and system assembly and drug use considerations. For the purposes of this disclosure, terms such as "weight fraction," "weight percentage," and "percentage by weight" with respect to any drug or API (active pharmaceutical ingredient) refer to the drug or API in the form used, whether in free base form, free acid form, salt form, or hydrate form. For example, a drug tablet having 90% by weight (90 wt%) of a drug or excipient in salt form may contain less than 90% by weight of this drug in free base form.

[0030] The erdafitinib drug tablet of the present disclosure comprises an erdafitinib content and an excipient content. The drug content may comprise one or more forms of erdafitinib, such as free base or salt forms, while the excipient content may comprise one or more excipients. Particular embodiments comprise a salt of erdafitinib, more specifically, erdafitinib lactate, such as mono-L-lactic acid of erdafitinib. The term "excipient" is well known in the art, and representative examples of excipients useful in the disclosed drug tablet may include, but are not limited to, ingredients such as binders, lubricants, glidants, disintegrants, solubilizers, colorants, fillers or diluents, wetting agents, stabilizers, formaldehyde scavengers, coating agents, and preservatives, or any combination thereof, as well as other ingredients to facilitate the manufacture, storage, or administration of the drug tablet.

[0031] In an embodiment, the erdafitinib drug tablet comprises erdafitinib in a salt form. In one aspect, the erdafitinib drug tablet may comprise 50% or more by weight of erdafitinib L-lactate, with the remainder of the weight comprising excipients that facilitate the manufacture and use of the drug tablet, such as lubricants, binders, and stabilizers. In an embodiment, the erdafitinib drug tablet comprises erdafitinib in a salt form. In one aspect, the erdafitinib drug tablet may comprise 50% or more by weight of erdafitinib L-lactate, with the remainder of the weight comprising excipients that facilitate the manufacture and use of the drug tablet, such as lubricants, fillers, binders, and glidants. Alternatively, the erdafitinib pharmaceutical tablet may comprise 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, or 75% or more, 80% or more, 85% or more, or 90% or more by weight of erdafitinib L-lactate. In one embodiment, the pharmaceutical tablet may comprise 50% to 90% by weight, 65% to 85% by weight, 70% to 80% by weight, e.g., 70% by weight, or 75% by weight, or 80% by weight, of erdafitinib in its L-lactate form, based on the total weight of the tablet.

[0032] In an embodiment, the erdafitinib in the erdafitinib drug tablet is in the form of erdafitinib L-lactate. The properties of erdafitinib L-lactate are advantageous for use in the disclosed osmotic systems, including its high solubility, its stability, and its ability to function as an osmotic agent without the need for an added osmotic agent.

[0033] Erdafitinib formulations with a range of excipient combinations, both intragranular and extragranular, are provided in the Examples in Tables 2, 9, 13, and 16. In particular, Table 16 shows formulation concepts 1-5. Concepts 1-5 are formulation embodiments encompassed by the present disclosure.

[0034] In some embodiments, the solid pharmaceutical composition comprises (a) 70% by weight of erdafitinib-L-lactate, (b) 1.43% by weight of hydroxypropyl methylcellulose, (c) 9.30% by weight of microcrystalline cellulose, (d) 7.22% by weight of silicified microcrystalline cellulose, (e) 9.30% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (f) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (g) 2.5% by weight of magnesium stearate, the weight percentages being based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 70% by weight of erdafitinib L-lactate (intragranular); (b) 1.43% by weight of hydroxypropyl methylcellulose (intragranular); (c) 9.30% by weight of microcrystalline cellulose (extragranular); (d) 7.22% by weight of silicified microcrystalline cellulose (extragranular); (e) 9.30% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (f) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (g) 2.5% by weight of magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 1.

[0035] In some embodiments, the solid pharmaceutical composition comprises (a) 70% by weight of erdafitinib-L-lactate, (b) 1.43% by weight of hydroxypropyl methylcellulose, (c) 12.91% by weight of microcrystalline cellulose, (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of magnesium stearate, the weight percentages being based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 70% by weight of erdafitinib L-lactate (intragranular); (b) 1.43% by weight of hydroxypropyl methylcellulose (intragranular); (c) 12.91% by weight of microcrystalline cellulose (extragranular); (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight of magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 2.

[0036] In some embodiments, the solid pharmaceutical composition comprises (a) 70% by weight of erdafitinib L-lactate, (b) 1.43% by weight of hydroxypropyl methylcellulose, (c) 12.91% by weight of microcrystalline cellulose, (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of sodium stearyl fumarate, the weight percentages being based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 70% by weight of Erdafitinib L-lactate (intragranular); (b) 1.43% by weight of hydroxypropyl methylcellulose (intragranular); (c) 12.91% by weight of microcrystalline cellulose (extragranular); (d) 12.91% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (intragranular); (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight of sodium stearyl fumarate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 3.

[0037] In some embodiments, the solid pharmaceutical composition comprises (a) 60% by weight of erdafitinib-L-lactate, (b) 1.23% by weight of hydroxypropyl methylcellulose, (c) 18.01% by weight of microcrystalline cellulose, (d) 18.01% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of magnesium stearate, the weight percentages being based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 60% by weight of Erdafitinib L-lactate (intragranular); (b) 1.23% by weight of hydroxypropyl methylcellulose (intragranular); (c) 18.01% by weight of microcrystalline cellulose (extragranular); (d) 18.01% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight of magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 4.

[0038] In some embodiments, the solid pharmaceutical composition comprises (a) 80% by weight of erdafitinib-L-lactate, (b) 1.63% by weight of hydroxypropyl methylcellulose, (c) 7.81% by weight of microcrystalline cellulose, (d) 7.81% by weight of vinylpyrrolidone-vinyl acetate (PVP VA), (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic), and (f) 2.5% by weight of magnesium stearate, the weight percentages being based on the total solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition comprises: (a) 80% by weight of erdafitinib L-lactate (intragranular); (b) 1.63% by weight of hydroxypropyl methylcellulose (intragranular); (c) 7.81% by weight of microcrystalline cellulose (extragranular); (d) 7.81% by weight of vinylpyrrolidone-vinyl acetate (PVP VA) (extragranular); (e) 0.25% by weight of colloidal silicon dioxide (hydrophilic) (extragranular); and (f) 2.5% by weight of magnesium stearate (extragranular). In some embodiments, the solid pharmaceutical composition is a tablet. In some embodiments, the formulation is Concept 5.

[0039] In an embodiment, the erdafitinib drug and excipients are selected and the tablet is formulated to allow the release of the drug from the tablet. In an embodiment, the erdafitinib is formulated in a pharmaceutical composition such that it can be sterilized either in or out of the drug delivery system without substantial or adverse changes to the chemical or physical composition of the drug tablet that would otherwise render the drug tablet unsuitable for delivery of erdafitinib as described herein. In one aspect, the erdafitinib drug and excipients are selected for their compatibility with sterilization processes. In one embodiment, the drug delivery system comprising the drug tablet is sterilized as a whole. In particular, the drug delivery system comprising the drug tablet is sterilized by gamma irradiation.

[0040] In one aspect, erdafitinib drug tablets can be sized and shaped to be used with the body-introducing drug delivery system, including the intravesical drug delivery system disclosed herein.For example, erdafitinib drug tablets can be "mini-tablets", which are generally smaller in size than conventional tablets, and mini-tablets can allow the drug tablets contained in the system to be inserted through a specific body cavity, such as the urethra, into a cavity, such as the bladder.Erdafitinib tablets can be coated or uncoated.In particular, uncoated tablets can work well in combination with the delivery system disclosed herein.

[0041] An embodiment of a mini-tablet is shown in FIG. 3, which shows a mini-tablet 312 having a circular flat end surface 326 and a cylindrical side wall 328 .

[0042] In embodiments, the pharmaceutical tablet for intravesical insertion may be in the form of a solid cylinder, the solid cylinder having a cylinder axis, a cylinder side, a circular end surface perpendicular to the cylinder axis, a diameter of the circular end surface, and a length along the cylinder side. In the cylindrical form, each mini-tablet may have a length (L) that exceeds its diameter (D), such that the mini-tablet has an aspect ratio (L:D) of greater than 1:1. For example, the aspect ratio (L:D) of each mini-tablet may be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or a range of values ​​between these aspect ratios. Mini-tablet embodiments may have a cylinder diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm, or 2.0 mm to 2.7 mm, or 2.5 mm to 2.7 mm. In some aspects, the mini-tablets may have a diameter of 2.4 mm to 2.8 mm. In some embodiments, the mini-tablets may have a length of 1.7 mm to 4.8 mm, or 2.0 mm to 4.5 mm, or 2.8 mm to 4 mm, or 3 mm to 3.5 mm. In some embodiments, the mini-tablets may have a length of 3.0 mm to 3.4 mm.

[0043] The API used in the solid tablet formulation can be erdafitinib, which is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, the chemical structure of which is shown below. The erdafitinib tablets for use in the disclosed intravesical systems can be formulated using a salt of erdafitinib. In some particular embodiments, the erdafitinib tablets for use in the disclosed intravesical systems can include a lactate salt of erdafitinib. In certain embodiments, the erdafitinib tablets for use in the disclosed intravesical systems can be an L-lactate salt of erdafitinib, in particular the mono L-lactate salt of erdafitinib.

[0044] [ka]

[0045] A general reference to a compound includes all stereoisomers unless otherwise expressly indicated, and a reference to a general structure or name includes all enantiomers, diastereomers, and other optical isomers, whether enantiomeric or racemic, as well as mixtures of stereoisomers, if the context permits or requires. For any particular formula or name provided, any general formula or name provided also includes all stereoisomers that may result from a particular set of substituents. Thus, for example, as used herein, a reference to "lactate" includes both D and L isomers.

[0046] In embodiments, the erdafitinib drug tablet may incorporate various excipients, including but not limited to at least one solubilizer, at least one binder, at least one wetting agent, at least one disintegrant, at least one stabilizer, at least one diluent, at least one glidant, at least one lubricant, at least one osmotic agent (osmogen), etc., or any combination thereof. In embodiments, the erdafitinib drug tablet may be free of various excipients or combinations of excipients, including but not limited to solubilizers, wetting agents, at least one stabilizer, at least one disintegrant, at least one osmotic agent (osmogen), or any combination thereof. In embodiments, the erdafitinib drug tablet includes at least one binder, at least one filler (excipient), at least one glidant, at least one lubricant, or any combination thereof. Any excipient or any combination of excipients may be present in the intragranular composition, the extragranular composition, or both the intragranular and extragranular compositions. In one embodiment, the at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient may be the same, i.e., selected from at least one common (present in both) pharmaceutical excipient. In a further embodiment, the intragranular pharmaceutical excipient and the extragranular pharmaceutical excipient do not include a common (present in both) pharmaceutical excipient, whereby the intragranular excipient and the extragranular excipient are mutually exclusive. In an embodiment, an erdafitinib drug tablet, particularly an erdafitinib lactate drug tablet comprising 50% to 90%, 60% to 80%, 65% to 75%, e.g., 70% by weight of erdafitinib in its lactate salt form, particularly its L-lactate form, comprises at least one binder, at least one diluent, at least one glidant, at least one lubricant, or any combination thereof.

[0047] It will be understood that these functional descriptions of the various excipients are generally used as follows: Solubilizers may improve or enhance the solubility of the API within the drug lumen of the disclosed system after in vivo insertion. Binders may hold the solid particles of the composition together for physical stability. Wetting agents may reduce the surface tension between the drug and the medium in which the drug occurs, helping to maintain the solubility of the drug. Disintegrants may aid in mini-tablet disintegration when in contact with water (urine) releasing the drug substance. Stabilizers may improve the chemical stability, e.g., thermal stability, of a formulation containing the API or protect the API from degradation. Diluents may function as bulking agents to increase the volume or weight of the composition, which may aid in providing a tablet of the desired size. Glidants may improve the flow properties of the (granulated) particles of the tablet components or the powder blend being compressed. Lubricants may prevent particles of the composition from adhering to components of the manufacturing equipment, e.g., the dies and punches of a tablet press. The osmotic agent dissolves in the aqueous fluid in the delivery system, causing an increase in osmotic pressure therein.

[0048] In embodiments, the erdafitinib L-lactate formulation may include all or only some of these excipients. For example, in one aspect, the erdafitinib L-lactate formulation may be free of solubilizers, free of wetting agents, free of disintegrants, free of stabilizers (e.g., free of meglumine), free of osmotic agents, or free of any combination of these excipients. For example, in another aspect, the drug itself, such as the lactate salt of erdafitinib, may function as an osmotic agent. In one aspect, the drug itself, such as the lactate salt of erdafitinib, functions as an osmotic agent, and the erdafitinib lactate formulation does not include other osmotic agents. In one aspect, the excipients may be water-soluble. In another aspect, the excipients may be colloidal in water. According to another aspect, the excipients may be soluble under the conditions of its deployment in a patient, for example, in the bladder. These and other excipients are described in more detail below.

[0049] Formaldehyde scavengers and other stabilizers In one aspect, erdafitinib API may be susceptible to degradation under certain conditions when incorporated into solid formulations.For example, erdafitinib may degrade or be converted in the presence of formaldehyde to form cyclization product 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.Formaldehyde may come into contact with erdafitinib from various sources in the environment, for example, from packaging materials, or as contaminants in excipients or other components of the formulation.

[0050] Thus, in one aspect, the erdafitinib pharmaceutical formulation may include a formaldehyde scavenger to improve the stability or shelf life of the formulation.Various formaldehyde scavengers may be used, but the formaldehyde scavenger may prevent, slow down, reduce, or postpone the formation of decomposition products when erdafitinib comes into contact with formaldehyde.Therefore, the stability of the erdafitinib pharmaceutical formulation, for example, its chemical stability, may be increased in the presence of a formaldehyde scavenger, compared to the erdafitinib pharmaceutical formulation in the absence of the formaldehyde scavenger.In one aspect, the formaldehyde scavenger may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular composition and the extragranular composition.In one aspect, the formaldehyde scavenger, particularly meglumine, may be present in the solid pharmaceutical composition as a component of the intragranular solid composition.

[0051] Formaldehyde scavengers may include or be selected from compounds that contain reactive nitrogen centers, such as compounds containing amine or amide groups. Without being bound by theory, these compounds react with formaldehyde to form Schiff base imines (R 1 R 2 C=NR 3 , where R 3It is believed that the Schiff base imine itself may bind formaldehyde (wherein the Schiff base imine is not hydrogen). Examples of such formaldehyde scavengers include, but are not limited to, amino acids, amino sugars, alpha-(α-)amine compounds, complexes and derivatives thereof, and mixtures thereof. Such formaldehyde scavenger compounds may contain two or more amine and / or amide moieties capable of scavenging formaldehyde.

[0052] In one embodiment, the formaldehyde scavenger may include or be selected from, for example, meglumine, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, taurine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolidine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, complexes thereof, pharma- ceutically acceptable salts thereof, or any combination thereof. According to one embodiment, the formaldehyde scavenger may include or be selected from meglumine or a pharma- ceutically acceptable salt thereof, in particular meglumine base.

[0053] Therefore, one aspect of the present disclosure is to use a formaldehyde scavenger, particularly meglumine, in an erdafitinib pharmaceutical formulation, such as a drug tablet, to increase the stability of any form of erdafitinib, including erdafitinib salt forms, such as erdafitinib L-lactate.The chemical stability of the erdafitinib pharmaceutical formulation is increased compared to an erdafitinib pharmaceutical formulation or composition that does not contain a formaldehyde scavenger.One aspect of the present disclosure is a method of preventing, slowing, reducing, or postponing the formation of degradation products that may be formed from erdafitinib in the presence of formaldehyde, such as the following compounds:

[0054] [ka]

[0055] In one aspect, decomposition products, such as those described above, may occur in solid tablet compositions, such as mini-tablet formulations, particularly the mini-tablets disclosed herein.

[0056] When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 2% by weight, 0.5% to 1.5% by weight, or about 1% by weight.When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of 5% to 10% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight.

[0057] In one aspect, the pharmaceutical compositions described herein, in particular the erdafitinib drug tablets, do not contain stabilizers or formaldehyde scavengers.

[0058] Solubilizer In one aspect, the erdafitinib formulation may include a solubilizer. The solubilizer may be in the intragranular component, the extragranular component, or both the intragranular and extragranular components of the formulation. In an embodiment, the solubilizer may include or be selected from, for example, (a) cyclic oligosaccharides, (b) cellulose functionalized with methoxy, 2-hydroxypropoxy, acetyl, or succinoyl moieties, or combinations thereof, or (c) salts thereof. In one embodiment, the solubilizer is present in the intragranular component. In other aspects, the erdafitinib formulation may not include a solubilizer.

[0059] In embodiments, the solubilizer for erdafitinib tablet formulation may include or be selected from oligosaccharides. In embodiments, the solubilizer may include or be selected from cyclic oligosaccharides, such as cyclodextrins. Cyclodextrin solubilizers suitable for erdafitinib tablet formulation include, but are not limited to, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin sodium salt, or any combination thereof. In other embodiments, the solubilizer may include or be hydroxypropylmethylcellulose E5 (HPMC-E5). In other embodiments, the solubilizer for erdafitinib tablet formulation may include or be hydroxypropylmethylcellulose acetate succinate.

[0060] The oligosaccharide solubilizer may be present in an erdafitinib tablet form at a concentration of 1% to 20% by weight, alternatively 3% to 18% by weight, alternatively 5% to 15% by weight, alternatively 7% to 12% by weight, or alternatively 10% by weight or about 10% by weight. The cyclodextrin solubilizer may be present in an erdafitinib tablet formulation, such as an erdafitinib salt formulation, at a concentration of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight, or any range between any of these weight percentages.

[0061] In one aspect, the solubilizer for the erdafitinib tablet formulation disclosed herein can include or can be hydroxypropyl-beta-cyclodextrin. One embodiment of the erdafitinib formulation includes a hydroxypropyl-β-cyclodextrin solubilizer, which may be present in the intragranular composition. In one aspect, the pharmaceutical compositions described herein, particularly the erdafitinib drug tablet, do not contain a solubilizer.

[0062] Binder The pharmaceutical excipients for erdafitinib solid pharmaceutical composition may include one or more binders. One or more binders may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. Suitable binders may be water-soluble, water-insoluble, or slightly water-soluble, or combinations thereof. In certain embodiments, the binder is an aspect, and the binder may include a water-soluble binder, such as a water-soluble polymer binder. The polymer binder may include a non-ionic polymer that is pH stable in aqueous solution.

[0063] Those skilled in the art will appreciate that binders can also function as diluents (also called bulking agents) in pharmaceutical compositions. Thus, the binders provided in this disclosure can also be used for these diluent functions, if desired, unless otherwise noted.

[0064] In one aspect, suitable binders may include or be selected from, but are not limited to, polyvinylpyrrolidone (PVP, also referred to as polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate), PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also referred to as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also referred to as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof. In one aspect, suitable binders may include or be selected from polyvinylpyrrolidone (PVP, also referred to as polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also referred to as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also referred to as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or combinations thereof. In one aspect, suitable binders may include or be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or combinations thereof. In one aspect, suitable binders may include or be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or combinations thereof.

[0065] In a further aspect, suitable binders may include or be selected from polymers or copolymers of vinylpyrrolidone (VP, also 1-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Suitable binders may also include or be selected from polymers or copolymers of ethylene oxide (EO) and propylene oxide (PO). Likewise, these binders may be used in combination with other binders, for example in combination with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0066] In one embodiment, the total concentration of the at least one binder in the solid pharmaceutical composition can be 5% to 30% by weight, 10% to 25% by weight, 12% to 22% by weight, or 14% to 19% by weight. In one embodiment, the total concentration of the at least one binder in the solid pharmaceutical composition can be about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

[0067] According to another embodiment, a suitable polymeric binder may include or be selected from a copolymer of vinylpyrrolidone and vinyl acetate, which may be referred to as poly(vinyl-pyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable binders include Kollidon® VA64 and Kollidon® VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), which have a molecular weight (Mw) range of 45,000 g / mol to 70,000 g / mol based on solution light scattering measurements. Another suitable binder is Kollidon® K30.

[0068] In embodiments, the polymeric binder, e.g., vinylpyrrolidone-vinyl acetate copolymer, may be present in the disclosed erdafitinib tablet formulation at a concentration of 2% to 15% by weight, alternatively 4% to 12% by weight, alternatively 6% to 10% by weight, or alternatively 8% or about 8% by weight. For example, the vinylpyrrolidone-vinyl acetate copolymer binder may be present in the erdafitinib tablet formulation at a concentration of 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, or any range between any of these weight percentages. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in an intragranular composition. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in an intragranular composition, which is prepared by roller compaction. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular composition at a concentration of 8% to 14% by weight, alternatively 7.5% to 18.5% by weight. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular composition at a concentration of 8% to 14% by weight, alternatively 9% to 13% by weight.

[0069] In one aspect, the binder can include or be microcrystalline cellulose. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition at a concentration of 5% to 20%, 6% to 15%, or 7% to 12% by weight.

[0070] In another embodiment, the binder may comprise silicified microcrystalline cellulose or may be microcrystalline cellulose. For example, the silicified microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 3% to 18%, 4% to 15%, or 5% to 12% by weight.

[0071] In another embodiment, the binder may include or be hydroxypropyl methylcellulose. For example, hydroxypropyl methylcellulose, e.g., HPMC 290 15 mPa.s, may be present in the solid pharmaceutical composition at a concentration of 0.5% to 5% by weight, or 0.5% to 2% by weight, or 1% to 2% by weight.

[0072] Wetting Agent The pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more wetting agents. The one or more wetting agents may be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In an exemplary embodiment, the wetting agent may include or be independently selected from an anionic surfactant or a nonionic surfactant, in particular an anionic surfactant. For example, the wetting agent may include or be independently selected from sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof. In an embodiment, the total concentration of the wetting agent in the solid pharmaceutical composition may be 0.01% to 2.5% by weight, 0.05% to 1.0% by weight, or 0.1% to 0.5% by weight. In one embodiment, the wetting agent is present in the intragranular composition.

[0073] In one embodiment, the erdafitinib solid pharmaceutical composition does not include one or more humectants.

[0074] Disintegrants The pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more disintegrants. One or more disintegrants may be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In one embodiment, the disintegrant is present in the intragranular composition. In one embodiment, the disintegrant is present in the intragranular composition, and the intragranular composition is prepared by roller compaction.

[0075] In an exemplary embodiment, the disintegrant may include or be independently selected from a functionalized polysaccharide or a cross-linked polymer. For example, in one aspect, the disintegrant may include or be selected from, for example, (a) a cellulose functionalized with methoxy, 2-hydroxypropoxy, or carboxymethoxy moieties, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a cross-linked polymer.

[0076] In embodiments, the disintegrant may include or be independently selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof.

[0077] When present, disintegrants may be present in a range of concentrations, in embodiments, the total concentration of disintegrant in the solid pharmaceutical composition may be 0.1% to 10% by weight, 0.2% to 8% by weight, 0.5% to 7% by weight, 1% to 5% by weight, or 2% to 3% by weight.

[0078] In one embodiment, the erdafitinib solid pharmaceutical composition does not contain one or more disintegrants.

[0079] Diluents or fillers Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more diluents. One or more diluents may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions.

[0080] In an exemplary embodiment, the diluent may include or be selected from sugar, starch, microcrystalline cellulose, sugar alcohol, hydrogen phosphate, dihydrogen phosphate, carbonate, or any combination thereof. In one aspect, the diluent may include or be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, anhydrous dicalcium phosphate, calcium carbonate, sucrose, or any combination thereof. In one aspect, the diluent may include or be selected from microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, anhydrous dicalcium phosphate, or any combination thereof. In one aspect, the diluent may include or be selected from microcrystalline cellulose and silicified microcrystalline cellulose, or any combination thereof.

[0081] In embodiments, the total concentration of the diluent in the solid pharmaceutical composition may be 10% to 30% by weight, 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight, or 10% to 25% by weight, or 10% to 20% by weight, or 10% to 15% by weight. In embodiments, the total concentration of the diluent in the solid pharmaceutical composition may be 5% to 30% by weight, 10% to 30% by weight, or 10% to 20% by weight. In some embodiments, the diluent comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. For example, in some aspects, the diluent may comprise or be selected from microcrystalline cellulose at a concentration of 15% to 25% by weight, or 20% to 22% by weight. For example, in some aspects, the diluent may comprise or be selected from microcrystalline cellulose at a concentration of 5% to 20%, or 7.5% to 18.5%, or 5% to 15%, or 8% to 14% by weight, and / or silicified microcrystalline cellulose at a concentration of 5% to 10%, or 7% to 8% by weight. In some embodiments, the diluent does not comprise silicified microcrystalline cellulose. In further aspects, the diluent may comprise or be selected from dicalcium phosphate at a concentration of 18% to 20% by weight.

[0082] Those skilled in the art will appreciate that some of the diluents / fillers disclosed herein may also function as binders in pharmaceutical compositions. Thus, some compounds or materials may be described herein as providing a binder function and as providing a diluent function.

[0083] Glidants The pharmaceutical excipients for erdafitinib solid pharmaceutical composition may include one or more glidants. One or more glidants may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In one embodiment, the glidant is present in the extragranular composition. As used in this disclosure, glidant refers to a pharmaceutical excipient that improves or optimizes the particle flow properties of granulated or powdered tablet components in particle form by reducing the interaction, attraction, cohesion, or friction between particles.

[0084] In one aspect, the glidant may include or be selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. In embodiments, the total concentration of the glidant in the solid pharmaceutical composition may be 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 1% by weight, or about 0.2% by weight, or about 0.25% by weight, or about 0.3% by weight, about 0.35% by weight, or about 0.4% by weight, or about 0.45% by weight, or about 0.5% by weight. In embodiments, the total concentration of the glidant in the solid pharmaceutical composition may be about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.25% by weight. In one embodiment, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide (hydrophilic). In some embodiments, the glidant is colloidal silicon dioxide (hydrophobic).

[0085] lubricant Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more lubricants. One or more lubricants may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular compositions. In one aspect, the lubricant is present in the extragranular composition. In one aspect, the lubricant is present in the intragranular composition, which is prepared by roller compaction. As used in this disclosure, a lubricant refers to a pharmaceutical excipient that is added to a tablet formulation to reduce friction at the surface of the tablet. In embodiments, the lubricant may reduce friction between the surface of the tablet and processing equipment, for example, between the surface of the tablet and the wall of the die cavity in which the tablet is formed. Thus, the lubricant may reduce friction between the die wall and the granules of the formulation as the tablet is formed and ejected. A pharma-ceutically acceptable lubricant is a non-toxic and pharmacologically inactive substance. Furthermore, the lubricant may be water-soluble or water-insoluble, although it is preferred that the lubricant be water-soluble in the drug delivery system of the present disclosure.

[0086] In one embodiment, the lubricant comprises or is magnesium stearate. In some embodiments, the lubricant comprises or is sodium stearyl fumarate. In some embodiments, the lubricant comprises or is polyethylene glycol (e.g., PEG8K).

[0087] In one aspect, the lubricant may include or be selected from, for example, fatty acids, fatty acid salts, fatty acid esters, talc, glyceride esters, metal silicates, or any combination thereof. In an embodiment, the lubricant may include or be selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearoyl fumarate, titanium dioxide, or any combination thereof. Examples of water-soluble lubricants include, but are not limited to, leucine, sodium lauryl sulfate, sucrose stearate, boric acid, sodium acetate, sodium oleate, sodium stearyl fumarate, and PEG. In another aspect, the total concentration of the lubricant in the solid pharmaceutical composition may be 0.05% to 5% by weight, 0.1% to 3% by weight, 1% to 2% by weight, or about 1.5% by weight, or about 2.5% by weight. In another embodiment, the total concentration of the lubricant in the solid pharmaceutical composition can be from 0.05% to about 5% by weight, from about 1% to about 5% by weight, or about 2.5% by weight.

[0088] Osmotic agents A drug or a particular salt form of a drug may function as an osmotic agent by itself, and a drug formulation having such a drug or its salt form may optionally include one or more additional pharma- ceutically acceptable osmotic agents that are pharmacologically inactive substances. A pharmaceutical excipient for an erdafitinib solid pharmaceutical composition may include one or more osmotic agents. One or more osmotic agents may be present in a solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. Examples of osmotic agents include, but are not limited to, inorganic salts and carbohydrates, such as urea, potassium chloride, sodium chloride, sucrose, fructose, lactose, and mannitol.

[0089] In one embodiment, the drug itself, particularly erdafitinib lactic acid, especially erdafitinib mono L-lactic acid, functions as an osmotic agent.

[0090] Method for preparing a tablet composition In one aspect, a process for making solid pharmaceutical compositions such as tablets, particularly mini-tablets, is provided. In some embodiments, the process comprises preparing an intragranular solid composition comprising erdafitinib L-lactate and at least one intragranular pharmaceutical excipient. In some embodiments, the intragranular pharmaceutical excipient comprises a binder. The binder may be any binder described herein. For example, the binder may be hydroxypropyl methylcellulose. In some embodiments, the process comprises combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend. In some embodiments, the intragranular excipient and the extragranular excipient do not comprise a common excipient. In some embodiments, the extragranular excipient comprises one or more of a binder, a filler, a glidant, and / or a lubricant. Each of the extragranular binders, fillers, glidants, and / or lubricants may be any binder, filler, glidant, and / or lubricant described herein, respectively. In some embodiments, the extragranular binder comprises vinylpyrrolidone-vinyl acetate (PVP VA). In some embodiments, the extragranular filler comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. In some embodiments, the extragranular filler comprises microcrystalline cellulose. In some embodiments, the extragranular filler comprises a combination of microcrystalline cellulose and silicified microcrystalline cellulose. In some embodiments, the extragranular glidant may be any glidant described herein. In some embodiments, the extragranular glidant comprises colloidal silicon dioxide (hydrophilic). In some embodiments, the extragranular lubricant may be any lubricant described herein. In some embodiments, the extragranular lubricant comprises magnesium stearate. In some embodiments, the extragranular lubricant comprises sodium stearyl fumarate. In some embodiments, the extragranular lubricant comprises polyethylene glycol. In some embodiments, the process comprises tableting the blend to form a solid pharmaceutical composition. In some embodiments, the tableting is characterized by an ejection force of less than about 1000 N.

[0091] Osmotic Drug Delivery Systems Described herein are drug delivery systems that are particularly suitable for effective release of drug formulations containing erdafitinib, such as those detailed above.These particular systems utilize osmotic pressure to drive the controlled release of drug through one or more openings in the system housing.The terms "opening" and "orifice" can be used interchangeably with "opening".

[0092] In certain embodiments, the system includes a water-permeable, drug-impermeable polymeric component that forms a housing. For example, the polymeric component may be formed from a biocompatible elastomeric composition, such as a silicone or thermoplastic polyurethane composition, that has desired mechanical properties (e.g., soft, elastically flexible). The polymeric component may have a tubular structure, such as a dual lumen tube.

[0093] In one aspect, as shown in FIGS. 1A-1B, a drug delivery system 100 includes a flexible device body 102 that defines a drug reservoir lumen 104 and a retaining frame lumen 106. The drug reservoir lumen 104 contains a plurality of solid drug tablets 108 disposed end-to-end within the drug reservoir lumen. In some embodiments, including the one shown, the drug tablets 108 have circular flat end faces and cylindrical side walls. The retaining frame lumen 106 houses an elastic wire or retaining frame 110. The retaining frame may be a superelastic alloy such as Nitinol. Silicone spacers 120 are secured to the ends of the drug reservoir lumen 104, for example using a silicone adhesive, to close / occlude the drug reservoir lumen 104 at its ends and retain the drug tablets 108 therein.

[0094] 1B, the device body 102 includes a tubular wall structure 112 that defines the drug reservoir lumen 104 and a smaller tubular wall structure 114 that defines the retaining frame lumen 106. The wall structures 112, 114 and lumens 104, 106 are substantially cylindrical as shown, although other variations in shape are possible.

[0095] In a preferred embodiment, the tubular wall structure 112, 114 is formed from silicone (MED-4750), and the tubular wall structure 112 has a wall thickness of 0.1 mm to 0.5 mm, or 0.15 mm to 0.4 mm, or 0.18 mm to 0.3 mm, or 0.2 mm. In some embodiments, the tubular wall structure 112 defining the drug reservoir lumen 104 may be formed from another elastomeric material that is impermeable to the drug. As used herein, the term "drug impermeable" or "drug impermeable" refers to a housing that is substantially impermeable to a solubilized drug, e.g., erdafitinib, over the course of a therapeutic period in which the system is deployed in vivo, such that a substantial amount of the solubilized drug cannot diffuse therethrough.

[0096] The device body 102 includes an opening 130 extending through a sidewall of the tubular wall structure 112 that defines the drug reservoir lumen 104. In the illustrated embodiment, the device body has a single drug release opening. In an exemplary embodiment, the opening has a diameter of about 20 μm to about 500 μm, such as about 25 μm to about 300 μm, and more particularly, about 30 μm to about 200 μm. In one example, the opening has a diameter of about 100 μm to about 200 μm, such as about 150 μm. In some other embodiments, the device body may have two or more openings.

[0097] 2, the drug delivery system 100 operates in vivo as an osmotic pump: Water or urine from the patient's body diffuses through the tubular wall structure 112, contacts and solubilizes the drug tablet 108, and creates osmotic pressure that drives the solubilized drug out of the drug delivery system through the orifice 130.

[0098] In some embodiments, the system includes a single opening, i.e., a through-hole, disposed in the sidewall of the tubular housing.

[0099] In some embodiments, the system is a closed structure configured to release a drug through the temporary formation of microchannels defined between and at the interface of two surfaces and / or two components within the system, as described in U.S. Pat. No. 9,814,671, the entirety of which is incorporated herein by reference.

[0100] In some particular embodiments, the system includes both a tubular housing and a through-hole in the housing structure configured to release the drug through the temporary formation of microchannels defined between and at the two surfaces and / or interfaces of the two components, as described in U.S. Pat. No. 11,020,575, which is incorporated herein by reference in its entirety. In some embodiments, the microchannels are formed in response to hydrostatic pressure building up within the permeable body due to osmotically driven influx of water. When the hydrostatic pressure increases beyond a certain threshold, the microchannels are formed, thereby forcing at least a portion of the drug out of the device and relieving the hydrostatic pressure buildup within the drug reservoir. The microchannels may at least partially collapse when the hydrostatic pressure is released. This process repeats itself until all or a substantial portion of the drug is released or until the influx of osmotically driven water is insufficient to continue the process. 16A and 16C, drug delivery device 50 includes a device body 52 having a water-permeable wall portion 64 that bounds a reservoir 60 (also referred to herein as a "reservoir lumen" or "drug reservoir lumen") that contains a payload 58, such as a drug formulation (e.g., mini-tablets). Water-permeable wall portion 64 may generally be configured to allow water to enter the device and contact the drug formulation (i.e., payload) 58 located within reservoir 60 to facilitate release of fluidized drug 58A from the device. For example, osmotically driven influx of water into reservoir 60 may create pressure within reservoir 60 that drives release of fluidized drug 58A from reservoir 60 via one or more mechanisms. For example, in the embodiments described herein, release of fluidized drug 58A from the device may occur through one or more preformed sidewall orifices 66 and / or through the temporary formation of one or more microchannels 62 leading to an opening in the end of the device. For example, device 50 may further include a resilient portion 54 that surrounds restraining plug 56 and controls release of drug from the device through the temporary formation of one or more microchannels 62 between 54 and 56.As indicated by the dashed arrow, water diffuses through the water-permeable wall 64 of the body 52 and enters the drug reservoir 60 to form a fluidized drug 58A, which may be, for example, an aqueous solution containing a drug provided in the payload 58 initially loaded into the reservoir 60. The hydrostatic pressure within the reservoir 60 forces the fluidized drug 58A out of the reservoir 60 between the elastic portion 54 and the restraining plug 56 through a microchannel 62 formed therebetween, for example, by elastic deformation of one or both of the interfaces. In certain embodiments described herein, a combination of these release mechanisms is used to provide a desired drug release profile.

[0101] As shown in FIG. 16B, the device 50 of FIG. 16A is shown in plan view in a relatively expanded configuration suitable for retention within the body, e.g., the bladder. The device includes a water-permeable body 52 having a drug reservoir portion 78 and a retention frame portion 76. The retention frame portion 76 may include a retention frame 74 that is deformable between a relatively expanded configuration and a relatively low-profile configuration suitable for insertion into the bladder via a catheter. In some embodiments, the retention frame 74 includes or is made of an elastic wire. For example, the retention frame 74 is an elastic wire formed from a superelastic alloy, such as Nitinol. The drug reservoir lumen may be loaded with multiple drug units 158 in a serial arrangement. The drug units may be tablets, such as mini-tablets. As used herein, the term "drug reservoir portion" refers to the portion of the device that forms and defines the "drug reservoir" or the "drug reservoir lumen." For purposes of this disclosure, the term "retention shape" generally refers to any shape suitable for retaining the device within the bladder, including, but not limited to, a coiled or "pretzel" shape as shown in FIG. 16B. This retention shape prevents the device from being entrapped and expelled in urine when the patient urinates. The terms "relatively expanded shape" and "relatively higher profile shape" may be used interchangeably with "retention shape."

[0102] 2, the device body 102 may be formed by a molding or extrusion process, or an additive manufacturing process. In some embodiments, where the drug and device components are produced separately and then combined, the drug construct (e.g., a tablet) is loaded into the drug reservoir lumen, which is then closed at its ends, for example, with a silicone spacer and / or adhesive. In some other embodiments, the drug and device components are manufactured together in an additive manufacturing process, such as a 3D printing process, which is well known in the art.

[0103] In an embodiment, the system is configured for intravesical insertion and retention in a patient. In a preferred embodiment, the system is elastically deformable between a low-profile deployed configuration (e.g., a relatively straightened configuration) suitable for insertion through the patient's urethra into the patient's bladder and a relatively expanded retention configuration (e.g., a pretzel shape, a bi-elliptical coil shape, an S-shape, etc.) suitable for retention in the bladder. For example, the housing or tube of the system may have two opposing free ends that are directed away from each other when the system is in the low-profile deployed configuration and toward each other when the system is in the relatively expanded retention configuration. The relatively expanded configuration may include a pair of overlapping coils, often referred to as a "pretzel" shape. In certain embodiments, the extended system ends are generally within the boundaries of the bi-elliptical expanded retention configuration.

[0104] Within the bladder, the system should be compliant (i.e., easily flexed and soft-feeling) during detrusor contraction to avoid or reduce discomfort and irritation to the patient. For example, the system may be configured for tolerability based on bladder characteristics and design considerations described in U.S. Patent No. 11,065,426, which is incorporated herein by reference.

[0105] In some embodiments, the system includes a retention frame lumen, and in some of these embodiments, the retention frame lumen includes a retention frame, i.e., an elastic wire, such as a Nitinol wire. In certain other embodiments, the retention frame lumen is filled with a shape-set elastic polymer. In some other embodiments, the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the housing is configured to be elastically deformable between a straightened shape and a retention shape in the absence of a retention frame or wire. For example, in certain embodiments, the tubular housing is heat-shape-set to have a coiled or other retention shape.

[0106] In embodiments, the tubular housing may be formed from a water-permeable material. In preferred embodiments, as described above for the erdafitinib solid formulation, the drug is in a solid form (e.g., a tablet or tablets) and the tubular body is water-permeable to allow in vivo solubilization of the drug while within the drug reservoir lumen. In some other embodiments, the solid formulation may be in a free-flowing particulate form, such as beads, granules, powder, etc.

[0107] In some embodiments, the material for the wall structure of the system is selected from silicones and suitable thermoplastic polyurethane (TPU) based materials well known in the art, hi some embodiments, the material for the wall structure is a platinum cured silicone elastomer.

[0108] In one aspect, the system housing is in the form of a ring, i.e., a cylindrical tube. In one embodiment, the inner diameter of the cylindrical tube may be 1.0 mm to 3.0 mm, or 2.0 mm to 3.0 mm, or 2.2 mm to 2.8 mm, or 2.6 mm to 2.7 mm, or 2.64 mm. In one embodiment, the outer diameter of the cylindrical tube is about 2.0 mm to about 4.1 mm. In one embodiment, the wall structure (annulus) of the cylindrical tube has a thickness of about 0.2 mm to about 1.0 mm.

[0109] In an embodiment, the systems described herein are configured to release a therapeutically effective amount of the drug, and the rate of release of the drug from the drug delivery system is zero order for at least 36 hours. In one embodiment, the rate of release of the drug from the drug delivery system is essentially zero order for at least 7 days. In an embodiment, the system is configured to release a therapeutically effective amount of the drug over a period of 2 days to 6 months, e.g., 2 days to 90 days, 7 days to 30 days, or 7 days to 14 days. Desirably, the rate of release of the drug from the drug delivery system is zero order for at least 7 days, e.g., 7 to 14 days or more, e.g., up to 3 months or 90 days. In certain embodiments, the system is configured to begin releasing the drug after a lag time.

[0110] In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day, depending on the desired treatment regimen. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 2 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 4 mg / day to 6 mg / day. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day or 4 mg / day. In some embodiments, the system is configured to release erdafitinib in a zero order release profile.

[0111] The osmotic drug delivery system may be loaded with a solid form of erdafitinib salt, such as a tablet, as described throughout this disclosure. For example, the system may have a drug reservoir lumen configured to hold a plurality of the disclosed drug tablets in an elongated form, arranged end-to-end in series. In some embodiments, the system holds about 10-100 cylindrical drug tablets (e.g., 44 tablets), e.g., mini tablets, which may be loaded sequentially into the drug reservoir lumen. In some embodiments, the system holds about 10-100 cylindrical drug tablets (e.g., about 40-50 tablets), e.g., mini tablets, which may be loaded sequentially into the drug reservoir lumen. In some embodiments, each mini tablet has a mass of about 20 mg to about 30 mg, or about 22 mg to about 24 mg. In some embodiments, the formulation comprises a mini-tablet having a total length of about 14 cm to about 16 cm, about 14.5 cm to about 15.5 cm, or about 14.7 cm to about 14.8 cm. In some embodiments, the total tablet mass loaded into the system is about 900 mg to about 1000 mg. In some embodiments, the total tablet mass loaded into the system is about 920 mg to about 965 mg. In some embodiments, the total tablet mass loaded into the system is about 920 mg to about 950 mg. In some embodiments, the system comprises about 500 mg to about 750 mg of erdafitinib (free base equivalent).

[0112] In some embodiments, the drug delivery system comprises a dual lumen system including a silicone tube having a wall thickness of 0.2 mm, the dual lumen system including (i) a retention frame lumen ("small lumen") that encapsulates a wireform as a retention feature, and (ii) a drug reservoir lumen ("large lumen") having an inner diameter of 2.64 mm that is filled with a plurality of mini-tablets, the silicone tube surrounding the drug reservoir lumen including a single 150 μm orifice, and the drug reservoir lumen sealed by two end plugs (e.g., parylene coated end plugs) that can be sealed (e.g., using silicone adhesive) to the silicone tube surrounding the drug reservoir lumen and form temporary microchannels. The mini-tablets may, for example, have a total mini-tablet length of about 15.0 cm and a total tablet mass of about 932 mg (e.g., 620 mg of erdafitinib (free base equivalent) when the mini-tablet comprises 80% by weight erdafitinib mono-L-lactic acid, 18% by weight microcrystalline cellulose, 0.5% by weight hydrophilic colloidal silicon dioxide, and 1.5% by weight magnesium stearate). The mini-tablets may have a total mini-tablet length of about 15.0 cm and a total tablet mass of about 932 mg (e.g., 620 mg erdafitinib (free base equivalent)), for example, when the mini-tablets contain 80 wt% erdafitinib mono-L-lactic acid intragranularly, 18 wt% microcrystalline cellulose (intragranular), 0.5 wt% hydrophilic colloidal silicon dioxide (e.g., 0.3 wt% intragranular + 0.2 wt% extragranular), and 1.5 wt% magnesium stearate (e.g., 0.75 wt% intragranular and 0.75 wt% extragranular). In some embodiments, the drug delivery system exists in two shapes, one with a wire form with a low profile (e.g., straight) deployed shape and the other with a relatively extended (e.g., pretzel) retained shape. In some embodiments, the drug delivery system is prototype 4.

[0113] In some embodiments, the drug delivery system comprises a dual lumen system including a silicone tube having a wall thickness of 0.2 mm, the dual lumen system including (i) a retention frame lumen ("small lumen") that encapsulates a wireform as a retention feature, and (ii) a drug reservoir lumen ("large lumen") having an inner diameter of 2.64 mm that is filled with a plurality of mini-tablets, the silicone tube surrounding the drug reservoir lumen including a single 150 μm orifice, and the drug reservoir lumen sealed by two end plugs (e.g., parylene coated end plugs) that can be sealed (e.g., using silicone adhesive) to the silicone tube surrounding the drug reservoir lumen and form temporary microchannels. The mini-tablets may, for example, have a total mini-tablet length of about 15.0 cm and a total tablet mass of about 961 mg (e.g., 726 mg of erdafitinib (free base equivalent) when the mini-tablet comprises 90.8 wt. % erdafitinib mono-L-lactic acid, 4.5 wt. % polyethylene glycol (e.g., PEG8K), and 4.7 wt. % polyvinylpyrrolidone). The mini-tablets may, for example, have a total mini-tablet length of about 15.0 cm and a total tablet mass of about 961 mg (e.g., 726 mg of erdafitinib (free base equivalent) when the mini-tablet comprises 90.8 wt. % erdafitinib mono-L-lactic acid, 4.5 wt. % polyethylene glycol (e.g., PEG8K) (extragranular), and 4.7 wt. % polyvinylpyrrolidone (intragranular). In some embodiments, the drug delivery system exists in two shapes, one with a wire form in a low profile (e.g., straight) deployed shape and the other with a relatively expanded (e.g., pretzel) retained shape. In some embodiments, the drug delivery system is Prototype 5.

[0114] Variations of Prototype 4 and Prototype 5, in which the mini-tablets may comprise any pharmaceutical formulation described herein, are also encompassed by the present disclosure. In some embodiments, Prototype 4 comprises a mini-tablet comprising 20% ​​by weight of water-insoluble excipients. In some embodiments, Prototype 5 comprises a mini-tablet comprising only water-soluble excipients. In some embodiments, Prototype 4 or Prototype 5 may comprise any pharmaceutical formulation described herein, including Concept 1, Concept 2, Concept 3, Concept 4, or Concept 5.

[0115] As discussed herein with respect to the erdafitinib pharmaceutical formulation, the drug may be provided in a solid form suitable for loading into the drug reservoir lumen of the system. In some embodiments, the individual drug tablets may essentially have any selected shape and dimensions that fit into the system described herein. In one embodiment, the drug unit is sized and shaped such that the drug reservoir lumen in the housing is substantially filled with a selected number of drug tablets. Each tablet may have a cross-sectional shape that substantially corresponds to the cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the tablet may be substantially cylindrical in shape for positioning in a substantially cylindrical drug reservoir lumen.

[0116] In one embodiment, the drug units (tablets) are shaped so that they are aligned when the system is in its deployed configuration. For example, each drug unit may have a cross-sectional shape that corresponds to the cross-sectional shape of the drug reservoir lumen in the housing, and each drug unit may have an end face shape that corresponds to the end face of an adjacent drug unit. The gaps or interruptions between the drug units may accommodate deformation or movement of the drug delivery system, for example, deformation or movement of the drug delivery system during deployment, while allowing each drug unit to retain the solid form of the drug unit. Thus, the drug delivery system may be relatively flexible or deformable even though it is loaded with solid drug, as it may allow each drug unit to move relative to adjacent drug units.

[0117] In an embodiment, the drug unit is a "mini-tablet" sized and shaped to be suitable for insertion through a natural lumen of the body, such as the urethra. For purposes of this disclosure, the term "mini-tablet" generally refers to a solid drug unit that is substantially cylindrical in shape, having end faces and sides that are substantially cylindrical. Mini-tablets have a diameter extending along the end faces ranging from about 1.0 to about 3.2 mm, e.g., from about 1.5 to about 3.1 mm. Mini-tablets have a length extending along the sides ranging from about 1.7 mm to about 4.8 mm, e.g., from about 2.0 mm to about 4.5 mm. The friability of the tablet may be less than about 2%.

[0118] Methods of Drug Delivery and Treatment The systems and methods disclosed herein may be adapted for use in humans or in veterinary or livestock applications. Thus, the term "patient" may refer to a human or other mammalian subject. In one embodiment, the patient is a human subject. The patient may be a cancer patient.

[0119] In certain embodiments, provided herein is a method for treating urothelial cancer, e.g., bladder cancer. In certain embodiments, provided herein is the use of a drug delivery system described herein for the manufacture of a medicament for the treatment of urothelial cancer, e.g., bladder cancer. In certain embodiments, provided herein is a drug delivery system described herein for use in the treatment of urothelial cancer, e.g., bladder cancer. In certain embodiments, provided herein is erdafitinib for use in a drug delivery system described herein for the treatment of urothelial cancer, e.g., bladder cancer. The method or use may include locally delivering or administering erdafitinib (e.g., erdafitinib in any of the formulations described herein) in an effective amount for the treatment of bladder cancer (e.g., about 1-10 mg / day as described herein) to a patient in need of treatment, particularly a cancer patient, in the bladder. For example, the treatment may be effective in treating muscle invasive bladder cancer (MIBC), non-muscle invasive bladder cancer (NMIBC), and / or Mycobacterium bovis Bacillus Calmette-Guerin (BCG) naïve bladder cancer. In one aspect, the patient, particularly a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one aspect, the patient, particularly a human, is a BCG-naïve bladder or NMIBC or MIBC cancer patient. In one aspect, the patient, particularly a human, is a recurrent Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-experienced high-risk papillary only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, particularly a human, is a recurrent BCG-experienced high-risk papillary only NMIBC (high-grade Ta / T1) cancer patient scheduled for RCy. In one embodiment, the patient, particularly a human, is a recurrent intermediate-risk NMIBC (Ta and T1) cancer patient with a history of only low-grade disease. In one embodiment, the patient, particularly a human, is a MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0120] In certain embodiments, the urothelial cancers described herein are susceptible to FGFR2 and / or FGFR3 genetic alterations.

[0121] As used herein, "FGFR gene alteration" refers to an alteration in a wild-type FGFR gene, including but not limited to an FGFR fusion gene, an FGFR mutation, an FGFR amplification, or any combination thereof, in particular an FGFR fusion gene, an FGFR mutation, or any combination thereof. In a particular embodiment, the FGFR2 or FGFR3 gene alteration is an FGFR gene fusion. "FGFR fusion" or "FGFR gene fusion" refers to a gene that encodes a portion of an FGFR (e.g., FGRF2 or FGFR3) and one or a portion of one of the fusion partners disclosed herein, which is created by a translocation between two genes. The terms "fusion" and "translocation" are used interchangeably herein. The presence of one or more of the following FGFR fusion genes in a biological sample from a patient, FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, can be determined using the disclosed methods or uses or by methods known to those skilled in the art. In a particular embodiment, FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3). Table A provides the FGFR fusion genes, as well as the fused FGFR and fusion partner exons. The sequences of the individual FGFR fusion genes are disclosed in Table A2. The underlined sequences correspond to either FGFR3 or FGFR2, and the other sequences represent the fusion partners.

[0122] [Table 1]

[0123] [Table 2-1]

[0124]

Table 2-2

[0125]

Table 2-3

[0126]

Table 2-4

[0127]

Table 2-5

[0128]

Table 2-6

[0129]

Table 2-7

[0130]

Table 2-8

[0131]

Table 2-9

[0132] FGFR genetic alterations include FGFR single nucleotide polymorphisms (SNPs). "FGFR single nucleotide polymorphisms" (SNPs) refer to FGFR2 or FGFR3 genes that differ between individuals by a single nucleotide. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR3 genetic mutation. In particular, "FGFR single nucleotide polymorphisms" (SNPs) refer to FGFR3 genes that differ between individuals by a single nucleotide. The presence of one or more of the following FGFR SNPs in a biological sample from a patient, namely FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof, may be determined by methods known to those skilled in the art or disclosed in WO2016 / 048833. The sequences of the FGFR SNPs are provided in Table B.

[0133] [Table 3] The sequence corresponds to nucleotides 920 to 1510 of FGFR3 (Genebank Identification Number NM_000142.4). Bold underlined nucleotides represent SNPs. * It is sometimes erroneously referred to as Y375C in the literature.

[0134] In certain embodiments, the method or use for treating urothelial carcinoma described herein comprises, consists of, or consists essentially of administering the drug delivery system described herein to a patient diagnosed with urothelial carcinoma described herein and carrying at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alterations, one or more FGFR3 genetic alterations, or a combination thereof). In certain embodiments, the FGFR2 genetic alteration and / or FGFR3 genetic alteration is an FGFR3 genetic mutation, or an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 genetic mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In still further embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0135] Also described herein is a method or use for treating urothelial carcinoma as described herein, comprising, consisting of, or consisting essentially of: (a) evaluating a biological sample from a patient having urothelial carcinoma as described herein for the presence of one or more FGFR genetic alterations, particularly one or more FGFR2 or FGFR3 genetic alterations; and (b) administering to the patient a drug delivery system as described herein if one or more FGFR genetic alterations, particularly one or more FGFR2 or FGFR3 genetic alterations, are present in the sample.

[0136] The following method for assessing a biological sample for the presence of one or more FGFR genetic alterations applies equally to any of the treatment methods and uses disclosed above.

[0137] Suitable methods for evaluating a biological sample for the presence of one or more FGFR genetic alterations are described herein and in WO 2016 / 048833 and U.S. Patent Application No. 16 / 723,975, which are incorporated herein in their entirety. For example, and not intended to be limiting, evaluating a biological sample for the presence of one or more FGFR genetic alterations may include any combination of isolating RNA from the biological sample, synthesizing cDNA from the RNA, and amplifying the cDNA (pre-amplified or not pre-amplified). In some embodiments, evaluating a biological sample for the presence of one or more FGFR genetic alterations may include amplifying cDNA from the patient using a primer pair that binds to and amplifies one or more FGFR genetic alterations, and determining whether one or more FGFR genetic alterations are present in the sample. In some aspects, the cDNA may be pre-amplified. In some aspects, the evaluating step may include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0138] Suitable primer pairs for carrying out the amplification step include, but are not limited to, those disclosed in WO 2016 / 048833, exemplified in Table C below.

[0139] [Table 4]

[0140] The presence of one or more FGFR genetic alterations can be assessed at any suitable time point, including at the time of diagnosis, following tumor removal, following the first line of treatment, during clinical treatment, or any combination of these.

[0141] The methods and uses may further comprise assessing the presence of one or more FGFR genetic alterations in the biological sample prior to the administering step.

[0142] Diagnostic tests and screening are typically performed on a biological sample selected from blood, lymph, bone marrow, a solid tumor sample, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample. In embodiments, the biological sample is a blood sample.

[0143] Methods for identifying and analyzing genetic alterations and protein upregulation are well known in the art. Screening methods may include standard methods such as, but are not limited to, reverse transcriptase polymerase chain reaction (RT PCR) or in situ hybridization, such as fluorescent in situ hybridization (FISH).

[0144] Identification of individuals carrying genetic alterations in FGFR, particularly those described herein, may mean that the patient is particularly suitable for treatment with erdafitinib. Tumors may be selectively screened for the presence of FGFR variants prior to treatment. The screening process typically involves direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies. It should be noted that diagnosis of tumors carrying such genetic alterations may be performed using methods such as RT-PCR and FISH, which are well known to those skilled in the art and are described herein.

[0145] For example, genetic alterations of FGFR can be identified by, for example, direct sequencing of tumor biopsy using PCR and the method for direct sequencing of PCR products as described above. Those skilled in the art will recognize that any of these well-known techniques for detecting overexpression, activation or mutation of the above proteins can be applied in the present invention.

[0146] In RT-PCR screening, the level of mRNA in the tumor is evaluated by making a cDNA copy of the mRNA and then amplifying the cDNA by PCR. Methods of PCR amplification, primer selection, and amplification conditions are well known to those skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods described, for example, in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al. (2001), 3rd Ed., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) may be used, or the methodology set forth in U.S. Patent Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 may be used, which are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression is fluorescent in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0147] In general, in situ hybridization involves the following major steps: (1) fixation of the tissue to be analyzed, (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding, (3) hybridization of the mixture of nucleic acids with the nucleic acid in the biological structure or tissue, (4) posthybridization washes to remove nucleic acid fragments not bound by hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are of sufficient length, for example, from about 50, 100, or 200 nucleotides to about 1000 nucleotides or more, to allow specific hybridization with the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and John MS Bartlet in Fluorescence In Situ Hybridization: Technical Overview, Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed. ISBN: 1-59259-760-2; March 2004, pps. 077-088, Series: Methods in Molecular Medicine.

[0148] The method for gene expression profiling is described in (DePrimo et al., 2003, BMC Cancer, 3:3). Briefly, the protocol is that double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer (SEQ ID NO: 38: tttttttttt tttttttttt tttt) to prime the first strand cDNA synthesis, followed by synthesis of the second strand cDNA with a random hexamer primer. This double-stranded cDNA is used as a template for in vitro transcription of cRNA with biotinylated ribonucleotides. The cRNA is hybridized overnight on the Human Genome Array after chemical fragmentation according to the protocol described by Affymetrix (Santa Clara, CA, USA).

[0149] Alternatively, the protein product expressed from the mRNA may be assayed by immunohistochemistry of tumor samples, solid-phase immunoassay using microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA (enzyme-linked immunosorbent assay), flow cytometry, and other methods well known in the art for detecting specific proteins. Detection methods include the use of site-specific antibodies. Those skilled in the art will recognize that any such well-known techniques for detecting the upregulation of FGFR or detecting FGFR variants or mutations may be applicable in the present invention.

[0150] Abnormal levels of proteins such as FGFR can be measured, for example, using standard enzyme assays such as those described herein. Activation or overexpression can also be detected in tissue samples, e.g., tumor tissue, by measuring tyrosine kinase activity with assays, e.g., those from Chemicon International. The tyrosine kinase of interest is immunoprecipitated from the sample lysate and its activity is measured.

[0151] Another method for measuring overexpression or activation of FGFR, including its isoforms, is to measure microvessel density, which can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers.

[0152] Thus, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the drug delivery systems of the present invention.

[0153] According to certain embodiments, FGFR2 and / or FGFR3 genetic alterations may be identified using commercially available kits, including but not limited to the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0154] In certain embodiments, a method of administering a drug to a patient includes inserting a drug delivery system described herein into a patient and allowing the drug to be released from the system. For example, the system may include any feature or combination of features described herein. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5 to 7.

[0155] In certain embodiments, allowing the drug to be released from the system includes allowing water to be imbibed through a water-permeable wall bounding the drug reservoir lumen to contact and solubilize the drug formulation and generate osmotic pressure within the drug reservoir lumen, and then allowing the solubilized drug to be released from the system through an opening in the system driven by osmotic pressure. That is, in certain embodiments, elution of the drug from the system occurs following dissolution of the drug within the system. A bodily fluid, such as urine, enters the system, contacts the drug, solubilizes the drug, and then the dissolved drug is pumped out of the system by osmotic pumping through one or more openings in fluid communication with the drug reservoir lumen.

[0156] In certain embodiments, inserting includes deploying the system through the patient's urethra and into the patient's bladder. The system may release the drug for days, weeks, months, or longer after the insertion procedure is completed. In one embodiment, deploying the drug delivery system into the patient includes inserting the system into the patient's body cavity or lumen via a deployment device. For example, the system may be deployed into a natural lumen of the body, such as the urethra, or through a deployment device, such as a catheter or cystoscope, positioned in a body cavity, such as the bladder. The deployment device is typically removed from the body lumen and the drug delivery system remains in the bladder or other body cavity for a prescribed treatment period.

[0157] In one example, the system is deployed by passing the drug delivery system through a deployment instrument and releasing the system from the deployment instrument into the bladder. In an embodiment, the system assumes a retained shape, e.g., an expanded or higher profile shape, when the system emerges from the deployment instrument into the bladder. The deployment instrument may be a commercially available system or a system specifically adapted for the present drug delivery system. In one embodiment, deploying the drug delivery system into a patient includes (i) elastically deforming the system into a relatively straightened shape, (ii) inserting the system through the patient's urethra, e.g., through a lumen of an insertion catheter driven by a stylet, and (iii) releasing the system from the insertion catheter into the patient's bladder such that the system assumes a coiled retained shape.

[0158] When deployed in vivo, the system then locally releases a drug (e.g., erdafitinib) for the treatment of one or more conditions or diseases to tissue at the deployment site. The release is controlled to release an effective amount of drug over an extended period of time. In certain embodiments, the system resides in the bladder releasing the drug for a predetermined period of time, such as 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months or more.

[0159] The deployed system releases the desired amount of drug for a desired, predetermined period of time. In embodiments, the system may deliver a desired dose of drug for an extended period of time, such as 2 days to 90 days (e.g., 3, 5, 7, 10, 14, 20, 21, 25, 28, 30, 40, 45, 50, 60, 70, 80, or 90 days), 1 month to 6 months (e.g., 6 weeks, 1 month, 2 months, 3 months, 4 months, or 5 months), or more. The rate of delivery and dosage of the drug may be selected depending on the drug being delivered and the disease or condition being treated. In one embodiment, the rate of release of the drug from the drug delivery system is zero order for at least 36 hours. In one embodiment, the rate of release of the drug from the drug delivery system is essentially zero order for at least 7 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or more.

[0160] The system may then be retrieved from the bladder through the urethra using a cystoscope or catheter, and if required, a freshly drug-loaded system may then be inserted during the same handling procedure as the retrieval or afterwards.

[0161] The present disclosure may be further understood with reference to the following non-limiting examples.

[0162] Enumerated embodiments 1. A drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharma- ceutically acceptable salt thereof; The drug delivery system is configured to release the erdafitinib from one or more openings in the elongate body. 2. The drug delivery system of embodiment 1, wherein the drug formulation comprises a salt form of the erdafitinib. 3. The drug delivery system of embodiment 2, wherein the salt form comprises the L-lactate salt of erdafitinib. 4. The drug delivery system of embodiment 1, wherein erdafitinib is present as the mono-L-lactate salt. 5. The drug delivery system of any one of embodiments 1 to 4, wherein the elongate body comprises a biocompatible elastomer. 6. The drug delivery system of embodiment 5, wherein the biocompatible elastomer comprises silicone or thermoplastic polyurethane. 7. A drug delivery system as described in any one of embodiments 1 to 6, wherein at least one of the one or more openings of the elongate body is located in a sidewall of the elongate body. 8. A drug delivery system as described in any one of embodiments 1 to 7, wherein at least one of the one or more openings of the elongate body is located at a first end and / or an opposing second end of the elongate body. 9. A drug delivery system as described in any one of embodiments 1 to 6, having a single opening located in the side wall of the elongate body at a position between the first end and the opposing second end of the elongate body. 10. The drug delivery system of any one of embodiments 1 to 9, wherein the drug formulation comprises at least one pharmaceutical excipient. 11. The drug delivery system of embodiment 10, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof. 12. The drug delivery system of embodiment 10, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof. 13. The drug delivery system of any one of embodiments 1 to 12, wherein the erdafitinib is present in the drug formulation in a concentration of 60% to 80% by weight. 14. The drug delivery system of embodiment 13, wherein the erdafitinib is present in the drug formulation in a concentration of 70% by weight. 15. The drug delivery system of any one of embodiments 1-14, wherein the drug formulation is in the form of a plurality of mini-tablets. 16. The drug delivery system of any one of embodiments 1 to 15, wherein the drug delivery system is configured to release the erdafitinib by osmotic pressure through one or more openings in the elongate body. 17. A drug delivery system as described in any one of embodiments 1 to 16, wherein the elongate body includes an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed. 18. The drug delivery system of embodiment 17, wherein the one or more openings of the elongate body comprise a single opening in the annular wall structure, and the elongate body is configured to release the erdafitinib through the opening and / or through microchannels temporarily formed in one or both end regions of the annular wall structure. 19. An intravesical drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising the L-lactate salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine); An intravesical drug delivery system, wherein the drug delivery system is configured to be osmotically driven to release the erdafitinib from one or more openings in the elongate body. 20. The system of any one of embodiments 1 to 19, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day. 21. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 6 mg / day. 22. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day. 23. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day. 24. The system of any one of embodiments 1-19, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day. 25. The system according to any one of embodiments 1 to 24, wherein the system comprises 500 mg of said erdafitinib (free base equivalent). 26. A system described in any one of embodiments 1 to 25, wherein the system is elastically deformable between a relatively straightened deployed shape suitable for insertion through the patient's urethra and into the patient's bladder, and a retained shape suitable for retaining the system within the bladder. 27. A system described in any one of embodiments 1 to 26, wherein the system is elastically deformable and comprises a tube having two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and toward each other when the system is in a relatively expanded retained shape. 28. A system described in any one of embodiments 1 to 27, wherein the system comprises an elastically deformable elongated body having two opposing free ends within the boundaries of a bi-elliptical expanded holding shape. 29. A system described in any one of embodiments 1 to 28, wherein the elongate body further comprises a retaining frame lumen. 30. The system of embodiment 29, further comprising a nitinol wire disposed within the retaining frame lumen. 31. A method for intravesical administration of erdafitinib, comprising: deploying a drug delivery system into the patient's bladder; and releasing erdafitinib from the drug delivery system by osmotic pressure. 32. A method for intravesical administration of erdafitinib, comprising: Deploying a system according to any one of embodiments 1 to 30 into the bladder of a patient; and releasing said erdafitinib from said system. 33. The method of embodiment 31 or 32, wherein releasing the erdafitinib from the system comprises releasing the erdafitinib from the drug reservoir lumen through the one or more openings driven by osmotic pressure within the drug reservoir lumen. 34. The method of any one of embodiments 31-33, wherein the system is elastically deformed into a low-profile deployed shape, inserted through the urethra and into the patient's bladder, and then assumes a relatively expanded retained shape within the bladder. 35. The method of any one of embodiments 31-34, wherein erdafitinib is released into the bladder at an average rate of 1 mg / day to 10 mg / day for a period ranging from 7 days to 90 days. 36. A method of treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising: inserting a drug delivery system into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the osmotically driven drug delivery system into the bladder of the patient. 37. A method of treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising: Inserting a system according to any one of embodiments 1 to 30 into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the system into the bladder of the patient. 38. The method of embodiment 36 or 37, wherein locally delivering the erdafitinib comprises releasing the erdafitinib from the system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 39. The method of any one of embodiments 36-38, wherein the system is maintained in the patient's bladder for up to 90 days and then, optionally, replaced with another erdafitinib releasing system. 40. A method of treating (i) recurrent non-muscle invasive or muscle invasive urothelial carcinoma of the bladder, (ii) high- or moderate-risk papillary urothelial carcinoma of the bladder, or (iii) stage cT2-T3a muscle invasive urothelial carcinoma of the bladder in a cancer patient, comprising: inserting a drug delivery system into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the drug delivery system into the bladder of the patient, particularly in an osmotically driven manner. 41. A method of treating (i) recurrent non-muscle invasive or muscle invasive urothelial carcinoma of the bladder, (ii) high- or moderate-risk papillary urothelial carcinoma of the bladder, or (iii) stage cT2-T3a muscle invasive urothelial carcinoma of the bladder in a cancer patient, comprising: Inserting a system according to any one of embodiments 1 to 30 into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the system into the bladder of the patient. 42. The method of embodiment 40 or 41, wherein the patient undergoes transurethral resection of bladder tumor (TURBT) to reduce total tumor(s) size to 3 cm or less, and then the erdafitinib is delivered locally into the bladder. 43. The method of any one of embodiments 40-42, wherein locally delivering the erdafitinib comprises releasing the erdafitinib from the system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 44. The method of any one of embodiments 40-43, wherein the system is maintained in the patient's bladder for up to 90 days and then, optionally, replaced with another erdafitinib-releasing system. 45. A method of treating a Mycobacterium bovis Bacille Calmette-Guerin (BCG)-experienced patient with recurrent high-grade Ta / T1 urothelial carcinoma of the bladder within 18 months of completion of a previous BCG therapy, comprising: inserting a drug delivery system into the bladder of the patient; and locally delivering a therapeutically effective amount of erdafitinib from the drug delivery system into the bladder of the patient. 46. ​​A method of treating a Mycobacterium bovis Bacille Calmette-Guerin (BCG)-experienced patient with recurrent high-grade Ta / T1 urothelial carcinoma of the bladder within 18 months of completion of a previous BCG therapy, comprising: A method comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of the patient from the system, in particular from a system described in any one of embodiments 1 to 30 inserted into the bladder of the patient. 47. The method of embodiment 45 or 46, wherein locally delivering the erdafitinib comprises releasing the erdafitinib from the system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 48. The method of any one of embodiments 45-47, wherein the system is maintained in the patient's bladder for up to 90 days and then, optionally, replaced with another erdafitinib-releasing system. 49. The method of any one of embodiments 36 to 48, wherein the patient carries at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration. 50. Erdafitinib lactate, in particular, erdafitinib L-lactate. 51. A pharmaceutical composition comprising erdafitinib lactate, in particular erdafitinib L-lactate, and one or more excipients. 52. The pharmaceutical composition of embodiment 51, wherein the composition is in the form of a tablet, in particular a mini-tablet. EXAMPLES

[0163] Example 1. Screening of materials and API forms for Erdafitinib release Several polymeric materials were tested to determine their suitability as construction materials for the elastomeric system body for the release of various erdafitinib formulations. The materials included silicone and several thermoplastic polyurethanes (TPUs) manufactured by Lubrizol Life Sciences (Bethlehem, PA). The results are listed in Table 1.

[0164] [Table 5]

[0165] In Table 1, "O" is permeable, "Δ" is substantially impermeable, and "X" is impermeable. This information can be useful in selecting osmotic system housing materials of construction and design that can be used with the various possible erdafitinib forms / formulations.

[0166] Example 2. Sample minitablet formulations Table 2 shows selected aspects and embodiments of mini-tablet formulations for use with the disclosed drug delivery system. The blends in Table 2 are for tablets with a target tablet weight of 20 mg and a drug loading of 70% by weight.

[0167] [Table 6]

[0168] Erdafitinib granules were composed of 98% by weight erdafitinib mono-L-lactic acid and 2% by weight HPMC (eg, HPMC 290 15 MPa.s).

[0169] Preparation: All compounds were screened through a 600 μm sieve. Erdafitinib granules, copovidone, microcrystalline cellulose, and colloidal silica were weighed and mixed for 10 minutes. The blend was screened through a 600 μm sieve. Magnesium stearate was added and the blend was mixed for 5 minutes. The resulting blend was tableted.

[0170] Example 3. Erdafitinib metabolism and pharmacokinetic properties for intravesical delivery Erdafitinib was determined to be sufficiently stable in freshly collected human, minipig, and rat urine for 6 hours at 37° C., indicating that the drug is stable in urine between urination cycles.

[0171] In vitro protein binding showed that erdafitinib exists primarily in the free form in urine. The percent free erdafitinib in rat, minipig, and human urine was estimated to be 84%, 97%, and 95%, respectively, and was concentration-independent. Erdafitinib was found to bind less to AGP than to albumin. Albuminuria / proteinuria had minimal effect on the percent free form in urine.

[0172] Erdafitinib in vitro binding to normal / tumor bladder tissue showed significant free fraction. The free fraction of erdafitinib in minipig bladder tissue was 79%, two-fold higher than that in rats (33%) and humans (39%). In tumor tissue, the free fraction was 40%.

[0173] Bladder irrigation studies in pigs and rats showed good distribution from the urine into the bladder, especially into the urothelium. Low systemic bioavailability after localized bladder dosing (approximately 5% in rats and 12% in minipigs) was observed.

[0174] Based on these studies, erdafitinib is stable in urine and exists in a high free fraction, which should therefore provide desirable exposure to bladder tumors. Erdafitinib is believed to have favorable drug metabolism and pharmacokinetic properties for intravesical administration.

[0175] Example 4: Pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose intravesical erdafitinib administration in rats bearing orthotopic bladder tumors. The objective of Example 4 was to compare the PK and PD effects of localized bladder versus oral administration of erdafitinib in nude rats bearing human UM-UC-1 bladder xenografts. Animals received a single oral dose of erdafitinib (20 mg / kg erdafitinib in 10% weight / volume (w / v) HP-β-CD solution) into the bladder or a 1-hour intravesical instillation of erdafitinib (6 mg / kg erdafitinib in 10% w / v HP-β-CD solution) into the bladder. Extracellular signal-regulated kinase (ERK)1 / 2 phosphorylation was assessed at various time points after administration / implantation as a PD marker for FGFR kinase inhibition in tumors. PK analysis of tumor and plasma samples was performed 2, 7, 48, and 120 hours after a single 6 mg / kg intravesical dose of erdafitinib or a 20 mg / kg oral dose of erdafitinib. Groups of nude rats bearing subcutaneous (sc) tumors (UM-UC-1) were given erdafitinib orally and concentrations were measured in plasma and tumors 2, 7, 48, and 120 hours after dosing.

[0176] Intravesical administration resulted in mean erdafitinib exposure levels that were equivalent to those of the 20 mg / kg oral dose (Table 3). Approximately 2-fold lower exposure levels were detected in subcutaneous (sc) tumors from orally dosed rats at 2 and 7 hours compared to orthotopic tumors from orally dosed rats, reflecting the commensurately lower plasma exposures observed in the same groups of rats (Figure 4).

[0177] [Table 7] HP-β-CD, hydroxypropyl β-cyclodextrin; IVES, intravesical (bladder instillation); LLOQ, lower limit of quantification; PO or po, oral. Values ​​are means with standard deviations in brackets. Mean exposures for the 48 and 120 hour time points were low (less than 35 ng / g). Erdafitinib was dosed as a 10% w / v solution in HP-β-CD. a LLOQ serum=0.05ng / mL b LLOQ tumor = 2ng / g c Mean = tumor concentration (ng / g) / plasma concentration (ng / mL)

[0178] The effect of a single 20 mg / kg oral or 6 mg / kg intravesical dose of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors was assessed at various time points by capillary immunoblotting. Proteins from tumor sample lysates taken 2, 7, 48, and 120 hours after treatment with erdafitinib or vehicle were separated by capillary electrophoresis and probed with antibodies detecting phosphorylated (p)ERK1 / 2 and total ERK1 / 2. The signal for pERK1 / 2 was divided by the total ERK1 / 2 signal in the same sample, and the average of the pERK1 / 2 values ​​for the corresponding vehicle-treated samples was set to a relative value of 1. At each time point, the pERK / ERK ratio for each tumor sample was divided by the average pERK / ERK ratio derived from the corresponding control sample. With one exception, there were no vehicle-treated samples at the 120 hour time point, so the pERK / ERK ratios for the erdafitinib-treated samples at the 120 hour time point were divided by the mean of the 48 hour vehicle-treated group.

[0179] Both 6 mg / kg intravesical and 20 mg / kg oral doses of erdafitinib resulted in a statistically significant decrease in ERK1 / 2 phosphorylation in UM-UC-1 tumors 2 hours after dosing (Figure 5, Table 4). Although not statistically significant, pERK levels were also lower in erdafitinib-treated tumors compared to vehicle-treated tumors at 7 and 48 hours, and by 120 hours, pERK1 / 2 levels were comparable to those in vehicle-treated rats.

[0180] [Table 8] ANOVA, analysis of variance; ERK, extracellular signal-regulated kinase; IVES, intravesical; NA, not applicable; pERK, phosphorylated extracellular signal-regulated kinase; po, oral. "Zero dose" animals received vehicle. a Ratio of pERK / ERK mean group values ​​divided by the vehicle-treated group mean. Standard deviation in brackets. b One-way ANOVA, Dunnett's test for multiple comparisons. c Divided by the 48 hour vehicle treatment group mean.

[0181] Overall, these data indicate that intravesical administration of erdafitinib provides adequate tumor PK / PD while dramatically reducing plasma exposure, thereby reducing the potential for on-target off-tumor toxicity compared to oral therapy.

[0182] Example 5: Continuous perfusion studies in an orthotopic bladder cancer model. Perfusion studies: The bladders of study animals were cannulated on day 1 and the animals were allowed to recover for 3 days. On day 5, UM-UC-1 cells (2 × 10 6 Cells) were injected into the lateral wall of each bladder. After a 2-day tumor growth period, erdafitinib was perfused continuously for 5 days, followed by autopsy within 24 hours. Based on the in vitro results, target urinary concentrations of 0.5, 1.0, and 5.0 μg / mL were used in the perfusion experiments. The study design is shown in FIG. 7. Body weight, daily urine production, and daily water consumption were recorded. At autopsy, plasma samples, bladder photographs, and bladder weight measurements were recorded. After autopsy, the total bladder weight, which consisted of normal bladder tissue plus urothelial tumor, was used to determine the effect of erdafitinib on tumor growth.

[0183] Human-derived tumor cells grew rapidly when implanted into the bladder wall of athymic rats. Within 7 days of implantation, the tumors occupied most of the urothelial surface and increased the total bladder weight up to 7-fold (Figure 6). Thus, the total bladder weight is an accurate measure of drug response.

[0184] Continuous erdafitinib perfusion for 5 days at nominal urinary concentrations of 0.5, 1.0, and 5.0 μg / mL was generally well tolerated. Body weight changes during the study are shown in FIG. 8. An initial small reduction in body weight (days 1-3) of less than 5% was found in most groups, including the vehicle control, due to the effects of the bladder cannulation surgery. Minimal body weight changes were noted after intravesical tumor cell injection on day 5. Transfer to metabolic cages and initiation of bladder perfusion resulted in a second small weight loss that was not related to perfusate drug concentration. Based on cage-side observations, no visible signs of abnormal behavior or clinical symptoms were observed in any of the treatment groups.

[0185] The percentage reduction in relative tumor weight between the control and drug perfusion groups was determined as an initial measure of efficacy. Bladder tissue and tumor samples were also subjected to analysis of FGFR signaling activity by determining phosphorylated fibroblast growth factor receptor substrate (FRS) 2a levels and pERK to ERK ratios. Additional urine, plasma, and bladder samples were collected to determine erdafitinib concentrations using an established liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. The mean bladder weight change in animals receiving different erdafitinib concentrations is shown in Figure 9. A significant dose-related reduction in bladder weight was observed in the erdafitinib treatment group (for erdafitinib at 0.5 μg / mL) when compared to the vehicle control group. ** p<0.01, for erdafitinib at nominal urinary concentrations of 1.0 and 5 μg / mL *** p<0.001),

[0186] Example 6: Dose-response evaluation of erdafitinib in bladder-perfused athymic rats with RT-112 implanted within the bladder wall. Perfusion Study: The experimental study design was the same as that described in Example 5 (Figure 7), except that perfusion was continued until necropsy on day 14. Continuous perfusion treatment with erdafitinib at nominal urinary concentrations of 0.25, 0.5, and 1.0 μg / mL for 6 days was well tolerated during the experimental period. Body weight changes observed during the study are shown in Figure 10. Mild body weight loss was observed during the study, with maximum mean values ​​ranging up to approximately -3% in the erdafitinib treatment group on day 11.

[0187] The effect of intravesical erdafitinib exposure on tumor growth, as determined by the change in total bladder weight, is shown in Figure 11. Mean bladder weights tended to be lower with increasing erdafitinib concentration, but the reduction was not statistically significant for the 0.25 and 0.5 μg / mL dose groups relative to vehicle control animals. Significant bladder weight reductions ( * p<0.05) was observed in animals receiving a perfusate concentration of 1.0 μg / mL compared to vehicle controls.

[0188] Dose-response evaluation of erdafitinib (0.25-5 μg / mL) in bladder-perfused athymic rats with UM-UC-1 or RT-112 cell lines implanted within the bladder wall demonstrated that the erdafitinib dosing regimen was well tolerated. A significant dose-dependent reduction in bladder weight was observed in the erdafitinib-treated groups compared to the vehicle control group, indicating that bladder perfusion with erdafitinib reduced tumor growth.

[0189] Example 7: Intravesical pharmacokinetic and distribution studies in rats and minipigs. Systemic and bladder PK studies were conducted after a single intravesical (bolus) administration of erdafitinib formulation in solution (HP-β-CD) to rats and minipigs. These studies were initially conducted to determine drug exposure in bladder tissue, urine, and plasma. Additionally, bladder tissue was evaluated for gross and microscopic examination to determine if there was any local effect of the drug or formulation in the study. The goal of Example 7 was to determine the feasibility of intravesical erdafitinib therapy with bladder placement of erdafitinib.

[0190] Single intravesical dose PK in rats: Systemic and bladder PK of erdafitinib was determined in female Sprague-Dawley rats following intravesical administration of erdafitinib solution at 2, 6, and 18 mg / kg body weight. Rats were kept under anesthesia using isoflurane (2-4%), a catheter was introduced into the urinary bladder via the urethra, and erdafitinib solution (HP-β-CD 10% w / v in citrate buffer pH 5.5) was instilled into the rat bladder via the catheter. Solution formulations were prepared in various strengths and administered to each rat bladder in a volume of 0.5 mL up to doses of 2, 6, and 18 mg / kg. The corresponding doses in nominal amounts of drug were 0.5, 1.5, and 4.5 mg, respectively. One hour after placement, rats were transferred to metabolic cages to collect samples for PK determination. Blood samples were collected from the tail vein (3 rats per time point) at 24, 48, 72, 96, and 168 hours after completion of the 1-hour compound exposure period after dosing. At each blood sampling time point, bladder samples were collected from each rat for drug analysis. In addition, in the 18 mg / kg dose (high dose) group, bladders collected at 96 hours were evaluated microscopically. Urine collection from all rats was restricted to the initial 0-6 hours after dosing.

[0191] In plasma, almost all samples were below the limit of quantification (0.02 ng / mL) for the 2 and 6 mg / kg dose groups. For the 18 mg / kg dose group, some measurable concentrations were observed at 24, 48, and 72 hours (0.0303-0.106 ng / mL), but at 96 and 168 hours, all samples were below the limit of quantification. In the bladder, concentrations could be measured up to 72 hours for the 2 and 6 mg / kg dose groups and up to 168 hours for the 18 mg / kg dose group. Concentrations were highest at the 24 hour time point and declined thereafter. There was no dose linearity that could be observed. Exposure was similar between the doses tested. The percentage of compound excreted as unchanged drug in the urine (within the first 6 hours) reached 23.5%, 19%, and 50.3% for the 2, 6, and 18 mg / kg dose groups.

[0192] Systemic and bladder PK of continuous intravesical erdafitinib in rats: Systemic and bladder PK of erdafitinib was determined in female Sprague-Dawley rats after continuous intravesical infusion of erdafitinib aqueous solution. The rat bladders (5 rat groups, n=3 / group) were surgically catheterized under anesthesia, and the catheters were exposed, tunneled subcutaneously, and connected to a vascular access harness (VAH) in the neck. The rats were transferred to individual metabolic cages and allowed free access to food and water for a 1-week postoperative recovery period. On the study day, erdafitinib solution (0.1 mg / mL, 0.1 mL / hr, citrate buffer pH 5.5 containing 5% w / v HP-β-CD) was perfused through the rat bladder via the catheter for 72 hours. The first group (n=3) was sacrificed after 24 hours of perfusion, and two of the four remaining groups were sacrificed after 48 and 72 hours of perfusion. Perfusion was stopped for the last two groups at 72 hours, and these groups were sacrificed at 96 and 120 hours to determine the drug elimination phase from the bladder. Plasma and bladder samples were collected at all time points. Urine was collected from the third group during the 48-72 hour perfusion period for drug analysis. Plasma concentrations in rats after 72 hours of bladder perfusion of erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose of 0.72 mg) are shown in FIG. 12A. No levels were detected in the samples (below the limit of quantification, 0.2 ng / mL) until up to 120 hours (i.e., an additional 48 hours) after perfusion was stopped at 72 hours. Intravesical levels in rats after 72 hours of bladder irrigation with erdafitinib solution (0.1 mg / mL, 0.1 mL / hr, cumulative dose of 0.72 mg) are shown in Figure 12B. Rat bladders irrigated with 0.1 mg / mL erdafitinib solution showed no changes and this formulation strength was considered well tolerated. Mean daily urinary concentrations were measured to be approximately 10,000 ng / mL for urine collected during the 48-72 hour irrigation interval.

[0193] [Table 9] AUC 0~xh , area under the plasma concentration-time curve from time of administration to x hours; C xh, plasma concentration at time x; BQL, below limit of quantification. a The average daily urinary concentration at this time point was approximately 10,000 ng / mL.

[0194] Results showed significant bladder tissue uptake and maintenance of high intravesical levels of erdafitinib upon continuous low-rate perfusion of erdafitinib, with minimal systemic exposure.

[0195] Systemic and bladder PK of continuous intravesical erdafitinib in pigs: Systemic and bladder PK of erdafitinib was evaluated in five female pigs (domestic Yorkshire crossbred) following continuous intravesical infusion of erdafitinib aqueous solution. On day 7, a catheter was surgically placed in the bladder of each animal. The distal end of the catheter was secured to a subcutaneous site and attached to a vascular access port (VAP). The port was secured and the animals were allowed to recover. Each animal was then fitted with a portable infusion pump attached to the bladder catheter via the VAP. Dose formulations (22.5 μg / mL erdafitinib solution in 50 mM citrate buffer pH 6.0) were prepared daily, sterile filtered daily, and analyzed to confirm concentration. Dose formulations were perfused into the bladder at a constant rate of 12.5 mL / hr for 6 consecutive days for two animals and 8 consecutive days for three animals. Total voided urine was collected at 24-hour intervals over days 6 or 8. Blood samples were collected daily on study days 1-8. Bladder tissue samples were collected from each animal at necropsy. Samples obtained from all animals were analyzed for erdafitinib using a validated LC-MS / MS method. Based on all day formulation analysis, the average daily dose administered for each animal ranged from 7.06-7.56 mg, with an overall average dose of 7.3 mg / day. Based on the average body weight (pre-dosing), the dose administered was 0.22 mg / kg / day.

[0196] Mean (±SD) erdafitinib urinary concentrations ranged from 1,255±554 to 873±179 ng / mL on days 2-8 (Figure 13). Mean (±SD) erdafitinib plasma concentrations on days 2-8 are shown in Figure 14 and ranged from 0.622±0.250 to 0.828±0.487 ng / mL on average. Over the 7-day period of the study, mean (±SD) daily urine volume was 966±253 mL. Inter- and intra-animal variability in daily urine production was observed, but no significant trends in urine production were observed over the treatment period. Erdafitinib urinary recovery was relatively consistent across all animals, averaging 910±812 to 1,135±760 ng on days 2-8. Daily erdafitinib recovery averaged 15.7% ± 5.67% of the mean daily erdafitinib dose administered.

[0197] Mean erdafitinib concentrations in full thickness bladder tissue were measured on days 6 and 8 (end of perfusion) with values ​​ranging from 315 to 998 ng / g and 346 to 2,688 ng / g, respectively. Erdafitinib concentrations were measured in the urothelium and in the underlying tissue layer (i.e., muscle). These data suggest that the concentration of erdafitinib in the urothelium layer of the bladder was more than 10-fold higher when compared to the underlying tissue layer, suggesting that the drug was primarily retained in the urothelium.

[0198] [Table 10] conc, concentration; Rem layer, bladder subtissue layer; Urothel layer, bladder urothelium.

[0199] Example 8: Stability and protein binding studies. Stability in urine: As part of an equilibrium dialysis study, urine was spiked with erdafitinib at 1, 3, and 5 μg / mL and the urine was incubated at 37° C. for 6 hours (in triplicate). At the end of the 6 hour post-dialysis incubation, the drug was analyzed and the recovery was calculated relative to the spiked concentration. The percent recovery of erdafitinib in the study ranged from 89%-98% in human urine, 90%-95% in rat urine, and 92%-93% in minipig urine, indicating that erdafitinib is stable in urine. These results suggest that erdafitinib remains stable in urine in the bladder, providing exposure to tumor and bladder tissue.

[0200] Example 9: Prototype Development. Based on experiments including animal studies, release rates of 1 mg / day, 2 mg / day, 4 mg / day, and 6 mg / day were selected for further development. Designs that allowed for 30-day and 90-day durations of use were evaluated. The 30-day design was designed to provide a higher drug release rate that also exceeded the 90-day payload capacity of the device. The minimum target release rate was defined as the rate required to obtain a mean erdafitinib urinary concentration of 1 μg / mL. Higher release rates were also evaluated to increase tumor exposure and to evaluate local tolerability and systemic exposure trends. Additional performance metrics included urine pH, urine volume, and urine composition independence.

[0201] Erdafitinib exhibits significant pH-dependent solubility over the normal urinary pH range of 5.5 to 7. As a result, different drug formats and mini-tablet excipient combinations were evaluated to minimize the effect of urinary pH and composition on system release rate.

[0202] A factorial system screen was first completed to evaluate the full range of possible release rates and pH effects. Approximately 900 combinations of device polymers and erdafitinib drug formats were tested using a powder-filled short-core system that is a 2 cm version known for precise adjustment to the full 15 cm design. Drug formats evaluated included erdafitinib free base, erdafitinib HCl salt, erdafitinib L-lactate salt, and erdafitinib free base + HP-β-CD.

[0203] Materials Screening In general, materials that are impermeable to the API, erdafitinib, are suitable for use in the osmotic system. Platinum-cured silicone, thermoplastic polyurethane (TPU), and ethylene vinyl acetate (EVA) materials were screened (Table 7). Test articles were filled with the formulated API (powder or tablet), sealed, placed in foil pouches, and gamma irradiated (nominal 35 kGy). The systems were placed in simulated urine (pH 6.8), stored at 37°C, and sampled periodically. The amount of API in each sample was determined by high performance liquid chromatography (HPLC) analysis.

[0204] [Table 11] EVA, ethylene vinyl acetate; NA, not available; TPU, thermoplastic polyurethane

[0205] The permeability screening results are shown in Figure 15. Materials suitable for use in the osmotic system were impermeable to the API. Silicone was used as the tubing material for the osmotic system and is also suitable as the osmotic tubing material for all four erdafitinib forms. Based on its impermeability, silicone was selected as the material for further development of the osmotic prototype.

[0206] Osmotic Pressure System Silicone tubing was selected for the osmotic system, and four API forms were screened with and without added osmotic agents (e.g., sodium chloride, potassium chloride, potassium bicarbonate, sodium phosphate dihydrate, sodium sulfate, and sodium L-(+)-tartrate dihydrate) capable of generating constant water influx through the silicone tubing for at least 30 days. Short-core osmotic systems were tested with the four API forms alone and with added osmotic agents. The HCl salt form was not tested with sodium chloride or potassium chloride due to the common ions between the API and the osmotic agent. The short-core system that showed the most promising release rate was the L-lactate API form with no added osmotic agent.

[0207] [Table 12]

[0208] Osmotic system using Erdafitinib L-lactate Two osmotic system prototypes using erdafitinib L-lactate were tested in minipigs (Prototype 4): Osmotic (orifice + end plugs), 0.2 mm wall, erdafitinib L-lactate, tablet (water insoluble at 20%), and Prototype 5: Osmotic (orifice + end plugs), 0.2 mm wall, erdafitinib L-lactate, tablet (water soluble), see Figures 16A and 16B). The drug construct formulations are listed in Table 9. Both prototypes included dual lumen silicone tubing (large lumen ID of 2.64 mm, wall thickness of 0.2 mm), 150 μm orifice, two end plugs, a 15 cm drug core, and wireform as a retention feature. Table 10 lists the drug construct payload for each prototype. IVR testing was performed on prototype 4 using simulated urine at three different pH ranges, pH 5, 6.8, and 8, as the release medium (n=3 systems tested in each medium). Prototype 5 was tested in simulated urine at pH 6.8 (n=2 systems tested in IVR). The IVR profile for prototype 4 showed good agreement between simulated urine at pH 5, 6.8, and 8, and exhibited near zero order release over 90 days (Figure 17). The IVR profile for prototype 5 was tested in simulated urine at pH 6.8 with only two replicates (Figure 18). This prototype also exhibited near zero order release over 90 days.

[0209] [Table 13] API, active pharmaceutical ingredient; NA, not applicable; w / w, weight / weight.

[0210] [Table 14] FBE, free base equivalent.

[0211] Pharmacokinetic evaluation in minipigs The osmotic design released erdafitinib at a rate designed to achieve a target urinary concentration of ≥1 μg / mL in minipigs. The zero order system demonstrated in vitro release rates (defined as release at a constant rate over at least 30 days) of up to 2 mg / day (with a sustained duration of >90 days). Inter-device and intra-device release rate variability was lowest for the zero order system.

[0212] Based on the short core data, a series of full-length systems 200 were developed and tested to confirm the short core results. A subset of these were tested in minipigs to determine the in vivo release rate characteristics of the osmotic designs and to obtain the release rates required to achieve the target urinary concentrations. The in vivo results largely confirmed the in vitro findings, demonstrating that a release rate of 2-4 mg / day in vitro was sufficient to maintain the target erdafitinib urinary concentrations. Figures 17 and 18 summarize the in vitro release characteristics of representative osmotic systems selected for minipigs testing. Figure 19 summarizes the urinary concentration versus time profiles of the same systems. Prototypes 4 and 5 were representative zero order osmotic designs utilizing release of osmotic systems.

[0213] Example 10: Chemical properties, stability, formulation, and device development. Erdafitinib has been assigned the number JNJ-42756493, with the suffix -AAA indicating the free base form and the suffix -AFK indicating the mono-L-lactate salt.

[0214] A summary of the solid state properties of both the free base and the L-lactate salt is provided in Table 11. The physical stability of the L-lactate salt was evaluated by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), thermogravimetric analysis (TGA), and infrared (IR) after storage in open dishes at different conditions for 6 weeks. The product was found to be crystallographically stable. No evidence of dissociation or form transformation was found (Table 12).

[0215] [Table 15] DVS, dynamic vapor sorption; RT, room temperature; TGA, thermogravimetric analysis; XRPD, X-ray powder diffractometry.

[0216] [Table 16] Cryst.Ref, crystal reference; DSC, differential scanning calorimetry; IR, infrared; Max, maximum; RH, relative humidity; RT, room temperature; TGA, thermogravimetric analysis; w / w, weight / weight; XRPD, X-ray powder diffractometry.

[0217] Formulation-Device Development Formulation development focused on the erdafitinib L-lactate mini-tablet concept (see Table 13 for an exemplary concept).

[0218] [Table 17] API, active pharmaceutical ingredient; w / w, weight / weight.

[0219] An osmotic silicone system (osmotically driven, with orifice) was evaluated.

[0220] The L-lactate salt has unexpectedly high solubility over a wide pH range and unexpected osmotic properties. The solubility of the L-lactate salt as a function of pH in water (FIG. 20A) and simulated urine (FIG. 20B) at 37° C. is shown.

[0221] Example 11: Synthesis of Erdafitinib L-lactate. Synthesis of Erdafitinib L-lactate: Erdafitinib mono-L-lactate was successfully produced via salt formation between erdafitinib free base and solid mono-L-lactic acid (Figure 21). Crystallization was performed by seeding with API.

[0222] Procedure 1

[0223] [Table 18]

[0224] Procedure involving wet grinding: Dissolving API Erdafitinib base was added to the reactor. 1.02 mol L-lactic acid / mol erdafitinib base was added. 1.006 L of isopropanol / mol of erdafitinib base was added to the reactor. 0.11178 L of water / mol of erdafitinib base was added to the reactor. Dissolve and hold at 70° C. Complete dissolution was confirmed visually. The receiving vessel is set at a jacket temperature of 80°C. A polishing filtration was performed and maintained at a temperature of at least 70°C. The filter was rinsed with 1.1178 L of isopropanol / mol of erdafitinib base. A wait was held until the temperature of the receiver vessel and reactor stabilized at 80°C.

[0225] Establishing seeding conditions The temperature was cooled to 69° C. at 0.3° C. / min. Wait until the temperature stabilizes. 1 m% of the seed material (5.4 g / mol) was seeded. I waited for four hours.

[0226] Cooling to wet grinding conditions The temperature was cooled to 20° C. at 0.2° C. / min. I waited for an hour. The suspension was wet milled in a high shear mill, configuration 2P-4M, for 60 minutes (CDMP scale). The reactor was heated to 35° C. at 0.2° C. / min. It was held for 30 minutes. The temperature was cooled to 20° C. at 0.2° C. / min. The reactor was heated to 40° C. at 0.2° C. / min. It was held for 30 minutes. The temperature was cooled to 20° C. at 0.2° C. / min.

[0227] Final cooling and filtration The temperature was cooled to 5° C. at 0.2° C. / min. Before filtration, the sample was kept at 5°C for more than 3 hours. -HOLD point

[0228] Cake washing and drying The wet cake was washed with isopropanol: 0.54 L of isopropanol / mol JNJ-42756493-AFK (erdafitinib mono-L-lactate). The reactor was washed through and the wash solvent was slightly pre-cooled. After removing the mother liquor, wash as quickly as possible. The solid was dried in a vacuum oven at 40° C. for 24 hours.

[0229] Procedure 2

[0230] [Table 19]

[0231] procedure: Dissolving API Erdafitinib base was added to the reactor. 1.02 mol L-lactic acid / mol erdafitinib base was added. 1.006 L of isopropanol / mol of erdafitinib base was added to the reactor. 0.11178 L of water / mol of erdafitinib base was added to the reactor. Dissolve and hold at 70° C. Complete dissolution was confirmed visually. The receiving vessel is set at a jacket temperature of 80°C. A polishing filtration was performed and maintained at a temperature of at least 70°C. The filter was rinsed with 1.1178 L of isopropanol / mol of erdafitinib base. A wait was held until the temperature of the receiving vessel and reactor stabilized at 80°C.

[0232] Establishing seeding conditions The temperature was cooled to 63° C. at 0.3° C. / min. Wait until the temperature stabilizes. 4.5m% of micronized seed material (24.39g / mol) was seeded. I waited for four hours.

[0233] Final cooling and filtration The temperature was cooled to 5° C. at 0.2° C. / min. Before filtration, the sample was kept at 5°C for more than 3 hours. -HOLD point

[0234] Cake washing and drying The wet cake was washed with isopropanol: 0.54 L of isopropanol / mol JNJ-42756493-AFK (erdafitinib mono L-lactic acid). The reactor was washed through and the washing solvent was slightly pre-cooled. After removing the mother liquor, wash as quickly as possible. The solid was dried in a vacuum oven at 40° C. for 24 hours.

[0235] Example 12: Mini-tablets containing Erdafitinib Lactate Manufacturing Process The manufacturing process of mini-tablets can be described as follows: First, a binder solution was made by dissolving hydroxypropyl methylcellulose 2910 (HPMC) in purified water until a clear solution without lumps was obtained. Then, the screened drug substance was transferred to a granulator and fluid bed granulation (FBG) was performed: the contents were warmed while fluidizing, the complete binder solution was sprayed onto the ingredients, and finally the granules were fluidized and dried after spraying. After FBG, the dried granules were screened using a suitable sieve. The screened extragranular excipients were then added to the granules and blended for 10 minutes to obtain a homogenous blend. Next, sieved magnesium stearate was added to the blend and blended for 5 minutes. The final blend was then compressed into core tablets using a suitable tablet press, and the tablets were passed through a dust remover and metal detector.

[0236] DoE research: A Design of Experiments study was performed. A primary compression force of 10 kN was used for the production of DoE concepts. Hardness, weight variation (RSD wt % which correlates with tablet defects) and ejection force of different concepts were studied.

[0237] From this DoE study it can be concluded that: 1) SMCC was preferred as a filler; 2) PVP VA, colloidal silicon dioxide (hydrophilic), and magnesium stearate were preferred as binders, glidants, and lubricants, respectively; 3) MCC was preferred as an additional filler / binder.

[0238] [Table 20]

[0239] A summary of the in-process control (IPC) results obtained for concepts 1–3 is presented in Table 17.

[0240] [Table 21]

[0241] When the IPC results were evaluated, similar values ​​were observed for the different concepts. A comparison of hardness versus ejection force was performed. A higher standard deviation for ejection force was observed when SSF was used as a lubricant. Both hardness and ejection force were comparable for concepts 1 and 2, with slightly better results for concept 1 (i.e., lower ejection force and better tablet hardness). Hardness as a function of compression force was investigated for each concept. The results demonstrated that the manufacturing processes for concepts 1 and 2 are very robust. Promising results were also obtained for concept 4. At higher compression forces, slight flashing was observed for concept 4. The compression profile for concept 5 showed comparable results to concept 2, but more variation in the data and visually less optimal tablets were observed for concept 5. Overall, concept 2 was preferred as it was the most robust concept for manufacturability and upscaling.

[0242] Many modifications and other implementations of the disclosure described herein will become apparent with the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the disclosure is not limited to the particular implementations disclosed, and that modifications and other implementations are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. 1. An intravesical drug delivery system comprising: an elongate body configured for intravesical insertion into a patient; a drug formulation disposed within the elongate body, the drug formulation comprising erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) or a pharma- ceutically acceptable salt thereof, in particular the L-lactate salt of erdafitinib; An intravesical drug delivery system, wherein the drug delivery system is configured to be osmotically driven to release the erdafitinib from one or more openings in the elongate body.

2. The drug delivery system of claim 1, wherein erdafitinib is present as the mono-L-lactate salt.

3. The drug delivery system of claim 1 or 2, wherein the elongate body comprises a biocompatible elastomer.

4. The drug delivery system of claim 3 , wherein the biocompatible elastomer comprises silicone or thermoplastic polyurethane.

5. The drug delivery system of claim 3 , wherein the biocompatible elastomer comprises silicone.

6. The drug delivery system of claim 3 , wherein the biocompatible elastomer comprises a platinum-cured silicone elastomer.

7. The drug delivery system of any one of claims 1 to 6, wherein at least one of the one or more openings in the elongate body is located in a sidewall of the elongate body.

8. 8. The drug delivery system of claim 1, wherein at least one of the one or more openings in the elongate body is located at a first end and / or an opposing second end of the elongate body.

9. 7. The drug delivery system of claim 1, having a single opening located in a sidewall of the elongate body at a location between a first end and an opposing second end of the elongate body.

10. The drug delivery system of any one of claims 1 to 9, wherein the one or more openings have a diameter of about 100 μm to about 200 μm.

11. 11. The drug delivery system of claim 10, wherein the one or more openings have a diameter of about 150 μm.

12. The drug delivery system according to any one of claims 1 to 11, wherein the drug formulation comprises at least one pharmaceutical excipient.

13. 13. The drug delivery system of claim 12, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof.

14. 13. The drug delivery system of claim 12, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

15. 15. The drug delivery system of claim 14, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof.

16. 16. The drug delivery system of claim 14 or 15, wherein the binder is present in the drug formulation in a total concentration of about 1% to about 30% by weight, about 5% to about 20% by weight, or about 10% to about 15% by weight.

17. The drug delivery system of any one of claims 14 to 16, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, or a combination thereof.

18. 18. The drug delivery system of any one of claims 14 to 17, wherein the diluent (filler) is present in the drug formulation in a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight.

19. A drug delivery system according to claims 14 to 18, wherein the flow enhancer comprises hydrophilic colloidal silicon dioxide or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide.

20. 20. The drug delivery system of any one of claims 14 to 19, wherein the glidant is present in the drug formulation at a total concentration of about 0.05% to about 1%, about 0.1% to about 0.5%, or about 0.25% by weight.

21. The drug delivery system of any one of claims 14 to 20, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

22. The drug delivery system of any one of claims 14 to 20, wherein the lubricant comprises magnesium stearate.

23. 23. The drug delivery system of any one of claims 14 to 22, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5%.

24. The drug delivery system of any one of claims 1 to 23, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharma- ceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient.

25. 25. The drug delivery system of claim 24, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient.

26. 26. The drug delivery system of claim 24 or 25, wherein the at least one intragranular excipient comprises an intragranular binder.

27. 27. The drug delivery system of any one of claims 24 to 26, wherein the intragranular binder comprises hydroxypropyl methylcellulose.

28. 28. The drug delivery system of any one of claims 24 to 27, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant.

29. 29. The drug delivery system of claim 28, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate.

30. 30. The drug delivery system of claim 28 or 29, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.

31. 31. The drug delivery system of any one of claims 28 to 30, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

32. The drug delivery system of any one of claims 28 to 31, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

33. 33. The drug delivery system of any one of claims 28 to 32, wherein the extragranular lubricant comprises magnesium stearate.

34. 34. The drug delivery system of any one of claims 1 to 33, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 60% to 91% by weight, or 60% to 80% by weight.

35. 35. The drug delivery system of claim 34, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 70% by weight.

36. 36. The drug delivery system of any one of claims 1 to 35, wherein the drug formulation is in the form of a plurality of mini-tablets.

37. 37. The drug delivery system of claim 36, wherein the drug formulation is in the form of about 10 to about 100 mini-tablets.

38. 38. The drug delivery system of claim 36 or 37, wherein (a) the formulation comprises mini-tablets having a total length of about 14.5 cm to about 15 cm, and / or (b) the formulation comprises mini-tablets of about 920 mg to about 965 mg, or mini-tablets of about 920 mg to about 950 mg.

39. 39. The drug delivery system of any one of claims 1 to 38, wherein the drug delivery system is configured to release the erdafitinib by osmotic pressure through the one or more openings in the elongate body.

40. 40. The drug delivery system of any one of claims 1 to 39, wherein the elongate body includes an annular wall structure defining a drug reservoir lumen in which the drug formulation is disposed.

41. 41. The drug delivery system of claim 40, wherein the annular wall structure has a thickness of about 0.1 mm to about 0.5 mm.

42. 42. The drug delivery system of claim 41, wherein the annular wall structure has a thickness of about 0.2 mm.

43. 43. The drug delivery system of any one of claims 40 to 42, further comprising a first end plug positioned at a first end of the annular wall structure and a second end plug positioned at a second end of the annular wall structure.

44. 44. The drug delivery system of any one of claims 40 to 43, wherein the one or more openings in the elongate body comprise a single opening in the annular wall structure, and the elongate body is configured to release the erdafitinib through the opening.

45. 45. The drug delivery system of any one of claims 40 to 44, wherein the elongate body is configured to release the erdafitinib through temporary formed microchannels in one or both end regions of the annular wall structure.

46. 46. ​​The drug delivery system of any one of claims 1 to 45, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

47. 46. ​​The drug delivery system of any one of claims 1 to 45, wherein the system is configured to release the erdafitinib at an average rate of between 1 mg / day and 6 mg / day.

48. 46. ​​The drug delivery system of any one of claims 1 to 45, wherein the system is configured to release the erdafitinib at an average rate of between 2 mg / day and 4 mg / day.

49. 46. ​​The drug delivery system of any one of claims 1 to 45, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

50. 51. The drug delivery system of any one of claims 1 to 50, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

51. 51. The drug delivery system of any one of claims 1 to 50, wherein the system is configured to release the erdafitinib in a zero order release profile.

52. 52. The drug delivery system of any one of claims 46 to 51, wherein the system is configured to release the erdafitinib for up to about 30 days.

53. 52. The drug delivery system of any one of claims 46 to 51, wherein the system is configured to release the erdafitinib for up to about 90 days.

54. 54. The drug delivery system of any one of claims 1 to 53, wherein the system comprises 500 mg of the erdafitinib (free base equivalent).

55. 55. A drug delivery system according to any one of claims 1 to 54, wherein the system is elastically deformable between a relatively straightened deployed configuration suitable for insertion through the patient's urethra and into the patient's bladder, and a retained configuration suitable for retaining the system within the bladder.

56. 56. A drug delivery system according to any one of claims 1 to 55, wherein the system is elastically deformable and comprises a tube having two opposing free ends that are directed away from each other when the system is in a low profile deployed configuration and toward each other when the system is in a relatively expanded retained configuration.

57. A drug delivery system according to any one of claims 1 to 56, wherein the system comprises an elastically deformable elongate body having two opposing free ends within the confines of a bi-elliptical expanded retention shape.

58. The drug delivery system of any one of claims 1 to 57, wherein the elongate body further comprises a retaining frame lumen.

59. 59. The drug delivery system of claim 58, further comprising a nitinol wire disposed within the retaining frame lumen.

60. The compound is erdafitinib lactate.

61. 61. The compound of claim 60 which is erdafitinib L-lactate.

62. 62. The compound of claim 61, which is erdafitinib mono-L-lactate.

63. A pharmaceutical composition comprising erdafitinib L-lactic acid and one or more pharmaceutical excipients.

64. 64. The pharmaceutical composition of claim 63, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, an osmotic agent, or any combination thereof.

65. 64. The pharmaceutical composition of claim 63, wherein the at least one pharmaceutical excipient comprises or is selected from a binder, a diluent (filler), a glidant, a lubricant, or any combination thereof.

66. 66. The pharmaceutical composition of claim 65, wherein the binder comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate (PVP-VA), or a combination thereof.

67. 67. The pharmaceutical composition of claim 65 or 66, wherein the binder is present in the drug formulation in a total concentration of about 1% to about 30%, about 5% to about 20%, or about 10% to about 15% by weight.

68. 68. The pharmaceutical composition of any one of claims 65 to 67, wherein the diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, or a combination thereof.

69. 69. The pharmaceutical composition of any one of claims 65-68, wherein the diluent (filler) is present in the drug formulation in a total concentration of about 5% to about 30% by weight, about 10% to about 30% by weight, or about 10% to about 20% by weight.

70. 70. The pharmaceutical composition according to claims 65 to 69, wherein the glidant comprises hydrophilic colloidal silicon dioxide, or hydrophobic colloidal silicon dioxide, in particular hydrophilic colloidal silicon dioxide.

71. 71. The pharmaceutical composition of any one of claims 65-70, wherein the glidant is present in the drug formulation in a total concentration of about 0.05% to about 1%, about 0.1% to about 0.5%, or about 0.25% by weight.

72. 72. The pharmaceutical composition of any one of claims 65 to 71, wherein the lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

73. 72. The pharmaceutical composition of any one of claims 65 to 71, wherein the lubricant comprises magnesium stearate.

74. 74. The pharmaceutical composition of any one of claims 65-73, wherein the lubricant is present in the drug formulation at a total concentration of about 0.05% to about 5% by weight, about 1% to about 5% by weight, or about 2.5%.

75. 75. The pharmaceutical composition of any one of claims 65 to 74, wherein the drug formulation comprises an intragranular composition comprising erdafitinib or a pharma- ceutically acceptable salt thereof, in particular a lactate salt of erdafitinib, and at least one intragranular excipient, and an extragranular composition comprising at least one extragranular excipient.

76. 76. The pharmaceutical composition of claim 75, wherein the at least one intragranular excipient and the at least one extragranular excipient do not comprise a common pharmaceutical excipient.

77. 77. The pharmaceutical composition of claim 75 or 76, wherein the at least one intragranular excipient comprises an intragranular binder.

78. 78. The pharmaceutical composition of claim 77, wherein the intragranular binder comprises hydroxypropyl methylcellulose.

79. 79. The pharmaceutical composition of any one of claims 75 to 78, wherein the at least one extragranular excipient comprises one or more of an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant.

80. 80. The pharmaceutical composition of claim 79, wherein the extragranular binder comprises vinylpyrrolidone-vinyl acetate.

81. 81. The pharmaceutical composition of claim 79 or 80, wherein the extragranular diluent (filler) comprises microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.

82. 82. The pharmaceutical composition of any one of claims 79-81, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

83. 83. The pharmaceutical composition of any one of claims 79 to 82, wherein the extragranular lubricant comprises magnesium stearate, or sodium stearyl fumarate, or polyethylene glycol.

84. 84. The pharmaceutical composition of any one of claims 79 to 83, wherein the extragranular lubricant comprises magnesium stearate.

85. 85. The pharmaceutical composition of any one of claims 63 to 84, wherein the erdafitinib L-lactate is present in the drug formulation at a concentration of 60% to 91% by weight, or 60% to 80% by weight.

86. 86. The pharmaceutical composition of claim 85, wherein the erdafitinib L-lactate is present in the drug formulation in a concentration of 70% by weight.

87. 87. The pharmaceutical composition of any one of claims 63 to 86, wherein the composition is in the form of a tablet.

88. 88. The pharmaceutical composition of claim 87, wherein the tablet is a mini-tablet.

89. 89. The pharmaceutical composition of claim 87 or 88, wherein the tablet has a hardness of at least about 100 N.

90. 90. The pharmaceutical composition of claim 89, wherein the tablet has a hardness of about 150N to about 250N.

91. 90. The pharmaceutical composition of claim 89, wherein the tablet has a hardness of about 175N to about 225N.

92. 92. The pharmaceutical composition of any one of claims 87 to 91, wherein the tablet has a thickness of about 3.2 mm to about 3.6 mm.

93. 1. A process for producing a pharmaceutical composition in the form of a tablet, comprising: (a) preparing an intragranular solid composition, comprising: (i) erdafitinib L-lactate, (ii) at least one intragranular pharmaceutical excipient; and preparing an intragranular solid composition comprising: (b) combining said intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; (c) compressing the blend to form the solid pharmaceutical composition; 1. A process for producing a pharmaceutical composition in the form of a tablet, comprising:

94. (a) the at least one intragranular pharmaceutical excipient comprises at least one intragranular binder; (b) the at least one extragranular pharmaceutical excipient comprises an extragranular binder, an extragranular filler (diluent), an extragranular glidant, and an extragranular lubricant; 94. A process for producing the solid pharmaceutical composition of claim 93.

95. 95. A process for manufacturing a tablet according to claim 93 or 94, wherein the intragranular solid composition is prepared by a fluid bed granulation process.

96. 96. A process for producing a solid pharmaceutical composition according to claim 94 or 95, wherein the at least one intragranular binder comprises hydroxypropyl methylcellulose.

97. 97. The process for producing a solid pharmaceutical composition according to any one of claims 94 to 96, wherein said at least one extragranular binder comprises vinylpyrrolidone-vinyl acetate (PVP VA).

98. 98. A process for producing a solid pharmaceutical composition according to any one of claims 94 to 97, wherein said at least one extragranular filler (diluent) comprises microcrystalline cellulose.

99. 99. A process for producing a solid pharmaceutical composition as described in claim 98, further comprising a second extragranular filler (diluent) comprising silicified microcrystalline cellulose.

100. 100. A process for producing a solid pharmaceutical composition according to any one of claims 94 to 99, wherein the extragranular glidant comprises hydrophilic colloidal silicon dioxide.

101. 101. A process for producing a solid pharmaceutical composition according to any one of claims 94 to 100, wherein the extragranular lubricant comprises magnesium stearate.

102. 101. A process for producing a solid pharmaceutical composition according to any one of claims 94 to 100, wherein the extragranular lubricant comprises sodium stearyl fumarate.

103. 103. A process for producing a solid pharmaceutical composition according to any one of claims 93 to 102, wherein the expulsion force is less than about 1000 N.

104. 89. The pharmaceutical composition of claim 88, wherein said mini-tablets are in the form of a solid cylinder, said solid cylinder having a cylindrical axis, a cylindrical side surface, a circular end surface perpendicular to said cylindrical axis, a diameter of said circular end surface, and a length along said cylindrical side surface.

105. 105. The solid pharmaceutical composition of claim 104, wherein the length of said mini-tablets exceeds the diameter of said mini-tablets so as to provide said mini-tablets with an aspect ratio (length:diameter) of greater than 1:

1.

106. 106. The solid pharmaceutical composition of claim 104 or 105, wherein the mini-tablets have a diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm.

107. 106. The solid pharmaceutical composition of claim 104 or 105, wherein the mini-tablets have a diameter of 2.5 mm to 2.7 mm.

108. 108. A solid pharmaceutical composition according to any one of claims 104 to 107, wherein said mini-tablets have a length of between 3.0 mm and 3.5 mm.

109. A solid pharmaceutical composition according to any one of claims 104 to 108, wherein said mini-tablets have a mass of between 22 mg and 24 mg.

110. 60. The drug delivery system of any one of claims 44 to 59, wherein the elongate body is configured to release the erdafitinib through the opening and through a microchannel temporarily formed in one end region of the annular wall structure.

111. 60. The drug delivery system of any one of claims 44 to 59, wherein the elongate body is configured to release the erdafitinib through the openings and through microchannels temporarily formed in both end regions of the annular wall structure.

112. 112. The drug delivery system of any one of claims 45, 110, or 111, wherein the microchannels form transiently when the osmotic pressure increases above a certain threshold.

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